Inhibition of human immunodeficiency virus type 1 replication in vitro by a novel combination of anti-Tat single-chain intrabodies and NF-kappa B antagonists.
Human immunodeficiency virus type 1 (HIV-1) Tat, an early regulatory protein that is critical for viral gene expression and replication, transactivates the HIV-1 long terminal repeat (LTR) via its binding to the transactivation response element (TAR) and, along with other cellular factors, increases viral transcription initiation and elongation. Tat also superactivates the HIV-1 promoter through a TAR-independent mechanism, including tumor necrosis factor alpha-induced and protein kinase C (PKC)-dependent activation of NF-kappa B, and inhibitors of Tat and NF-kappa B cooperatively down-regulate this Tat-mediated LTR superactivation. In this study, a combined pharmacologic and genetic strategy using two PKC (NF-kappa B) inhibitors, pentoxifylline (PTX) and Gö-6976, and a stably expressed anti-Tat single-chain intracellular antibody (sFv intrabody) was employed to obtain cooperative inhibition of both HIV-1 LTR-driven gene expression and HIV-1 replication. Treatment of cells with PTX and Gö-6976 resulted in cooperative inhibition of both HIV-1 LTR-driven gene expression and HIV-1 replication. In addition, the combined use of anti-Tat sFv intrabodies and the two NF-kappa B inhibitors retained the virus in the latent state for as long as 45 days. The combined treatment resulted in more durable inhibition of HIV-1 replication than was seen with the NF-kappa B inhibitors alone or the anti-Tat sFv intrabodies alone. Together, these results suggest that in future clinical gene therapy trials, a combined pharmacologic and genetic strategy like the one reported here may improve the survival of transduced cells and prolong clinical benefit.


Failure mode in first-principles computational tensile tests of grain boundaries: effects of a bulk-region size, dominant factors, and local-energy and local-stress analysis.
A first-principles computational tensile test (FPCTT) is a powerful tool to investigate intrinsic strength and failure processes of grain boundaries (GBs), according to atomic and electronic behaviors based on density-functional theory, while careful interpretation is required in comparison with experiments, because of ideal conditions used in FPCTTs. We observed serious effects of a bulk-region size in FPCTTs of the {0 0 1} [Formula: see text]5 GB in Al. For a GB supercell with enough thick bulk regions, the energy-strain curve shows spontaneous failure with catastrophic energy release just after the maximum stress point, which we name Type-A failure. For a GB supercell with thin bulk regions, the energy increases gradually even after the maximum stress and continuously becomes that of relaxed fracture surfaces, which we name Type-B failure, although the stress-strain curves are almost common until the maximum stress point in both the supercells. The peculiar failure of Type B occurs by the lack of accumulated strain energies for creating fracture surfaces even after the maximum stress point, because the accumulated strain energy is nearly proportional to the bulk-region size. We clarified that the failure mode in a FPCTT depends on the relationship among the three factors; the accumulated strain energy depending on the bulk-region size, the work of separation (the formation energy of fractured surfaces into a GB), and the maximum stress of the GB (the GB strength). We showed that the failure mode of previous FPCTTs of Al tilt GBs with segregated impurities can be reinterpreted from this viewpoint, by considering the changes of the work of separation and the GB strength by impurities. We should be aware of the distinction of the failure mode in FPCTTs, because experimentally Type-B failure does not occur except for special cases. Finally, we applied ab initio local-energy and local-stress analysis to the FPCTT of the {0 0 1} [Formula: see text]5 GB in Al, and discussed how to extract local energy-strain or energy-separation relations independent of the bulk-region size to be combined with meso- or macroscopic simulations.


Transplantation of cardiac progenitor cell sheet onto infarcted heart promotes cardiogenesis and improves function.
Cell-based therapy for myocardial infarction (MI) holds great promise; however, the ideal cell type and delivery system have not been established. Obstacles in the field are the massive cell death after direct injection and the small percentage of surviving cells differentiating into cardiomyocytes. To overcome these challenges we designed a novel study to deliver cardiac progenitor cells as a cell sheet. Cell sheets composed of rat or human cardiac progenitor cells (cardiospheres), and cardiac stromal cells were transplanted onto the infarcted myocardium after coronary artery ligation in rats. Three weeks later, transplanted cells survived, proliferated, and differentiated into cardiomyocytes (14.6 +/- 4.7%). Cell sheet transplantation suppressed cardiac wall thinning and increased capillary density (194 +/- 20 vs. 97 +/- 24 per mm(2), P < 0.05) compared with the untreated MI. Cell migration from the sheet was observed along the necrotic trails within the infarcted area. The migrated cells were located in the vicinity of stromal-derived factor (SDF-1) released from the injured myocardium, and about 20% of these cells expressed CXCR4, suggesting that the SDF-1/CXCR4 axis plays, at least, a role in cell migration. Transplantation of cell sheets resulted in a preservation of cardiac contractile function after MI, as was shown by a greater ejection fraction and lower left ventricular end diastolic pressure compared with untreated MI. The scaffold-free cardiosphere-derived cell sheet approach seeks to efficiently deliver cells and increase cell survival. These transplanted cells effectively rescue myocardium function after infarction by promoting not only neovascularization but also inducing a significant level of cardiomyogenesis.


A simple derivation and analysis of a helical cone beam tomographic algorithm for long object imaging via a novel definition of region of interest.
We derive and analyse a simple algorithm first proposed by Kudo et al (2001 Proc. 2001 Meeting on Fully 3D Image Reconstruction in Radiology and Nuclear Medicine (Pacific Grove, CA) pp 7-10) for long object imaging from truncated helical cone beam data via a novel definition of region of interest (ROI). Our approach is based on the theory of short object imaging by Kudo et al (1998 Phys. Med. Biol. 43 2885-909). One of the key findings in their work is that filtering of the truncated projection can be divided into two parts: one, finite in the axial direction, results from ramp filtering the data within the Tam window. The other, infinite in the z direction, results from unbounded filtering of ray sums over PI lines only. We show that for an ROI defined by PI lines emanating from the initial and final source positions on a helical segment, the boundary data which would otherwise contaminate the reconstruction of the ROI can be completely excluded. This novel definition of the ROI leads to a simple algorithm for long object imaging. The overscan of the algorithm is analytically calculated and it is the same as that of the zero boundary method. The reconstructed ROI can be divided into two regions: one is minimally contaminated by the portion outside the ROI, while the other is reconstructed free of contamination. We validate the algorithm with a 3D Shepp-Logan phantom and a disc phantom.


Diagnosis and treatment of lead-dependent infective endocarditis.
We report a typical case of lead-dependent infective endocarditis in an 84 year-old patient, occurring two years after pacemaker implantation. Before the correct diagnosis was reached, the patient was repeatedly hospitalised in several centres due to fever of unknown origin. Eventually, the diagnosis was confirmed when the patient was referred for transoesophageal echocardiography by a consulting cardiologist from the pacemaker implantation centre. The successful treatment included the removal of the whole pacing system with endocardial leads and adequate antibiotic therapy.


Escherichia coli mutants defective in the uncH gene.
Plasmids carrying cloned segments of the unc operon of Escherichia coli have been used in genetic complementation analyses to identify three independent mutants defective in the uncH gene, which codes for the delta subunit of the ATP synthetase. Mutations in other unc genes have also been mapped by this technique. ATPase activity was present in extracts of the uncH mutants, but the enzyme was not as tightly bound to the membrane as it was in the parental strain. ATP-dependent membrane energization was absent in membranes isolated from the uncH mutants and could not be restored by adding normal F1 ATPase from the wild-type strain. F1 ATPase prepared from uncH mutants could not restore ATP-dependent membrane energization when added to wild-type membranes depleted of F1. Membranes of the uncH mutants were not rendered proton permeable as a result of washing with low-ionic-strength buffer.


Antimicrobial Susceptibility of Fresh Produce-Associated Enterobacteriaceae and Enterococci in Oman.
Fresh produce bacteria may have phenotypic and/or genotypic antimicrobial resistance traits that may lead to various consequences on the environment and human health. This study evaluated the susceptibility of fresh produce bacteria (banana, cabbage, capsicum, carrots, cucumber, dates, lettuce, mango, papaya, pomegranate, radish, tomato and watermelon) to chlorhexidine and the antibiotic resistance of enterococci. Eighty-eight Enterobacteriaceae bacteria and 31 enterococci were screened for their susceptibility to chlorhexidine using the broth microdilution method. Susceptibility of enterococci to various antibiotics was determined using agar dilution, colorimetric, and Kirby-Bauer disc diffusion methods. Enterococci were more susceptible to chlorhexidine than Enterobacteriaceae indicated by chlorhexidine minimum inhibitory concentration (MIC) of 1 to 8 µg/mL for the former and 1 to 64 µg/mL for the latter. The IntI 1, qacEΔ1, qacE and qacG genes were distributed weakly in three, two, two, and three Enterobacteriaceae isolates, respectively. Enterococci had resistance to chloramphenicol (3%), tetracycline (19%), erythromycin (68%), ciprofloxacin (55%), and vancomycin (10%) while 19% of them were multi-drug resistant. In conclusion, this research detected a low to moderate level of antibiotic resistance in enterococci. Some Enterobacteriaceae bacteria had reduced chlorhexidine MICs that were not 10x less than the recommended concentration (100-200 µg/mL) in food production areas which might challenge the success of the disinfection processes or have clinical implications if the involved bacteria are pathogens. The prevalence of antimicrobial-resistant bacteria in fresh produce should be monitored in the future.


[Metformin-associated lactic acidosis and acute kidney injury].
Metformin is recommended as the treatment of choice in patients with type 2 diabetes mellitus because of its efficacy, general tolerability and low cost. Recent guidelines have extended the use of metformin to patients with Chronic Kidney Disease (CKD) up to stage III. However, in the recent literature, cases of MALA (metformin-associated lactic acidosis) are increasingly reported. MALA is the most dangerous side effect of the drug, with an incidence rate of 2-9 cases per 100000 person-years of exposure. We report on two patients with accidental metformin overdose, severe lactic acidosis and acute kidney injury. In both cases, the usual dose of metformin was inappropriate with respect to the level of kidney dysfunction (CKD stage III). As both patients met the criteria for renal replacement therapy in metformin poisoning, they were treated effectively with sustained low-efficiency dialysis until normalization of serum lactate and bicarbonate values. Clinical status and kidney function improved and both patients could be discharged from the hospital.


Direct observation of the THz Kerr effect (TKE) in deionized, distilled and buffered (PBS) water.
Nonlinear THz pump-optical probe (THz-OKE) measurements in deionized, distilled and buffered (PBS) water are reported. A laser system that produces pulses at 800 nm, 30 fs FWHM, at a repetition rate of 1 kHz and an energy of 6 μJ per pulse, was a source of the probe optical beam and of the pump beam of THz 2 ps pulses. The electric field strength inducing birefringence in water samples was ETHz = 1.35 × 106 V m-1. These samples were chosen in order to study the effect of ionic concentration on water behavior in the ultrafast time scale. Differentiation between ultrafast effects resulting from internal H2O properties and those resulting from H2O-ion interactions was analyzed. These two effects may be connected to a difference in the fluctuations of the network of intermolecular hydrogen bonds of water molecules in the presence and absence of ions in solution. The results indicate that such fluctuations significantly alter water birefringence amplitude and its dynamics.


Differential use of multiple replication origins in the ribosomal DNA episome of the protozoan parasite Entamoeba histolytica.
The factors that control the initiation of eukaryotic DNA replication from defined origins (oris) on the chromosome remain incompletely resolved. Here we show that the circular rDNA episome of the human pathogen Entamoeba histolytica contains multiple potential oris, which are utilized in a differential manner. The primary ori in exponentially growing cells was mapped close to the promoter of rRNA genes in the upstream intergenic spacer (IGS) by two-dimensional gel electrophoresis. Replication initiated predominantly from the upstream IGS and terminated in the downstream IGS. However, when serum-starved cells were allowed to resume growth, the early oris which became activated were located in other parts of the molecule. Later the ori in the upstream IGS became activated, with concomitant silencing of the early oris. When the upstream IGS was located ectopically in an artificial plasmid, it again lost ori activity, while other parts of the rDNA episome could function as oris in this system. Therefore, the activation or silencing of the ori in this episome is context dependent, as is also the case with many eukaryotic replicons. This is the first replication origin to be mapped in this primitive protozoan and will provide an opportunity to define the factors involved in differential ori activity, and their comparison with metazoans.


The relationship between socio-economic status and access to eye health services in the UK: a systematic review.
Lower socio-economic status has been shown to adversely affect access to general health care. This study aims to determine the existence and nature of an association between socio-economic status and access to eye health services in the UK. Systematic review. Search terms were run in four databases and reviewed against a pre-agreed set of inclusion and exclusion criteria by two independent reviewers. Quality of studies was assessed according to calculations of statistical significance, size of effect, primary research question and a quality score against an adapted STROBE checklist. Good quality studies included in the review most commonly concluded that lower socio-economic groups had less access to eye health services than higher socio-economic groups. However there were a comparable number of studies that concluded that there was no association. This discrepancy was largely attributed to different ways of measuring socio-economic status, access, and types of eye health services, and so studies did not compare the same thing. The evidence base was of low quality, limiting the ability of this review to make definitive conclusions. The review concluded that there is equal and weak evidence of lower socio-economic groups having reduced access to eye health services in the UK, and there being no association. This subject would benefit from further research to improve the quality of the evidence base.


Reappraisal of the extinct seal "Phoca" vitulinoides from the Neogene of the North Sea Basin, with bearing on its geological age, phylogenetic affinities, and locomotion.
Discovered on the southern margin of the North Sea Basin, "Phoca" vitulinoides represents one of the best-known extinct species of Phocidae. However, little attention has been given to the species ever since its original 19th century description. Newly discovered material, including the most complete specimen of fossil Phocidae from the North Sea Basin, prompted the redescription of the species. Also, the type material of "Phoca" vitulinoides is lost. "Phoca" vitulinoides is redescribed. Its phylogenetic position among Phocinae is assessed through phylogenetic analysis. Dinoflagellate cyst biostratigraphy is used to determine and reassess the geological age of the species. Myological descriptions of extant taxa are used to infer muscle attachments, and basic comparative anatomy of the gross morphology and biomechanics are applied to reconstruct locomotion. Detailed redescription of "Phoca" vitulinoides indicates relatively little affinities with the genus Phoca, but rather asks for the establishment of a new genus: Nanophoca gen. nov. Hence, "Phoca" vitulinoides is recombined into Nanophoca vitulinoides. This reassignment is confirmed by the phylogenetic analysis, grouping the genus Nanophoca and other extinct phocine taxa as stem phocines. Biostratigraphy and lithostratigraphy expand the known stratigraphic range of N. vitulinoides from the late Langhian to the late Serravallian. The osteological anatomy of N. vitulinoides indicates a relatively strong development of muscles used for fore flipper propulsion and increased flexibility for the hind flipper. The extended stratigraphic range of N. vitulinoides into the middle Miocene confirms relatively early diversification of Phocinae in the North Atlantic. Morphological features on the fore- and hindlimb of the species point toward an increased use of the fore flipper and greater flexibility of the hind flipper as compared to extant Phocinae, clearly indicating less derived locomotor strategies in this Miocene phocine species. Estimations of the overall body size indicate that N. vitulinoides is much smaller than Pusa, the smallest extant genus of Phocinae (and Phocidae), and than most extinct phocines.


Beneficial therapeutic effect of plasmapheresis after unsuccessful treatment with corticosteroids in two patients with severe toxic epidermal necrolysis.
Toxic epidermal necrolysis (TEN) is a rare, life-threatening disease with a high mortality rate. It is linked to drug toxicity and characterized by epidermal necrolysis with mucositis and conjunctivitis. Treatment is not established due to the unknown pathogenesis and lack of randomized clinical trials. It is mostly based on withdrawal of the culprit drug and symptom-related approach. The role of corticosteroids and plasmapheresis in the disease treatment remains controversial. We present two patients with severe TEN (both with >80% body skin surface involvement) treated unsuccessfully with corticosteroids followed by plasmapheresis. Plasmapheresis led to prompt improvement, with extensive reepithealization of the skin, and eventually total recovery of both patients. In severe TEN unresponsive to corticosteroids, treatment with plasmapheresis should be considered.


Expression of Ganglioside Disialosyl Globopentaosyl Ceramide in Prostate Biopsy Specimens as a Predictive Marker for Recurrence after Radical Prostatectomy.
Carbohydrate antigens are associated with carcinogenesis, cancer invasion, and metastasis and their expression reflect biological activities of various cancers. We previously reported that expression of disialosyl globopentaosyl ceramide (DSGb5), one of carbohydrate antigens, in radical prostatectomy specimens independently predicted biochemical recurrence (i.e., elevating serum prostate specific antigen without recurrent lesions in the image) after radical prostatectomy. However, it is important to evaluate the prognosis at the diagnosis. In this study we investigated DSGb5 expression in prostate biopsy specimens to develop a novel biomarker for providing appropriate management. Between 2005 and 2011, patients who underwent both prostate biopsy and radical prostatectomy in our institution were included. The median follow-up period was 88 months. DSGb5 expression was assessed by immunohistochemical staining and defined 116 patients as high DSGb5 expression (42 patients) or low DSGb5 expression (74 patients). High DSGb5 expression was significantly associated with lymphovascular invasion in radical prostatectomy specimens on both univariate and multivariable analyses (p = 0.028, 0.027). On multivariable analysis, Gleason Score in prostatectomy specimen, positive resection margin, and DSGb5 expression in the biopsy specimen were independently associated with biochemical recurrence-free survival following radical prostatectomy (p = 0.004, 0.008, 0.024). When targeting only patients with negative resection margin, DSGb5 expression was significantly associated with biochemical recurrence-free survival on both univariate and multivariable analyses (p = 0.006, 0.007). DSGb5 expression in prostate biopsy specimens is predictive of lymphovascular invasion and biochemical recurrence-free survival following radical prostatectomy. DSGb5 is a potential biomarker for preoperatively predicting oncological outcomes of prostate cancer.


[Influence of health centers and social class in the prevalence of breast feeding].
To find out the prevalence of breastfeeding in the Health District of Córdoba, taking into account the basic health areas it is composed of; to find out if breastfeeding is less frequent in lower social classes than in high ones and the influence of health centers on breastfeeding. Cross-sectional descriptive study. Home survey. SITE: Health District of Córdoba, urban area. 1, 3, 6 months old babies taken from the computerized newborn register of the Health District of Córdoba. Age of the babies; breastfeeding, social class, primary care model (basic health areas attended by Health Centers or not attended by Health Centers), weight at birth, parents' jobs, pregnancy control, maternal education and number of visits. 77.2% of the mothers start breastfeeding. 51.7% of one month-old babies are breastfed. One out of four three-month-old babies are breastfed and one out of ten six-month-old babies are breastfed. Low weight at birth has a negative influence on breastfeeding. The prevalence of breastfeeding is higher in favoured classes, and in the basic health areas attended by health centers. The rest of variables analyzed are not significant. The health centers improve the prevalence and duration of breastfeeding.


[A case report of prostatic stromal tumor of uncertain malignant potential (STUMP)].
Sarcomas and related proliferative lesions of specialized stroma of prostate are rare. Lesions have been classified into prostatic stromal tumor of uncertain malignant potential (STUMP) and prostatic stromal sarcoma (SS) based on the degree of stromal cellularity, presence of mitotic figures, necrosis, and stromal overgrowth. STUMPs are considered neoplastic, based on the observations that they may diffusely infiltrate the prostate gland and extend into adjacent tissues, and often recur. Although most cases of STUMP do not behave in an aggressive fashion, occasional cases have been documented to recur rapidly after resection and a minority have progressed to stromal sarcoma. Here we describe a case of STUMP. A 42-year-old male was seen at a hospital with the chief complaint of elevated levels of prostate specific antigen. Since digital examination revealed abnormal findings in the prostate, then he was referred to our hospital. We diagnosed STUMP by ultra-sound-guided needle biopsy of the prostate. Then we performed radical prostatectomy. Finally we made the pathological diagnosis of prostatic STUMP. Ten months later, there was no sign of metastasis or recurrence.


Microtubule gelation-contraction: essential components and relation to slow axonal transport.
Preparations of microtubule proteins isolated by assembly and disassembly undergo gelation-contraction after addition of adenosine triphosphate (ATP). A particulate fraction from these preparations that is required, along with purified tubulin, to produce ATP-dependent microtubule gelation-contraction in vitro has been isolated. The particulates exhibited microtubule-stimulated adenosine triphosphatase activity and moved slowly (about 1 micrometer per minute) along microtubule walls in the presence of ATP. The particulates contained tubulin, neurofilament, and spectrin polypeptides. The composition, solubility, and motility of the particulates are consistent with those of slow component a of axonal transport.


Polymorphism of the HLA system and weak antibody response to BNT162b2 mRNA vaccine.
The polymorphism of the HLA system has been extensively studied in COVID-19 infection, however there are no data about the role of HLA on vaccine response. We report here the HLA-A, -B, -C, and DRB1 allelic frequencies of n = 111 individuals after BNT162b2 mRNA vaccine, selected on the basis of lower antibody levels (<5% percentile) after the second dose among a total of n = 2569 vaccinees, and compare them with the frequencies of a reference population. We found that differences in the frequencies of the alleles HLA-A*03:01, A*33:03, B*58:01 and at least one haplotype (HLA-A*24:02~C*07:01~B*18:01~DRB1*11:04) are associated with a weaker antibody response after vaccination, together with the age of vaccinees. Our results might suggest a role played by some HLA alleles or haplotypes in antibody production after the BNT162b2 mRNA vaccine, giving insights into the tracking of potentially susceptible individuals across populations. Further studies are needed to better define our exploratory findings and dissect the role of HLA polymorphism on response to anti-COVID-19 vaccines.


Increased expression of the calcium-activated chloride channel hCLCA1 in airways of patients with obstructive chronic bronchitis.
Interleukin (IL)-9 and its effect on enhancing the human calcium-activated chloride channel 1 (hCLCA1) expression have been shown to induce mucin production. Increased expression of hCLCA1 may, in turn, contribute to mucus overproduction in chronic obstructive pulmonary disease (COPD) with a chronic bronchitis (CB) phenotype. To determine the expression of IL-9, IL-9 receptor (IL-9R), hCLCA1 and mucoglycoconjugates in COPD. Bronchial biopsies were obtained from six patients with obstructive CB and six healthy control subjects. IL-9, IL-9R and hCLCA1 expression were detected using immunohistochemistry. Additionally, in situ hybridization was performed to determine the expression of hCLCA1 messenger RNA. Mucin production was assessed using periodic acid-Schiff staining. There was a significantly higher number of IL-9 immunoreactive cells in the submucosa of patients with COPD than that of healthy control subjects (P<0.05). Also, a significant increase in the expression of IL-9R, hCLCA1 (protein and messenger RNA) and mucin (periodic acid-Schiff-positive cells) was noted in the bronchial epithelium of patients with COPD compared the control subjects (P<0.05). Increased expression of IL-9, IL-9R and hCLCA1 in the bronchial mucosa of patients with obstructive CB suggests that mucus overproduction in this disease may be, at least in part, due to hCLCA1.


Idiopathic pupillary capture 7 years after extracapsular cataract extraction and intraocular lens implantation.
Pupillary capture is a pathology commonly associated with traumatic or inflammatory processes of the eye. We present a case of idiopathic pupillary capture, 7 years after extracapsular cataract extraction and intraocular lens implantation. This case highlights the need for ongoing patient surveillance, especially in elderly patients who are less able to detect subtle changes in their vision.


Evaluation of the LiPA MYCOBACTERIA assay for identification of mycobacterial species from BACTEC 12B bottles.
The LiPA MYCOBACTERIA (Innogenetics NV, Ghent, Belgium) assay was used to identify mycobacterial isolates using culture fluid from positive BACTEC 12B bottles. The LiPA method involves reverse hybridization of a biotinylated mycobacterial PCR fragment, a 16 to 23S rRNA spacer region, to oligonucleotide probes arranged in lines on a membrane strip, with detection via biotin-streptavidin coupling by a colorimetric system. This system identifies Mycobacterium species and differentiates M. tuberculosis complex, M. avium-M. intracellulare complex, and the following mycobacterial species: M. avium, M. intracellulare, M. kansasii, M. chelonae group, M. gordonae, M. xenopi, and M. scrofulaceum. The mycobacteria were identified in the laboratory by a series of tests, including the Roche AMPLICOR Mycobacterium tuberculosis (MTB) test, the Gen-Probe ACCUPROBE, and a PCR-restriction fragment length polymorphism (PCR-RFLP) analysis of the 65-kDa heat shock protein gene. The LiPA MYCOBACTERIA assay detected 60 mycobacterium isolates from 59 patients. There was complete agreement between LiPA and the laboratory identification tests for 26 M. tuberculosis complex, 9 M. avium, 3 M. intracellulare complex, 3 M. kansasii, 4 M. gordonae, and 5 M. chelonae group (all were M. abscessus) isolates. Three patient samples were LiPA positive for M. avium-M. intracellulare complex, and all were identified as M. intracellulare by the PCR-RFLP analysis. Seven additional mycobacterial species were LiPA positive for Mycobacterium spp. (six were M. fortuitum, and one was M. szulgai). The LiPA MYCOBACTERIA assay was easy to perform, and the interpretation of the positive bands was clear-cut. Following PCR amplification and gel electrophoresis, the LiPA assay was completed within 3 h.


Translational competence of ribosomes released from a premature termination codon is modulated by NMD factors.
In addition to their well-documented roles in the promotion of nonsense-mediated mRNA decay (NMD), yeast Upf proteins (Upf1, Upf2/Nmd2, and Upf3) also manifest translational regulatory functions, at least in vitro, including roles in premature translation termination and subsequent reinitiation. Here, we find that all upf Delta strains also fail to reinitiate translation after encountering a premature termination codon (PTC) in vivo, a result that led us to seek a unifying mechanism for all of these translation phenomena. Comparisons of the in vitro translational activities of wild-type (WT) and upf1 Delta extracts were utilized to test for a Upf1 role in post-termination ribosome reutilization. Relative to WT extracts, non-nucleased extracts lacking Upf1 had approximately twofold decreased activity for the translation of synthetic CAN1/LUC mRNA, a defect paralleled by fewer ribosomes per mRNA and reduced efficiency of the 60S joining step at initiation. These deficiencies could be complemented by purified FLAG-Upf1, or 60S subunits, and appeared to reflect diminished cycling of ribosomes from endogenous PTC-containing mRNAs to exogenously added synthetic mRNA in the same extracts. This hypothesis was tested, and supported, by experiments in which nucleased WT or upf1 Delta extracts were first challenged with high concentrations of synthetic mRNAs that were templates for either normal or premature translation termination and then assayed for their capacity to translate a normal mRNA. Our results indicate that Upf1 plays a key role in a mechanism coupling termination and ribosome release at a PTC to subsequent ribosome reutilization for another round of translation initiation.


Spatiotemporal changes in the structure and composition of a less-abundant bacterial phylum (Planctomycetes) in two perialpine lakes.
We used fingerprinting and cloning-sequencing to study the spatiotemporal dynamics and diversity of Planctomycetes in two perialpine lakes with contrasting environmental conditions. Planctomycetes, which are less-abundant bacteria in freshwater ecosystems, appeared to be structured in the same way as the entire bacterial community in these ecosystems. They were more diversified and displayed fewer temporal variations in the hypolimnia than in the epilimnia. Like the more-abundant bacterial groups in aquatic systems, Planctomycetes communities seem to be composed of a very small number of abundant and widespread operational taxonomic units (OTUs) and a large number of OTUs that are present at low abundance. This indicates that the concept of "abundant or core" and "rare" bacterial phylotypes could also be applied to less-abundant freshwater bacterial phyla. The richness and diversity of Planctomycetes were mainly driven by pH and were similar in both of the lakes studied, whereas the composition of the Planctomycetes community seemed to be determined by a combination of factors including temperature, pH, and nutrients. The relative abundances of the dominant OTUs varied over time and were differently associated with abiotic factors. Our findings demonstrate that less-abundant bacterial phyla, such as Planctomycetes, can display strong spatial and seasonal variations linked to environmental conditions and suggest that their functional role in the lakes studied might be attributable mainly to a small number of phylotypes and vary over space and time in the water column.


Internal and external TEA block in single cloned K+ channels.
Tetraethylammonium (TEA) has been used recently to probe natural and mutational variants of voltage-dependent K+ channels encoded by cDNA clones. Its usefulness as a probe of channel structure prompted us to examine the molecular mechanism by which TEA blocks single-channel currents in Xenopus oocytes expressing the rat brain K+ channel, RCK2. TEA at the intracellular surface of membrane patches decreased channel open time and increased the duration of closed intervals. Tetrapentylammonium had similar but more potent effects. Extracellular application of TEA caused an apparent reduction of single-channel amplitude. Block was slower at the high-affinity internal site than at the low-affinity external site. Internal TEA selectively blocks open K+ channels, and the voltage dependence of the block indicates that the binding site lies within the membrane electric field at a point 25% of the distance from the cytoplasmic margin. External TEA also interacts with the open channel but is less sensitive to membrane potential. The results indicate that the internal and external TEA binding sites define the inner and outer margins of the aqueous pore.


Use of in vivo/in vitro unscheduled DNA synthesis for identification of organ-specific carcinogens.
There are still only a few in vivo short-term assay methods for predicting potential organ-specific carcinogens and mutagens in mammals, although such methods are required for evaluating the in vivo effects of in vitro mutagens. In the in vivo/in vitro UDS assay methods described here, chemicals are given to experimental animals and induction of UDS in target organs is determined by in vitro organ culture or primary cell culture in the presence of [3H]dThd. Incorporation of [3H]dThd into DNA is measured with a liquid scintillation counter or by autoradiography. These methods have now been applied to the glandular stomach, forestomach, colon, liver, kidney, pancreas, tracheal epithelium, nasal epithelium, and spermatocytes. With minor modifications, they may also be applied to other organs. The present review shows that induction of UDS in various organs correlated well with the induction of cancer in these organs. The present authors have used the present methods to identify some potential organ-specific mutagens and carcinogens in mammals. The present authors found that three dicarbonyl compounds, glyoxal, methylglyoxal, and diacetyl, induced apparent UDS and TDS in the glandular stomach, and other groups found that 2-NT, MA6BT, and CNEt6BT induced UDS in the liver. These in vivo/in vitro UDS assays are better than in vitro UDS assay for identification of potential organ-specific mutagens and carcinogens in mammals and are especially useful for identifying potential mutagens and carcinogens that are specific for certain organs, such as the stomach, liver, and kidney. They are also useful for examining the potential mutagenicities and carcinogenicities of carcinogen analogs. However, these methods are not suitable for general in vivo screening because they are not yet available for all organs. A further advantage of the methods is that they can be used to examine larger numbers of animals at one time than other methods for detecting DNA damage, such as alkaline elution or alkaline sucrose density gradient centrifugation. Glyoxal enhanced cancer induction in the glandular stomach by the administration of a limited amount of MNNG and then glyoxal afterward in the two-stage stomach carcinogenesis.


Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review.
To systematically assess the effect of pharmacologic treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life. We searched PubMed and Cochrane Database of Systematic Reviews for systematic reviews from 2011 to October 12, 2015, and PubMed, Embase, and the Cochrane Central Register of Controlled Trials for primary studies from January 1, 2013, to May 24, 2016. We searched Clinicaltrials.gov on March 9, 2016. Two reviewers independently evaluated studies for eligibility, serially abstracted data, and independently evaluated risk of bias and graded strength of evidence (SOE). We updated a recently completed systematic review of 57 eligible studies with 24 additional published studies and 25 unpublished studies. For reducing neuropathy-related pain, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine (moderate SOE), the anticonvulsants pregabalin and oxcarbazepine (low SOE), the drug classes tricyclic antidepressants (low SOE) and atypical opioids (low SOE), and botulinum toxin (low SOE) were more effective than placebo. We could not draw conclusions about quality of life due to incomplete reporting. All studies were short-term (less than 6 months), and all effective drugs had more than 9% dropouts from adverse effects. For reducing pain, duloxetine and venlafaxine, pregabalin and oxcarbazepine, tricyclic antidepressants, atypical opioids, and botulinum toxin were more effective than placebo. However, quality of life was poorly reported, studies were short-term, drugs had substantial dropout rates, and opioids have significant risks. Future studies should evaluate longer-term outcomes, use methods and measures recommended by pain organizations, and assess patients' quality of life.


Mitochondrial shuttling of CAP1 promotes actin- and cofilin-dependent apoptosis.
Mitochondria play a central role in regulating apoptosis by releasing proapoptotic contents such as cytochrome c, and generating reactive oxygen species (ROS). Early in apoptosis, proteins translocate to mitochondria to promote the release of their contents. Here, we show that the actin- and cofilin-interacting protein CAP1 has a role in apoptosis. When we induced apoptosis, CAP1 rapidly translocated to the mitochondria independently of caspase activation. Translocation was proapoptotic because CAP1-knockdown cells were resistant to apoptosis inducers. Overexpression of wild-type CAP1 did not stimulate apoptosis on its own, but stimulated cofilin-induced apoptosis. Apoptosis induction required a mitochondrial-targeting domain, localized in the N-terminus and also the actin-binding domain in the C-terminus. Taken together, these studies suggest that CAP1 provides a direct link from the actin cytoskeleton to the mitochondria by functioning as an actin shuttle.


Self-powered hydrogels induced by ion transport.
Electroactive hydrogels are needed to enable stretchable electronics because of their flexible mechanical characteristics and electrical conductive properties. We describe a class of viscoelastic, porous, ion-conductive, and self-powered hydrogels that are fabricated based on a PHEMA hydrogel (poly(2-hydroxyethyl methacrylate)) and PPy (polypyrrole). They are capable of creating synchronous ionic current in electrolyte solution when enduring mechanical deformation. The conditions that impact the electric response of the hydrogel, such as stress, strain rate, pH of electrolyte solution, and concentration of ions in the electrolyte solution, have been investigated and reported in this paper. The mechanism of creating ionic current under deformation is elaborated through numerical simulation and experimental tests. Moreover, by embedding the electrically self-powered hydrogel into a movable object, such as a sports shoe, the patterns of mechanical actions (e.g. walking, running, or jumping) can be identified from the generated electrical current without any assistance of external batteries or power sources. It presents the outstanding potential of this hydrogel in building self-powered soft devices including active sensors and artificial skins.


Abscisic acid is an endogenous stimulator of insulin release from human pancreatic islets with cyclic ADP ribose as second messenger.
Abscisic acid (ABA) is a plant stress hormone recently identified as an endogenous pro-inflammatory cytokine in human granulocytes. Because paracrine signaling between pancreatic beta cells and inflammatory cells is increasingly recognized as a pathogenetic mechanism in the metabolic syndrome and type II diabetes, we investigated the effect of ABA on insulin secretion. Nanomolar ABA increases glucose-stimulated insulin secretion from RIN-m and INS-1 cells and from murine and human pancreatic islets. The signaling cascade triggered by ABA in insulin-releasing cells sequentially involves a pertussis toxin-sensitive G protein, cAMP overproduction, protein kinase A-mediated activation of the ADP-ribosyl cyclase CD38, and cyclic ADP-ribose overproduction. ABA is rapidly produced and released from human islets, RIN-m, and INS-1 cells stimulated with high glucose concentrations. In conclusion, ABA is an endogenous stimulator of insulin secretion in human and murine pancreatic beta cells. Autocrine release of ABA by glucose-stimulated pancreatic beta cells, and the paracrine production of the hormone by activated granulocytes and monocytes suggest that ABA may be involved in the physiology of insulin release as well as in its dysregulation under conditions of inflammation.


Effects of Saffron Extract (Affron®) with 100 mg/kg and 200 mg/kg on Hypothalamic-Pituitary-Adrenal Axis and Stress Resilience in Chronic Mild Stress-Induced Depression in Wistar Rats.
Stress-related symptoms are a global concern, impacting millions of individuals, yet effective and safe treatments remain scarce. Although multiple studies have highlighted the stress- alleviating properties of saffron extract, the underlying mechanisms remain unclear. This study employs the unpredictable chronic mild stress (CMS) animal model to investigate the impact of a standardized saffron extract, Affron® (AFN), on hypothalamic-pituitary-adrenal (HPA) axis regulation and neuroplasticity in Wistar rats following repeated oral administration. The research evaluates AFN's effects on various stress-related parameters, including hypothalamic gene expression, stress hormone levels, and the sucrose preference test. In animals subjected to continuous unpredictable CMS, repetitive administration of AFN at doses of 100 mg/kg and 200 mg/kg effectively normalized HPA axis dysregulation and enhanced neuroplasticity. Increased concentrations of AFN demonstrated greater efficacy. Following AFN oral administration, adrenocorticotropic and corticosterone hormone levels exhibited significant or nearly significant reductions in comparison to subjects exposed to stress only. These changes align with the alleviation of stress and the normalization of the HPA axis. These findings elucidate AFN's role in stress mitigation, affirm its health benefits, validate its potential as a treatment for stress-related symptoms, confirm its physiological effectiveness, and emphasize its therapeutic promise.


What it takes to get it right: A qualitative study exploring optimal handover of health programmes in Tonkolili District, Sierra Leone.
Since 2015 Médecins Sans Frontières (MSF) has been supporting the Ministry of Health (MoH) in Tonkolili district, Sierra Leone, with an integrated health care approach at the community, primary health centre (PHC), and hospital level. This programme is planned to be handed over to MoH. To prepare for this handover, a qualitative study exploring elements of a successful handover was undertaken in 2019. Focus group discussions (FGD) with the community members (n-48) and in-depth interviews (IDI) with MSF staff, community leaders, and MoH staff in Sierra Leone (n-15) were conducted. Data were audio-recorded, transcribed verbatim from English, Creole, and Themne, coded, and thematically analysed. Participants expressed that an optimal project handover and exit strategy should be a continuous, long-term, the staggered process included from the inception of the programme design. It requires clear communication and relationship building by all relevant stakeholders and demands efficient resources and management capacity. Associated policy implications are applicable across humanitarian settings on the handover of programmes where the government is functional and willing to accept responsibilities.


Effect of thymidine auxotrophy, thymidine starvation and nalidixic acid inhibition on the properties of DNA labelled by a pulse of [3H]thymidine in Staphylococcus aureus.
The labelling of DNA by pulse/chase experiments in Staphylococcus aureus has been investigated, analysing the products by alkaline sucrose velocity centrifugation. In S. aureus NCTC 8325 a short (60 s) pulse of [3H]thymidine labels both small (10 to 20 S) fragments and DNA that co-sediments with long-term label. In a thymidine-requiring derivative, 8325thy, most pulse label is incorporated into small fragments. In both bacterial strains small fragments can be chased into high molecular weight DNA. Thymidine starvation of 8325thy prior to pulse labelling results in smaller fragments (4 to 10S) being labelled. In a subsequent chase with unlabelled thymidine this label is incorporated into high molecular weight DNA, although more slowly than in the absence of thymidine starvation. The fact that nalidixic acid, an antibiotic which specifically inhibits DNA replication in S. aureus, does not inhibit the [3H]thymidine incorporation immediately after thymidine starvation and that nalidixic acid shows down the increase in size of pulse-labelled fragments through inhibition of DNA synthesis suggests that thymidine starvation results in changes at the replication fork. The possible nature of these changes is discussed. It is proposed that one of the results of thymidine starvation is to cause a long-lived gap between DNA synthesized before starvation and DNA synthesized after starvation.


Conjugated-Polypyridine-Derivative-Derived Semiconductive Iodoplumbates with Tunable Architectures and Efficient Visible-Light-Induced Photocatalytic Property.
By mediation of the pH values, three novel inorganic-organic iodoplumbate hybrids, [Me3TPT][Pb3I9] [1; Me3TPT = trimethyl-2,4,6-tris(4-pyridyl)-1,3,5-triazine], [Me3TPT]2[Pb9I24] (2), and [Me3TPT]2[Pb19I44] (3), have been achieved under solvothermal conditions. The large conjugated in situ N-alkylation polypyridine derivatives act as structure-directing agents and electron acceptors, making the materials feature adjustable structural variations with 0D, 1D, and 2D structures and a potential semiconductive performance with narrow energy gaps (1.72, 1.80, and 1.78 eV for 1-3, respectively), which result in their efficient photocatalytic activity under visible-light irradiation. Theoretical calculation reveals that the conjugated organic moieties greatly contribute to the conduction band, leading to narrow band gaps. It is expected that the work will contribute to the exploitation of novel semiconducting halometallates by employing conjugated organic species as structure-directing agents.


Pathophysiology of the cardio-renal syndromes types 1-5: An uptodate.
According to the recent definition proposed by the Consensus conference on Acute Dialysis Quality Initiative Group, the term cardio-renal syndrome (CRS) has been used to define different clinical conditions in which heart and kidney dysfunction overlap. Type 1 CRS (acute cardio- renal syndrome) is characterized by acute worsening of cardiac function leading to AKI (5, 6) in the setting of active cardiac disease such as ADHF, while type - 2 CRS occurs in a setting of chronic heart disease. Type 3 CRS is closely link to acute kidney injury (AKI), while type 4 represent cardiovascular involvement in chronic kidney disese (CKD) patients. Type 5 CRS represent cardiac and renal involvement in several diseases such as sepsis, hepato - renal syndrome and immune - mediated diseases.


Improving PMTCT uptake in rural South Africa.
Despite the widespread availability of prevention of mother-to-child transmission (PMTCT) programs, many women in sub-Saharan Africa do not participate in PMTCT. This pilot study aimed to utilize partner participation in an intervention to support PMTCT uptake. Couples (n ¼ 239) were randomized to receive either a comprehensive couples-based PMTCT intervention or the standard of care. Compared to the standard of care, participants receiving the intervention increased HIV- and PMTCT-related knowledge (F1,474 ¼ 13.94, p ¼ .004) and uptake of PMTCT, as defined by infant medication dosing (74% vs. 46%, w2 ¼ 4.69, p ¼ .03). Results indicate that increasing male attendance at antenatal clinic visits maybe "necessary but not sufficient" to increase PMTCT uptake. Increasing HIV knowledge of both partners and encouraging active male participation in the PMTCT process through psychoeducational interventions may be a strategy to increase the uptake of PMTCT in South Africa.


High-frequency versus theta burst transcranial magnetic stimulation for the treatment of poststroke cognitive impairment in humans
Because the reliability of repetitive transcranial magnetic stimulation (rTMS) in treating poststroke cognitive impairment has not been convincingly demonstrated, we systematically examined the effectiveness of this regimen with 2 protocols. We randomly allocated 41 patients with poststroke cognitive impairment to receive 5 Hz rTMS (n = 11), intermittent theta burst stimulation (iTBS; n = 15) or sham stimulation (n = 15). Each group received 10 stimulation sessions over the left dorsolateral prefrontal cortex. We performed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Beck Depression Inventory at baseline and after the intervention. The 5 Hz rTMS group showed significantly greater improvement than the sham group in RBANS total score (p = 0.006), attention (p = 0.001) and delayed memory (p < 0.001). The iTBS group showed significantly greater improvement than the sham group in RBANS total score (p = 0.005) and delayed memory (p = 0.007). The 5 Hz rTMS group exhibited a superior modulating effect in attention compared to the iTBS group (p = 0.016). Patients without comorbid hypertension (p = 0.008) were predisposed to favourable therapeutic outcomes. Although we included only patients with left hemispheric stroke, heterogeneity associated with cortical and subcortical implications existed. We did not investigate the remote effects of rTMS. Our results demonstrated that both 5 Hz rTMS and iTBS were effective for poststroke cognitive impairment in terms of global cognition, attention and memory function; the domain of attention was susceptible to 5 Hz modulation. Treatment with 5 Hz rTMS may slow cognitive decline, representing both a pivotal process in poststroke cognitive impairment and an aspect of neuroplasticity that contributes to disease-modifying strategies. NCT02006615; clinicaltrials.gov/ct2/show/NCT02006615.


Supplementation with alpha-tocopherol or a combination of alpha-tocopherol and ascorbic acid protects the gastrointestinal tract of iron-deficient rats against iron-induced oxidative damage during iron repletion.
Recently we have shown the susceptibility of Fe-deficient rat intestine to oxidative damage during Fe repletion. The role of dietary antioxidants like ascorbic acid, alpha-tocopherol and a combination of both in counteracting the oxidative stress was tested in this study. Five groups of thirteen weanling WKY female rats were fed with an Fe-deficient diet for a period of 5 weeks. Another set of thirteen rats received an Fe-sufficient diet and served as the control group (Con). Oral administration of either vehicle (D), 8 mg Fe alone (D+) or in the presence of 24 mg ascorbic acid (D+ + C), 40 mg alpha-tocopherol (D+ + E) or a combination of both (D+ + C + E) per d for 15 d was carried out in Fe-depleted rats. The impact of this treatment protocol on Fe status, oxidative stress and antioxidant status at the site of Fe absorption was assessed. It was observed that though the indicators of Fe status were normalised on Fe supplementation, the oxidative stress as reflected by the levels of both thiobarbituric-acid reactive substances (TBARS) and protein carbonyls were significantly greater in D+ and D+ + C compared to D+ + E, D+ + C + E and Con groups. The mucosal cell DNA damage was seen in D+, D+ + C and D+ + E groups on electrophoresis. Functional integrity as assessed by the activities of alkaline phosphatase and lys-ala-dipeptidyl aminopeptidase were normalized in all the groups treated with the antioxidant(s). There were significant positive alterations in some of the endogenous antiperoxidative systems and in serum caeruloplasmin activity in D+ + E and D+ + C + E groups. Paradoxically, serum ascorbate levels were significantly lower in D+ + C than in D+ + E and D+ + C + E groups. This could be due to the protection offered by alpha-tocopherol in the presence of Fe. It is concluded that supplementation of alpha-tocopherol alone or in combination with ascorbic acid protects the gastrointestinal tract of Fe-deficient rats against Fe-mediated oxidative damage during Fe repletion. However, ascorbic acid alone does not protect the gastrointestinal tract against Fe-induced oxidative stress.


[Modulation of the axillary lymph node dissection in breast cancer].
Several studies showed the reliability of the sentinel lymph node (SN) technique in the evaluation of the N parameter in breast cancer so much to induce surgeons to limit the axillary dissection to the biopsy of the SN alone (SNB) in case this is negative to the extemporaneous examination. After a period of focusing on the identification technique, biopsy and histological examination of the SN (October 97-January 98) always followed by a complete dissection of the three axillary node levels (ALND), we started a study to evaluate the reliability of a limited dissection of the 1st level of the axilla (FLND) in women with T < 3 cm, N0-1a, M0, that did not undergo any neoadjuvant treatment and in which the SN resulted free from metastases. We started this phase of the study in February 1998 till May 2001. In the present paper we show the results related to this period. We enrolled 256 women with T < 3 cm, N0-1a, M0. In 49 cases we used vital dye, in 23 dye + radioguided surgery (RGS) and in 184 RGS only. The extemporaneous histological examination of the SN has been performed with thin sections, dyed with EE. When SN was negative to the intraoperative examination, we limited the dissection to the 1st level of the axilla, except that in 3 patients, with SN located to the 2nd level, in which we did an ALND. The FLND has been performed in 17 cases with a minimally invasive technique. The definitive histological examination of the SN always included the immunohistochemistry. If the SN was positive, usually underestimated to the intraoperative examination, the patients had an adjuvant chemotherapy. In 203/207 patients (98.1%) SN was found to the pre-operative lymphoscintigraphy. During surgery the SN was identified in 46/49 (94%) using the vital dye, in 22/23 (96%) using the vital dye + RGS and in 176/179 (98.3%) using RGS. To the extemporaneous histological examination SN was negative in 140, metastatic in 101; to the histological definitive results of the SN we noticed 6 false negative, since others lymph nodes than SN were positive (4 cases) or for evidence of micrometastases at the immunohistochemistry which were not detected at the extemporaneous examination (2 cases). On 107 cases of N+ the SN was the only metastatic lymph node in 42 (39.3%). The false negative percentage was 5.6% and the diagnostic accuracy of the SNB was 97.5%. In the group treated with FLND we only noticed two cases of light lymphedema (1.4%). Our results are in concordance with the international literature and they induced us, from June 2001, to begin a new phase of the study in which we limit the dissection of the axilla to the SN only, if not metastatic, in women with T1 breast carcinoma.


Kidney transplantation from donors aged 65 years or more as single or dual grafts.
The organ shortage and aging donor population force transplant centers to accept donors previously considered unusable for kidney transplantation. We report the experience of two Italian transplant centers with single (SKTx) and dual (DKTx) kidney transplantation from donors aged 65 years or more. The study population comprised 75 SKTx (mean donor age 70.5 years) and 28 DKTx (mean donor age 75.0 years). Kidneys from donors with a calculated admission creatinine clearance <50 mL/min, a Karpinski's score on kidney biopsy between 5 and 7, or both were allocated to DKTx. Grafts with better function or lower biopsy scores were employed for SKTx. Delayed graft function occurred in 45.3% of SKTx and in 39.3% of DKTx. After a mean follow-up period of 30.0 +/- 19.5 months, the acute rejection rate was 24.0% in SKTx and 7.1% in DKTx. Mean serum creatinine was 1.8 +/- 0.9 and 1.8 +/- 1.3 mg/dL in SKTx, and 1.8 +/- 1.6 mg/dL and 1.3 +/- 0.2 mg/dL in DKTx at 1 and 5 years, respectively. Patient survival was 93.3% and 91.2% in SKTx, and 92.9% and 92.9% in DKTx at 1 and 5 years, respectively. Graft survival was 92.0% and 88.3% in SKTx, and 89.3% and 89.3% in DKTx at the same time intervals. Keeping preservation time below 16 hours and avoiding calcineurin inhibitors were both associated with improved graft survival and function. Careful donor selection, short preservation time, and tailored immunosuppression allow safe and efficient use of elderly donor kidneys.


Exploring bulky natural and natural-like periphery in the design of p-(benzyloxy)phenylpropionic acid agonists of free fatty acid receptor 1 (GPR40).
Six derivatives of 3-phenylpropionic acid bearing various natural and natural-like, spatially defined peripheral motifs have been synthesized and evaluated in vitro for free fatty acid receptor 1 (FFA1) activation. Two frontrunner compounds (bearing a bornyl and cytosine groups) were evaluated in an oral glucose tolerance test in mice where both demonstrated the ability to sustain blood glucose levels following a glucose challenge. The bornyl compound displayed a somewhat superior, dose-dependent efficacy and, therefore, can be regarded as a lead compounds for further development as a therapeutic agent for type 2 diabetes mellitus. Its high affinity to FFA1 was rationalized by docking experiments.


Could Circumcision of HIV-Positive Males Benefit Voluntary Medical Male Circumcision Programs in Africa? Mathematical Modeling Analysis.
The epidemiological and programmatic implications of inclusivity of HIV-positive males in voluntary medical male circumcision (VMMC) programs are uncertain. We modeled these implications using Zambia as an illustrative example. We used the Age-Structured Mathematical (ASM) model to evaluate, over an intermediate horizon (2010-2025), the effectiveness (number of VMMCs needed to avert one HIV infection) of VMMC scale-up scenarios with varying proportions of HIV-positive males. The model was calibrated by fitting to HIV prevalence time trend data from 1990 to 2014. We assumed that inclusivity of HIV positive males may benefit VMMC programs by increasing VMMC uptake among higher risk males, or by circumcision reducing HIV male-to-female transmission risk. All analyses were generated assuming no further antiretroviral therapy (ART) scale-up. The number of VMMCs needed to avert one HIV infection was projected to increase from 12.2 VMMCs per HIV infection averted, in a program that circumcises only HIV-negative males, to 14.0, in a program that includes HIV-positive males. The proportion of HIV-positive males was based on their representation in the population (e.g. 12.6% of those circumcised in 2010 would be HIV-positive based on HIV prevalence among males of 12.6% in 2010). However, if a program that only reaches out to HIV-negative males is associated with 20% lower uptake among higher-risk males, the effectiveness would be 13.2 VMMCs per infection averted. If improved inclusivity of HIV-positive males is associated with 20% higher uptake among higher-risk males, the effectiveness would be 12.4. As the assumed VMMC efficacy against male-to-female HIV transmission was increased from 0% to 20% and 46%, the effectiveness of circumcising regardless of HIV status improved from 14.0 to 11.5 and 9.1, respectively. The reduction in the HIV incidence rate among females increased accordingly, from 24.7% to 34.8% and 50.4%, respectively. Improving inclusivity of males in VMMC programs regardless of HIV status increases VMMC effectiveness, if there is moderate increase in VMMC uptake among higher-risk males and/or if there is moderate efficacy for VMMC against male-to-female transmission. In these circumstances, VMMC programs can reduce the HIV incidence rate in males by nearly as much as expected by some ART programs, and additionally, females can benefit from the intervention nearly as much as males.


A multidimensional model of optimal participation of children with physical disabilities.
To present a conceptual model of optimal participation in recreational and leisure activities for children with physical disabilities. The conceptualization of the model was based on review of contemporary theories and frameworks, empirical research and the authors' practice knowledge. A case scenario is used to illustrate application to practice. The model proposes that optimal participation in recreational and leisure activities involves the dynamic interaction of multiple dimensions and determinants of participation. The three dimensions of participation are physical, social and self-engagement. Determinants of participation encompass attributes of the child, family and environment. Experiences of optimal participation are hypothesized to result in long-term benefits including better quality of life, a healthier lifestyle and emotional and psychosocial well-being. Consideration of relevant child, family and environment determinants of dimensions of optimal participation should assist children, families and health care professionals to identify meaningful goals and outcomes and guide the selection and implementation of innovative therapy approaches and methods of service delivery. Implications for Rehabilitation Optimal participation is proposed to involve the dynamic interaction of physical, social and self-engagement and attributes of the child, family and environment. The model emphasizes the importance of self-perceptions and participation experiences of children with physical disabilities. Optimal participation may have a positive influence on quality of life, a healthy lifestyle and emotional and psychosocial well-being. Knowledge of child, family, and environment determinants of physical, social and self-engagement should assist children, families and professionals in identifying meaningful goals and guiding innovative therapy approaches.


Retrolabyrinthine or retrosigmoid vestibular neurectomy: indications.
Selective vestibular nerve section is indicated for the treatment of vertigo in unilateral Meniere's disease or other inner ear disorders, in patients with salvageable hearing. Since 1978, the retrolabyrinthine approach to the vestibular nerve in the cerebellopontine angle has been used extensively with good success and minimal morbidity. In an attempt to obtain more complete section of the vestibular nerve, the retrosigmoid-internal auditory canal approach was developed in 1985 and has been employed in 13 patients, all of whom obtained complete control of vertigo. The surgical techniques are presented with emphasis on the advantages and disadvantages of each approach. Relative indications and contraindications are suggested.


Is PCNA unloading the central function of the Elg1/ATAD5 replication factor C-like complex?
Maintaining genome stability is crucial for all cells. The budding yeast Elg1 protein, the major subunit of a replication factor C-like complex, is important for genome stability, since cells lacking Elg1 exhibit increased recombination and chromosomal rearrangements. This genome maintenance function of Elg1 seems to be conserved in higher eukaryotes, since removal of the human Elg1 homolog, encoded by the ATAD5 gene, also causes genome instability leading to tumorigenesis. The fundamental molecular function of the Elg1/ATAD5-replication factor C-like complex (RLC) was, until recently, elusive, although Elg1/ATAD5-RLC was known to interact with the replication sliding clamp PCNA. Two papers have now reported that following DNA replication, the Elg1/ATAD5-RLC is required to remove PCNA from chromatin in yeast and human cells. In this Review, we summarize the evidence that Elg1/ATAD5-RLC acts as a PCNA unloader and discuss the still enigmatic relationship between the function of Elg1/ATAD5-RLC in PCNA unloading and the role of Elg1/ATAD5 in maintaining genomic stability.


[24-Hour arterial pressure profile in chronic obstructive lung diseases in combination with arterial hypertension treated with enalapril].
To evaluate peculiarities and trends in 24-hour arterial pressure (AP) profile and bronchoobstructive syndrome (BOS) in patients with chronic obstructive pulmonary diseases (COPD) and arterial hypertension (AH) on combined treatment including enalapril maleate. Changes in BOS as shown by clinical data, data of peakflowmetry and external respiration function as well as in AP 24-hour profile according to 24-hour monitoring were studied in 50 patients with exacerbation of bronchial asthma and chronic bronchitis treated for 4 weeks with conventional broncholytic and antiinflammatory modalities, in 28 patients with mild and moderate AH receiving combined therapy including enalapril maleate. In exacerbation of COPD, 24-h AP profile is characterized by high frequency of the curve "non-dipper". Concomitant mild and moderate AH was diagnosed in more than half of the examinees. The addition of enalaprile maleate to the treatment in many cases lowered systolic and diastolic AP, normalized sympathicoadrenal system and 24-hour AP rhythm, reduced dyspnea, improved exercise tolerance, sleep. Good tolerance of the drug was seen in patients with exacerbation of COPD. In exacerbation of COPD it is recommended to monitor AP for 24 hours for early detection of AH and initiation of combined treatment with correction of bronchoobstructive syndrome and hemodynamic disorders. As a hypotensive drug, enalapril maleate is adequate in such patients.


Gas evolution in electrochemical flow cell reactors induces resistance gradients with consequences for the positioning of the reference electrode.
With the transfer of the electrochemical CO2-reduction from academic labs towards industrial application, one major factor is the increase in current density. This can be achieved via the usage of a gas diffusion electrode. It allows for electrochemical reactions at the three-phase boundary between gaseous CO2, liquid electrolyte and electrocatalyst. Thus, current densities in commercially relevant magnitudes of 200 mA cm-2 and beyond can be reached. However, when increasing the current density one faces a new set of challenges, unknown from low current experiments. Here, we address the issue of gas evolution causing a local increase in resistance and the impact on the operation of flow cells with gas diffusion electrodes. We set up a simple simulation model and compared the results with experiments on a real setup. As a result, the gas evolution's strong impact on current-, potential- and resistance-distributions along the flow axis can be described. Main consequence is that the positioning of the reference electrode has a significant effect on the locally measured IR-drop and thus on the measured or applied potential. Therefore, data from different setups must be compared with great care, especially with respect to the potentials, on which the cell is operated.


Epidemiology and microbiology of Shiga toxin-producing Escherichia coli other than serogroup O157 in England, 2009-2013.
The implementation of direct testing of clinical faecal specimens for gastrointestinal (GI) pathogens by PCR offers a sensitive and comprehensive approach for the detection of Shiga toxin-producing Escherichia coli (STEC). The introduction of a commercial PCR assay, known as GI PCR, for the detection of GI pathogens at three frontline hospital laboratories in England between December 2012 and December 2013 led to a significant increase in detection of STEC other than serogroup O157 (non-O157 STEC). In 2013, 47 isolates were detected in England, compared with 57 in the preceding 4 years (2009-2012). The most common non-O157 STEC serogroup detected was O26 (23.2 %). A total of 47 (47.5 %) STEC isolates had stx2 only, 28 (28.3 %) carried stx1 and stx2, and the remaining 24 (24.2 %) had stx1 only. Stx2a (64.0 %) was the most frequently detected Stx2 subtype. The eae (intimin) gene was detected in 52 (52.5 %) non-O157 STEC isolates. Six strains of STEC O104 had aggR, but this gene was not detected in any other STEC serogroups in this study. Haemolytic ureamic syndrome was significantly associated with STEC strains possessing eae [odds ratio (OR) 5.845, P = 0.0235] and/or stx2a (OR 9.56, P = 0.0034) subtypes. A matched case-control analysis indicated an association between non-O157 STEC cases and contact with farm animals. Widespread implementation of the PCR approach in England will determine the true incidence of non-O157 STEC infection, highlight the burden in terms of morbidity and mortality, and facilitate the examination of risk factors to indicate whether there are niche risk exposures for particular strains.


Cross-Verification of COVID-19 Information Obtained From Unofficial Social Media Accounts and Associated Changes in Health Behaviors: Web-Based Questionnaire Study Among Chinese Netizens.
As social media platforms have become significant sources of information during the pandemic, a significant volume of both factual and inaccurate information related to the prevention of COVID-19 has been disseminated through social media. Thus, disparities in COVID-19 information verification across populations have the potential to promote the dissemination of misinformation among clustered groups of people with similar characteristics. This study aimed to identify the characteristics of social media users who obtained COVID-19 information through unofficial social media accounts and were (1) most likely to change their health behaviors according to web-based information and (2) least likely to actively verify the accuracy of COVID-19 information, as these individuals may be susceptible to inaccurate prevention measures and may exacerbate transmission. An online questionnaire consisting of 17 questions was disseminated by West China Hospital via its official online platforms, between May 18, 2020, and May 31, 2020. The questionnaire collected the sociodemographic information of 14,509 adults, and included questions surveying Chinese netizens' knowledge about COVID-19, personal social media use, health behavioral change tendencies, and cross-verification behaviors for web-based information during the pandemic. Multiple stepwise regression models were used to examine the relationships between social media use, behavior changes, and information cross-verification. Respondents who were most likely to change their health behaviors after obtaining web-based COVID-19 information from celebrity sources had the following characteristics: female sex (P=.004), age ≥50 years (P=.009), higher COVID-19 knowledge and health literacy (P=.045 and P=.03, respectively), non-health care professional (P=.02), higher frequency of searching on social media (P<.001), better health conditions (P<.001), and a trust rating score of more than 3 for information released by celebrities on social media (P=.005). Furthermore, among participants who were most likely to change their health behaviors according to social media information released by celebrities, female sex (P<.001), living in a rural residence rather than first-tier city (P<.001), self-reported medium health status and lower health care literacy (P=.007 and P<.001, respectively), less frequent search for COVID-19 information on social media (P<.001), and greater level of trust toward celebrities' social media accounts with a trust rating score greater than 1 (P≤.04) were associated with a lack of cross-verification of information. The findings suggest that governments, health care agencies, celebrities, and technicians should combine their efforts to decrease the risk in vulnerable groups that are inclined to change health behaviors according to web-based information but do not perform any fact-check verification of the accuracy of the unofficial information. Specifically, it is necessary to correct the false information related to COVID-19 on social media, appropriately apply celebrities' star power, and increase Chinese netizens' awareness of information cross-verification and eHealth literacy for evaluating the veracity of web-based information.


Monitoring of chlorination disinfection by-products and their associated health risks in drinking water of Pakistan.
This study reports the baseline data of chlorination disinfection by-products such as trihalomethanes (THMs) and their associated health risks in the water distribution network of Islamabad and Rawalpindi, Pakistan. THM monitoring was carried out at 30 different sampling sites across the twin cities for 6 months. The average concentration of total trihalomethanes (TTHMs) and chloroform ranged between 575 and 595 μg/L which exceeded the permissible US (80 μg/L) and EU (100 μg/L) limits. Chloroform was one of the major contributors to the TTHMs concentration (>85%). The occurrence of THMs was found in the following order: chloroform, bromodichloromethane > dibromochloromethane > bromoform. Lifetime cancer risk assessment of THMs for both males and females was carried out using prediction models via different exposure routes (ingestion, inhalation, and dermal). Total lifetime cancer risk assessment for different exposure routes (ingestion, inhalation, and skin) was carried out. The highest cancer risk expected from THMs seems to be from the inhalation route followed by ingestion and dermal contacts. The average lifetime cancer risk for males and females was found to be 0.51 × 10⁻³ and 1.22 × 10⁻³, respectively. The expected number of cancer risks per year could reach two to three cases for each city.


Ascorbic acid deficiency in arabidopsis induces constitutive priming that is dependent on hydrogen peroxide, salicylic acid, and the NPR1 gene.
The ascorbic acid (AA)-deficient Arabidopsis thaliana vtc1-1 mutant exhibits increased resistance to the virulent bacterial pathogen Pseudomonas syringae. This response correlates with heightened levels of salicylic acid (SA), which induces antimicrobial pathogenesis-related (PR) proteins. To determine if SA-mediated, enhanced disease resistance is a general phenomenon of AA deficiency, to elucidate the signal that stimulates SA synthesis, and to identify the biosynthetic pathway through which SA accumulates, we studied the four AA-deficient vtc1-1, vtc2-1, vtc3-1, and vtc4-1 mutants. We also studied double mutants defective in the AA-biosynthetic gene VTC1 and the SA signaling pathway genes PAD4, EDS5, and NPR1, respectively. All vtc mutants were more resistant to P. syringae than the wild type. With the exception of vtc4-1, this correlated with constitutively upregulated H(2)O(2), SA, and messenger RNA levels of PR genes. Double mutants exhibited decreased SA levels and enhanced susceptibility to P. syringae compared with the wild type, suggesting that vtc1-1 requires functional PAD4, EDS5, and NPR1 for SA biosynthesis and pathogen resistance. We suggest that AA deficiency causes constitutive priming through a buildup of H(2)O(2) that stimulates SA accumulation, conferring enhanced disease resistance in vtc1-1, vtc2-1, and vtc3-1, whereas vtc4-1 might be sensitized to H(2)O(2) and SA production after infection.


Opioids Preconditioning Upon Renal Function and Ischemia-Reperfusion Injury: A Narrative Review.
Kidneys have an important role in regulating water volume, blood pressure, secretion of hormones and acid-base and electrolyte balance. Kidney dysfunction derived from acute injury can, under certain conditions, progress to chronic kidney disease. In the late stages of kidney disease, treatment is limited to replacement therapy: Dialysis and transplantation. After renal transplant, grafts suffer from activation of immune cells and generation of oxidant molecules. Anesthetic preconditioning has emerged as a promising strategy to ameliorate ischemia reperfusion injury. This review compiles some significant aspects of renal physiology and discusses current understanding of the effects of anesthetic preconditioning upon renal function and ischemia reperfusion injury, focusing on opioids and its properties ameliorating renal injury. According to the available evidence, opioid preconditioning appears to reduce inflammation and reactive oxygen species generation after ischemia reperfusion. Therefore, opioid preconditioning represents a promising strategy to reduce renal ischemia reperfusion injury and, its application on current clinical practice could be beneficial in events such as acute renal injury and kidney transplantation.


A case of malignant mesothelioma detected hydropneumothorax.
A 61-year-old man was admitted to the emergency room because of sudden right chest pain and dyspnea. A chest X-ray and chest computed tomography (CT) revealed severe right pneumothorax with massive pleural effusion. Chest drainage was performed and approximately 1.2 L of pleural fluid was removed. Hemothorax was suspected based on the imaging findings, but the pleural effusion was serous. Active air leakage continued for 4 days after chest drainage, thus we decided to surgically control the air leakage and performed video-assisted surgery. A thoracoscopic examination revealed a large number of nodule parietal pleural and epiphrenic pleural nodule lesions. A pathological examination of frozen sections of the nodules indicated malignant pleural mesothelioma (MPM). Continuous air leakage was observed from the pleural surface of the right lower lobe. The air leak developed from the visceral pleura and the point of visceral pleura had a normal macroscopic appearance. The patient was treated with wedge lung resection and pleurodesis.


The Asheville Project: short-term outcomes of a community pharmacy diabetes care program.
To assess short-term clinical, economic, and humanistic outcomes of pharmaceutical care services (PCS) for patients with diabetes in community pharmacies. Intention-to-treat, pre-post cohort-with-comparison group study. Twelve community pharmacies in Asheville, N.C. Eighty-five patients with diabetes who were employees, dependents, or retirees from two self-insured employers; community pharmacists who completed a diabetes certificate program and received reimbursement for PCS. Patients scheduled consultations with pharmacists over 7 to 9 months. Pharmacists provided education, self-monitored blood glucose (SMBG) meter training, clinical assessment, patient monitoring, follow-up, and referral. Group 1 patients began receiving PCS in March 1997, and group 2 patients began in March 1999. Change from baseline in the two employer groups in glycosylated hemoglobin (A1c) values, serum lipid concentrations, health-related quality of life (HRQOL), satisfaction with pharmacy services, and health care utilization and costs. Patients used SMBG meters at home, stored all readings, and brought their meters with them to 87% of the 317 PCS visits (3.7 visits per patient). Patients' A1c concentrations were significantly reduced, and their satisfaction with pharmacy services improved significantly. Patients experienced no change in HRQOL. From the payers' perspective, there was a significant dollars 52 per patient per month increase in diabetes costs for both groups, with PCS fees and diabetes prescriptions accounting for most of the increase. In contrast, both groups experienced a nonsignificant but economically important 29% decrease in nondiabetes costs and a 16% decrease in all-diagnosis costs. A clear temporal relationship was found between PCS and improved A1c, improved patient satisfaction with pharmacy services, and decreased all-diagnosis costs. Findings from this study demonstrate that pharmacists provided effective cognitive services and refute the idea that pharmacists must be certified diabetes educators to help patients with diabetes improve clinical outcomes.


Guidelines for treatment of acute pain in children - the consensus statement of the Section of Paediatric Anaesthesiology and Intensive Therapy of the Polish Society of Anaesthesiology and Intensive Therapy.
RATIONALE AND SCOPE OF THE GUIDELINES Pain is a subjective unpleasant sensory and emotional experience. Acute pain occurs irrespective of age and has a prevalence of about 5% of the general population. Surgical procedures and painful diagnostic procedures are the main causes of this unpleasant and dangerous phenomenon for hospitalized children. It should be remembered that maintaining homeostasis in a child undergoing surgery is also affected by provision of an adequate level of analgesia and sedation as well as nerve conduction block within the surgical site. Even though both paediatric anaesthesiologists and paediatric surgeons know that the therapeutic activities during the perioperative period should be focused on ensuring sufficient analgesia and haemodynamic stability in surgical patients, as many as 70% of children undergoing surgery may experience moderate to severe pain [1-7]. Moreover, pain management is one of the fundamental human rights, i.e. the right to relief of suffering. According to the declaration of the 13th World Congress on Pain in Montreal (September 2010), this right also includes children [8, 9]. In Poland, the law was amended in 2017, and now each patient is guaranteed the right to relief and treatment of pain (Journal of Laws of 2017, item 836). Unfortunately, this right is not always respected in paediatric patients. Many factors contribute to ineffective analgesia in paediatric patients, mainly insufficient knowledge and lack of experience (concerning the use of opioids in particular), as well as lack of management standards, the negative attitude of the personnel or poor organization [10-13]. In hospitals which, as a result of organizational changes, have implemented analgesic treatment regimens and regularly educate their personnel in these issues, both efficiency and effectiveness of pain relief in children are high [14]. For many years, Polish paediatric anaesthesio-logists have been promoting and streamlining the analgesic management of children, which has led to the development of the present publication. The regimens presented in it are based on both the latest medical reports and many years of the authors' experience. The classes of recommendations and levels of evidence have been prepared (Tables 1 and 2, respectively). The presented recommendations were formulated based on a survey of medical reports published in the last two decades.


A multicenter survey of enteroscopy for the diagnosis of intestinal follicular lymphoma.
The importance of enteroscopy examinations to investigate the entire length of the small intestines has been emphasized in follicular lymphoma patients with intestinal involvement. The aim of the present study was to determine the current state of enteroscopy examinations, including the performance rate, and the prevalence of small intestinal lesions in a patient population in Japan. A retrospective multicenter survey of 17 institutions collected the case information of 110 follicular lymphoma patients with gastrointestinal involvement. The results of the enteroscopy examinations were reviewed, and in order to identify potential factors affecting the performance rate of enteroscopy, patient gender, age at lymphoma diagnosis, histopathological grade, clinical stage, the date of the initial diagnosis and the annual volume of enteroscopy at the institution were compared between the patients who underwent one or more enteroscopy procedures and the patients who did not undergo enteroscopy. A total of 34 patients (30.9%) underwent enteroscopy, and 24 of these (70.6%) presented with involvement in the jejunum and/or ileum. It was found that more patients diagnosed in recent years and more patients treated at an ultra-high volume institution (≥101 enteroscopy examinations/year) underwent an enteroscopy. In conclusion, although the prevalence of small intestinal lesions was high (70.6%) in the follicular lymphoma patients presenting with intestinal involvement, the performance rate of enteroscopy was only 30.9%, and thus the majority of the patients have not undergone enteroscopy examinations. Further investigation is required to define the clinical significance of enteroscopy at the initial diagnostic work-up and during the follow-up period of these patients.


[Infections of the lungs in returning travellers].
Travellers to foreign countries can acquire infections with pathogens that are not endemic in Germany. In light of the steadily increasing foreign travel these infections in returning travellers are of growing importance. Older travellers and those with underlying diseases constitute a special risk group. The knowledge of pathogens endemic to foreign countries and of the respective clinical picture is essential for determining a suspected diagnosis, especially in patients not responding to a first empirical antibacterial treatment. The documentation of a thorough travel history is crucial for taking a possible exposure to specific pathogens into account and thus for guiding the diagnostic pathway. In addition to pathogens which primarily lead to an infection of the lungs, non-pulmonary infections, which can cause pulmonary symptoms, e.g. schistosomiasis and malaria also have to be considered. Two examples of infectious diseases of the lungs, which can only be acquired abroad, are melioidosis and coccidioidomycosis. While a pulmonary manifestation of melioidosis can take an acute and fulminant course associated with a high mortality rate, coccidioidomycosis primarily presents mostly as oligosymptomatic, but with a substantial latent period can lead to pulmonary manifestations that in their diversity resemble tuberculosis or malignancies.


Breakthrough invasive fungal disease in patients receiving posaconazole primary prophylaxis: a 4-year study.
Posaconazole (PSC) is currently recommended as primary prophylaxis in neutropenic patients with acute myeloid leukaemia (AML) and in allogenic haematopoietic stem cell transplantation (AHSCT) recipients with graft-versus-host disease (GVHD). Studies focusing on breakthrough invasive fungal disease (IFD) upon PSC prophylaxis show disparate results. In order to evaluate the incidence of IFD in patients on PSC prophylaxis and identify IFD risk factors, we carried out a retrospective study of all consecutive patients on PP from January 2007 to December 2010 in our hospital. Breakthrough IFDs were identified from the database of the central pharmacy and the French administrative database (PMSI), registering final medical diagnoses of hospitalized patients. Medical data were reviewed to study proven or probable IFD, according to EORTC/MSG definition. PSC plasma concentrations (PPC) were also retrieved. Poisson models were used for statistical analysis. Two hundred and seventy-nine patients received PSC prophylaxis for a median duration of 1.4 months (range 0.2-17.9). Proven (n=6) or probable (n=3) IFDs were diagnosed in nine cases (3.2%). IFD incidence rate per 100 person-month was 1.65 (95% CI, 0.79-2.97). IFDs were candidaemia (Candida glabrata, n=2), pulmonary invasive aspergillosis (n=3), disseminated fusariosis (n=2) and pulmonary mucormycosis (n=2). Seven deaths were reported, directly related to IFD in three patients (33.3%). First dosage of PPC under 0.3 mg/L was the single significant risk factor for IFD (RR, 7.77; 95% CI, 1.30-46.5; p 0.025). Breakthrough IFD in patients receiving PSC prophylaxis is rare but associated with a poor outcome. Low PSC plasma concentrations are associated with an increased risk of IFD.


Screening of soy protein-derived hypotriglyceridemic di-peptides in vitro and in vivo.
Soy protein and soy peptides have attracted considerable attention because of their potentially beneficial biological properties, including antihypertensive, anticarcinogenic, and hypolipidemic effects. Although soy protein isolate contains several bioactive peptides that have distinct physiological activities in lipid metabolism, it is not clear which peptide sequences are responsible for the triglyceride (TG)-lowering effects. In the present study, we investigated the effects of soy protein-derived peptides on lipid metabolism, especially TG metabolism, in HepG2 cells and obese Otsuka Long-Evans Tokushima fatty (OLETF) rats. In the first experiment, we found that soy crude peptide (SCP)-LD3, which was prepared by hydrolyze of soy protein isolate with endo-type protease, showed hypolipidemic effects in HepG2 cells and OLETF rats. In the second experiment, we found that hydrophilic fraction, separated from SCP-LD3 with hydrophobic synthetic absorbent, revealed lipid-lowering effects in HepG2 cells and OLETF rats. In the third experiment, we found that Fraction-C (Frc-C) peptides, fractionated from hydrophilic peptides by gel permeation chromatography-high performance liquid chromatography, significantly reduced TG synthesis and apolipoprotein B (apoB) secretion in HepG2 cells. In the fourth experiment, we found that the fraction with 0.1% trifluoroacetic acid, isolated from Frc-C peptides by octadecylsilyl column chromatography, showed hypolipidemic effects in HepG2 cells. In the final experiment, we found that 3 di-peptides, Lys-Ala, Val-Lys, and Ser-Tyr, reduced TG synthesis, and Ser-Tyr additionally reduced apoB secretion in HepG2 cells. Novel active peptides with TG-lowering effects from soy protein have been isolated.


Deep-Learning-Guided Point Cloud Modeling with Applications in Intelligent Manufacturing.
Machining feature recognition is a key technology to realize CAD/CAPP/CAM system integration. Aiming at high robustness of traditional processing feature recognition in image reasoning, an automatic processing shape recognition method based on fuzzy learning of processing surrounding point black data is proposed. The Cloud RNN in the PointNet stage strongly demonstrates that the framework originates from convolutional neural spider webs. Protector shape for detailed discoloration data on constructed prominence surfaces for automatic rifle recognition is conducted. Spot staining data sample library is also constructed. The prosecuting feature recognizer gained advantages through sample training, which realized robot-style notification of 36 processing shapes. This is conducted with a recognition accuracy rate of over 90%. The method is simple and efficient, although it is not suitable for point cloud data with backlash and defects. It is sensible and still has usable robustness and confirmation performance against mischief around shape peripheries due to shape intersections.


Protective effects of Allium sativum against defects of hypercholesterolemia on pregnant rats and their offspring.
Sixty fertile female and male albino rats of Wistar strain (I male/ 3 females) were used in the present study. The females were divided into four groups of ten rats each. Group 1 received water and standard feeds for thirty-four days. Group 2 was fed with a cholesterol-containing diet (1%) for two weeks prior to onset of gestation and maintained administration till parturition, produce atherosclerosis (34 days). Group 3 received intragastric administration of 100mg homogenate of garlic (Allium sativum)/kg body weight for three weeks prior to onset of gestation as well as throughout the gestation period. Group 4 intragastrically administered garlic for one week of group B and maintained with combined garlic-treatment for the mentioned period. At parturition, the pregnant were sacrificed and serum total cholesterol (TCL), triglycerides (TG), HDL, LDL and creatine kinase activity (CK) were determined. The total numbers of offspring were recorded and examined morphological for congenital abnormalities. Biopsies of heart and dorsal aorta of both pregnant and their offspring (1 day-age) were processed for investigation at light and transmission electron microscopy. The skeleton of the newborn of different experimental groups were stained with alizarin red s and mor-phometric assessment of mandibular and appendicular bone length. The study revealed that the myocardium of atherosclerotic mother exhibited leuhkocytic inflammatory cell infiltration associated with necrosis, eosinophilia of myocardiai fibers, and edema of blood vessels. Ultrastructural studies revealed swelling of mitochondria, disruption of cristae in the myocardiai muscle fibers. The dorsal aorta possessed accumulation of extra-cellular lipid in intima lining of endothelium. The collagenous fibrils in the tunica adventitia became fragile and loosely separated from each other. Numerous foamy lipid loaden cells were detected within the tunica intima causing deterioration of the elastic fibers, resulting in fibrinoid necrosis. Oral supplementation with Allium sativum (100 mg/ kg) ameliorated these effects in myocardium muscle of mothers and offspring; however the dorsal aorta of mothers showed partial amelioration. Hypercholesterolemic mothers exhibited marked alterations in serum TCL, TG, LDL and CK activity. Supplementation with Allium sativum ameliorated the drastic biochemical alterations. Concerning pregnancy, hypercholesterolemia increased the incidence of abortion and abnormalities of the newborn including decreased body weight, reduced ossification of axial (mandible) and appendicular bones. All these effects were markedly ameliorated by supplementation with Allium sativum. The author finally concluded that hypercholesterolemia exhibits pathological alterations of myocardiai muscles reducing its optimal capacity for pumping blood to different body organs along with atherosclerosis of dorsal aorta which intern affect the progress of gestation and development of both morphological and skeletal abnormalities. Allium sativum-supplementation leads to amelioration of both mother and their offspring investigated parameters as a result of its antioxidant activity.


Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway.
Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) promotes mitochondrial biogenesis and slow fiber formation in skeletal muscle. We hypothesized that activation of the p38 mitogen-activated protein kinase (MAPK) pathway in response to increased muscle activity stimulated Pgc-1alpha gene transcription as part of the mechanisms for skeletal muscle adaptation. Here we report that a single bout of voluntary running induced a transient increase of Pgc-1alpha mRNA expression in mouse plantaris muscle, concurrent with an activation of the p38 MAPK pathway. Activation of the p38 MAPK pathway in cultured C2C12 myocytes stimulated Pgc-1alpha promoter activity, which could be blocked by the specific inhibitors of p38, SB203580 and SB202190, or a dominant negative p38. Furthermore, the p38-mediated increase in Pgc-1alpha promoter activity was enhanced by increased expression of the downstream transcription factor ATF2 and completely blocked by ATF2DeltaN, a dominant negative ATF2. Skeletal muscle-specific expression of a constitutively active activator of p38, MKK6E, in transgenic mice resulted in enhanced Pgc-1alpha and cytochrome oxidase IV protein expression in fast-twitch skeletal muscles. These findings suggest that contractile activity-induced activation of the p38 MAPK pathway promotes Pgc-1alpha gene expression and skeletal muscle adaptation.


[Cholinesterase inhibitors in dementia: the precarious balance between efficacy and safety].
Cholinesterase inhibitors are widely prescribed in patients with Alzheimer's disease. Recently it has become clear that using these medications increases the risk of serious adverse events like cardiac arrhythmias, and some studies report a much-increased mortality in the treatment group on comparison with the placebo group. In the light of the at best, modest, treatment effects, we advocate that the safety of cholinesterase inhibitors should be the subject of continuing, intense scrutiny. Efforts should be made to delineate the profile of a true 'cholinergic deficiency syndrome', in order to be able to prescribe these medications to a group of patients in whom the benefits outweigh the risks.