ATP/P2X7r axis mediates the pathological process of allergic asthma by inducing M2 polarization of alveolar macrophages.
Recent studies revealed that macrophages are polarized towards the M2 phenotype in an ovalbumin (OVA)-induced asthmatic model. Alveolar macrophages (AMs) are immune barriers in alveoli to various pathogens in the respiratory tract; AMs suppress Th2 cell proliferation, inhibit interleukin (IL)-4, IL-5, and IL-13 secretion, and protect against airway hyperresponsiveness in allergic asthma. However, the polarization status and effects of different types of AMs in the pathogenesis of asthma are not known. ATP/P2X7r, expressed mainly on macrophages and dendritic cells, is associated with acute and chronic asthmatic airway inflammation and Th2 immune responses in mice and humans and functions by activating the NLRP3 inflammasome complex and inducing proinflammatory cytokine release (IL-1β and IL-18). Therefore, we evaluated the association between the ATP/P2X7r axis and different types of AMs in the pathology of allergic asthma. A murine AM-depleted asthma model was established by administration of clodronate-encapsulated liposomes, and M1-or M2-AMs were adoptively transferred to confirm the effects of different AMs in allergic asthma. Brilliant Blue G and BzATP were administered to OVA/HDM-induced mice in vivo. Lipopolysaccharide + OVA, ATP, Brilliant Blue G, and BzATP were used to stimulate AMs isolated from control and asthmatic mice. We found that selective depletion of AMs aggravated lung inflammation in asthmatic mice. Further, M2-type AMs may play a key role in mediating asthmatic inflammatory responses via the adoptive transfer of M2-type AMs to AM-depleted asthmatic mice, and the phenotype of AMs differentiated to M2 type in asthma. P2X7r expression in M2-type AMs was higher than that in M1-type AMs. Activating P2X7r induced polarization of M2-type AMs and inhibited polarization of M1-type AMs, while blockage of P2X7r had the opposite effect. The ATP/P2X7r axis may participate in the pathogenesis of asthma by mediating the M2-type AM polarization.


Obstructive ureteropathy following radiation therapy for carcinoma of the cervix.
Between January 1959 and December 1986, 10 of 328 patients (3%) treated with curative intent using primary radiation therapy for carcinoma of the cervix developed obstructive ureteropathy due to fibrosis. The mean age of the patients with obstructive ureteropathy was 45 years and the median time to obstruction was 26 months. The obstruction was unilateral in 8 cases and involved the parametrial portion of the ureter in at least 5 cases. No predisposing risk factor was found to be associated with the development of obstructive ureteropathy. After corrective surgery, renal function remained normal in 8 patients, and resolution of the hydronephrosis occurred in 4 patients.


Central organization of the electrosensory lateral line system in bullhead catfish Ictalurus nebulosus.
The connections of the electrosensory lateral line lobe (ELL) of ictalurid catfish were examined by means of horseradish peroxidase tracing methods. The ELL receives direct input from the anterior and posterior lateral line nerves. Some of these nerve fibers continue through the ELL to end as mossy fibers in the lateral portion of the eminentia granularis. Granule cells in this area as well as those in lobus caudalis of the cerebellum project back to the ELL as parallel fibers in the upper molecular layer. The lower molecular layer of the ELL receives its input from the n. praeeminentialis. The ELL projects via the lateral lemniscus to the n. praeeminentialis and torus semicircularis bilaterally, but more heavily on the contralateral side. In addition, the n. praeeminentialis receives the bulk of its input from the ipsilateral torus semicircularis. The caudal lobe of the cerebellum both projects to the electrosensory portion of the torus semicircularis and receives indirect input from the torus semicircularis via the anterior olivary nucleus. In summary, the central organization of this ampullary receptor electrosensory system in catfish is similar to that of the ampullary-tuberous receptor electrosense of mormyrids and gymnotids.


Can residual leg shortening be predicted in patients with Legg-Calvé-Perthes' disease?
Although Legg-Calvé-Perthes' disease (LCPD) is frequently associated with varying degrees of femoral head deformity and leg length discrepancy (LLD), no factors that predict residual shortening have been clearly identified. We attempted to determine whether (1) the extent of femoral head involvement; (2) varus osteotomy; and (3) patient demographic characteristics are associated with LLD at skeletal maturity in patients with LCPD. We retrospectively reviewed the records of 168 skeletally mature patients with unilateral LCPD. The mean age at diagnosis was 7 years (range, 2-14 years). The extent of femoral head involvement was determined from the initial radiographs using the Herring lateral pillar and Catterall classifications. LLD was defined as shortening by ≥ 1.0 cm as measured from scanograms. The patient's sex and the treatment modalities used were also recorded. LLD ranging from 10 to 38 mm (mean, 19 mm) occurred in 93 (55%) patients and was associated with the extent of femoral head involvement. Varus osteotomy was not associated with residual shortening. The patient's age at diagnosis did not affect the LLD at skeletal maturity. The strongest predictor of LLD was a lateral pillar classification of B/C or C (odds ratio, 3.5; 95% confidence interval, 1.39-8.79). The extent of femoral head involvement, but not the patient's age at diagnosis or sex or the treatment modality, can predict the LLD at skeletal maturity in patients with unilateral LCPD.


Selection Signatures Analysis Reveals Genes Associated with High-Altitude Adaptation in Tibetan Goats from Nagqu, Tibet.
Tibetan goat is an ancient breed, which inhabits the adverse conditions of the plateaus in China. To investigate the role of selection in shaping its genomes, we genotyped Tibetan goats (Nagqu Prefecture, above 4500 m) and three lowland populations (Xinjiang goats, Taihang goats and Huanghuai goats). The result of PCA, neighbor-joining (N-J) tree and model-based clustering showed that the genetic structure between the Tibetan goat and the three lowland populations has significant difference. As demonstrated by the di statistic, we found that some genes were related to the high-altitude adaptation of Tibetan goats. Functional analysis revealed that these genes were enriched in the VEGF (vascular endothelial growth factor) signaling pathway and melanoma, suggesting that nine genes (FGF2, EGFR, AKT1, PTEN, MITF, ENPEP, SIRT6, KDR, and CDC42) might have important roles in the high-altitude adaptation of Nagqu Tibetan goats. We also found that the LEPR gene was under the strongest selection (di value = 16.70), and it could induce upregulation of the hypoxic ventilatory response. In addition, five genes (LEPR, LDB1, EGFR, NOX4 and FGF2) with high di values were analyzed using q-PCR. Among them, we found that LEPR, LDB1 and FGF2 exhibited higher expression in the lungs of the Tibetan goats; LEPR, EGFR and LDB1 exhibited higher expression in the hearts of the Huanghuai goat. Our results suggest that LEPR, LDB1, EGFR and FGF2 genes may be related to the high-altitude adaptation of the goats. These findings improve our understanding of the selection of the high-altitude adaptability of the Nagqu Tibetan goats and provide new theoretical knowledge for the conservation and utilization of germplasm resources.


Identification of different molecular forms of human airway lysozyme.
Human airway lysozyme (HAL) was separated into fractions of distinct molecular forms using a Mono S cation-exchange column on a fast-protein liquid chromatography system. This new and rapid (30 min) purification procedure of human lysozyme enabled the preparation of fractions, highly enriched in different isoenzymes of HAL. Purified HAL from pathological purulent airway secretions, nonpurulent airway secretions, and normal tracheobronchial tissue culture medium was characterized by four, three, and only one enzymatically active molecular forms, respectively. All charge forms (separated or combined) recovered from either purulent or nonpurulent airway secretions or tracheobronchial culture medium exhibited the same apparent molecular weight of 15,000.


KSHV LANA acetylation-selective acidic domain reader sequence mediates virus persistence.
Viruses modulate biochemical cellular pathways to permit infection. A recently described mechanism mediates selective protein interactions between acidic domain readers and unacetylated, lysine-rich regions, opposite of bromodomain function. Kaposi´s sarcoma (KS)-associated herpesvirus (KSHV) is tightly linked with KS, primary effusion lymphoma, and multicentric Castleman's disease. KSHV latently infects cells, and its genome persists as a multicopy, extrachromosomal episome. During latency, KSHV expresses a small subset of genes, including the latency-associated nuclear antigen (LANA), which mediates viral episome persistence. Here we show that LANA contains two tandem, partially overlapping, acidic domain sequences homologous to the SET oncoprotein acidic domain reader. This domain selectively interacts with unacetylated p53, as evidenced by reduced LANA interaction after overexpression of CBP, which acetylates p53, or with an acetylation mimicking carboxyl-terminal domain p53 mutant. Conversely, the interaction of LANA with an acetylation-deficient p53 mutant is enhanced. Significantly, KSHV LANA mutants lacking the acidic domain reader sequence are deficient for establishment of latency and persistent infection. This deficiency was confirmed under physiological conditions, on infection of mice with a murine gammaherpesvirus 68 chimera expressing LANA, where the virus was highly deficient in establishing latent infection in germinal center B cells. Therefore, LANA's acidic domain reader is critical for viral latency. These results implicate an acetylation-dependent mechanism mediating KSHV persistence and expand the role of acidic domain readers.


Short- and long-term effects of rapamycin on ischemic damage and apoptotic changes in torsion of rat testes.
Rapamycin has antioxidant defense mechanisms and immune suppressive effects. To detect the short- and long-term effects of rapamycin on ischemic damage and apoptotic changes in torsion of rat testes, mature male albino Wistar rats (n = 48) were included in the study as control, sham, early torsion-detorsion (T/D), early rapamycin treatment, early rapamycin control, late T/D, late rapamycin treatment, and late rapamycin control. The right testis was rotated 720° in a clockwise direction during 4 h in operation groups. Rapamycin was administered orally three times: 30 min before detorsion and 24 and 48 h after detorsion. The animals were killed on the third day in early groups and on the tenth day in late groups after detorsion. Statistically significant differences among all groups were detected for SOD and TBARS, mean seminiferous tubule diameter (MSTD) and Cosentino's histologic score (CHS), caspase 3, bax, average number of apoptotic cells per tubule (ANPCT), and percentage of apoptotic tubule (PAT) values. ANPCT values were 10% lower in the rapamycin treatment groups compared with the untreated T/D groups, and the PAT values were also approximately 1.3 times lower. Although short-term usage of rapamycin may reduce to the tubular injury caused by I/R conversely to apoptosis in the testicular tissue after testicular torsion, rapamycin may have the potential to increase the long-term apoptosis with/without testicular torsion and a subsequent regression in fertility.


Clonal dissemination of carbapenem-resistant Klebsiella pneumoniae ST16 co-producing NDM-1 and OXA-232 in Thailand.
Klebsiella pneumoniae ST258 and ST11 carrying bla KPC are among the most widespread carbapenem-resistant K. pneumoniae strains worldwide. Our carbapenem-resistant Enterobacteriaceae surveillance in Thailand revealed a nationwide dissemination of K. pneumoniae ST16 isolates carrying bla NDM-1 and bla OXA-232. To analyse the genomic details of this nationwide dissemination by focusing on plasmids and virulence factors. Using WGS data of 119 K. pneumoniae ST16 isolates carrying bla NDM-1 obtained in our previous surveillance study, clonality of chromosomes and plasmids of the isolates with carriage of virulence factors was evaluated. Of the 119 isolates, 111 carried plasmid pKP151_NDM1, and all 104 isolates harbouring bla OXA-232 carried plasmid pKP151_OXA232. These 104 K. pneumoniae ST16 isolates showing chromosomal clonality possessed both pKP151_NDM1 and pKP151_OXA232, demonstrating clonal dissemination of K. pneumoniae ST16 with these plasmids. The isolates had essentially similar virulence factors as those of K. pneumoniae ST16 clones carrying bla KPC, which were recently reported as highly invasive clones in Brazil. The potential global dissemination of these invasive clones with resistance to several antibiotics highlights the importance of appropriate monitoring and strict standard precautions.


Effect of intervertebral disc height on postoperative motion and outcomes after ProDisc-L lumbar disc replacement.
Retrospective study of patients enrolled in prospective randomized Food and Drug Administration trial. To evaluate the influence of pre- and postoperative disc height on postoperative motion and clinical outcomes. Our understanding of the factors that influence motion and ultimately patient satisfaction after lumbar disc replacement continues to evolve. Forty-two patients with a single level ProDisc-L at either the L4/5 or L5-S1 were selected. Pre- and postoperative disc height and range of motion (ROM) were measured from standing lateral and flexion-extension radiographs. Oswestry Disability Index and visual analog scale were also collected. Student t test and Spearman rho tests were performed to determine if there was any correlation or "threshold" effect between the disc height and ROM or clinical outcome. The mean anterior and posterior disc height significantly increased from 10.8 mm to 17.6 mm and 4.4 mm to 7.9 mm, respectively (P < 0.01). The mean ROM decreased from 7.0 degrees to 5.7 degrees (P = 0.21). Patients with less than 9 mm of preoperative anterior disc height had an increase in their ROM (2.2 degrees) compared with a loss of ROM (-2.2 degrees) in patients with more than 9 mm of preoperative disc height (P = 0.02). Patients with between 16 mm and 18 mm of postoperative anterior disc height have greater ROM (7.5 degrees) than those above or below this range (3.6 degrees and 3.6 degrees respectively, P < 0.05). There was no correlation or threshold effect between clinical outcomes and disc height. Patients with greater disc collapse benefit more in ROM from a total disc replacement. The optimal range to maximize ROM for postoperative anterior disc height is 16 mm to 18 mm. This optimal range did not translate into better clinical outcome at 2 years follow-up.


Temporal effect of Afro-Caribbean race on serum pregnancy-associated plasma protein-a at 9-13 weeks' gestation in screening for aneuploidies.
It was the aim of this study to investigate the pregnancy characteristics that influence the measured concentrations of maternal serum-free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 9(+0)-13(+6) weeks' gestation. In singleton pregnancies attending for routine care, serum-free β-hCG and PAPP-A were measured at 9(+0)-13(+6) weeks' gestation and fetal nuchal translucency was measured at 11(+0)-13(+6) weeks. The population included 27,908 chromosomally normal and 104 trisomy 21 pregnancies. Multiple regression analysis was used to examine the pregnancy characteristics that have a significant effect on the measured concentrations of free β-hCG and PAPP-A. We also examined the impact of incorporating temporal effects on performance of screening for trisomy 21. Serum-free β-hCG and PAPP-A concentrations were significantly affected by gestational age, maternal weight, racial origin, parity, preexisting diabetes mellitus type 2, smoking and conception by in vitro fertilization. There was a significant gestational age-dependent effect of Afro-Caribbean race on PAPP-A levels (p = 0.0005), with a weekly increase of 4.9% (95% CI 2.1-7.8). Serum-free β-hCG and PAPP-A concentrations at 9(+0)-13(+6) weeks' gestation are affected by several pregnancy characteristics and the effect of Afro-Caribbean race on PAPP-A increases with gestational age.


Subcutaneous administration of IgG.
The availability of IgG preparations that could be administered safely by the intravenous route was finally achieved in the early to mid-1980s. Intravenous immunoglobulin (IVIG) revolutionized the treatment of primary immune deficiency diseases (PIDD) and led to the discovery of the therapeutic value of high-dose IgG in autoimmune and inflammatory diseases not associated with PIDD. Improved therapy has improved outcomes and expectations, and most PIDD patients can lead fully active and productive lives. Administration of IgG by the subcutaneous route is effective and safe and overcomes obstacles to the use of IVIG in some patients. Many patients find administration of subcutaneous IgG at home more convenient than receiving IVIG at the Doctor's office or hospital. The coming years will see increased use of subcutaneous immunoglobulin in PIDD, which will be facilitated by advances leading to higher-concentration IgG products and easier delivery.


Merkel cell polyomavirus in non-small cell lung carcinomas from Chile.
Lung cancer is a leading pathology strongly associated with the smoking habit. However, a viral etiology for a subset of patients developing lung cancer has been suggested. Polyomaviruses (PyVs) are small double stranded DNA viruses associated with the development of some human diseases. However, a causal role of these viruses in human cancer has been difficult to demonstrate. In this study, eighty-six non-small cell lung carcinomas (NSCLCs), including adenocarcinomas (AdCs) and squamous cell lung carcinomas (SQCs) from Chile were analyzed for the presence of PyVs using polymerase chain reaction (PCR). All of the specimens were positive for a fragment of the betaglobin gene. We found that 4/86 (4.7%) of lung carcinomas were positive for PyVs. After sequencing and BlastN alignment, all four cases were identified as Merkel cell polyomaviruses (MCV) that corresponded to two AdCs and two SQCs. A non-significant statistical association was found between the presence of MCV and clinic-pathological features of the patients and tumors. In addition, 1/4 (25%) of the carcinomas were actively expressing large T antigen (LT) transcripts, as demonstrated by reverse-transcriptase PCR (RT-PCR). Thus a possible role of MCV in a very small subset of patients with lung cancer cannot be ruled out and warrants more investigation.


Return to work after heart transplantation: the New Zealand experience.
Return to work and social re-integration following heart transplantation is a significant challenge for patients. The aim of this study is to provide a snapshot of the current employment status and factors associated with return to work in New Zealand recipients over the past decade. Consecutive surviving patients who underwent heart transplantation in the 10 years from June 2001 to June 2011, alive in July 2012, were retrospectively identified. Details on demographics, employment before and after transplantation were obtained and recorded. A total of 87 patients were included, out of a total of 111 patients who underwent heart transplantation in the 10 year period from June 2001 (24 patients had died prior to July 2012). The median age of the study cohort was 52 years (range 15-75 years) and 19 were female. A total of 51 (58.6%) patients were in paid employment at the time of review. Of the 36 (41.4%) patients not in paid employment, 5 were students, 12 were retired and 10 were homemakers or not working through lifestyle choice. Two patients were unable to work for health reasons. Seven (8%) patients considered able to work were on an unemployment or invalid's benefit. Of the patients working prior to heart transplantation, 88.9% returned to work after a median of 8.5 months, and 70.6% remained on paid employment at a median follow-up of 77 months after transplantation. There was a statistically significant correlation between the time of stopping work prior to transplant and return to work after transplant (r = 0.497, P < .01). The current rate of paid employment in patients who underwent heart transplantation was similar to the overall employment rate in New Zealand. The most important predictor of returning to work was employment status prior to transplantation. Discussions regarding return to work early in the transplantation assessment process and actively assisting patients to seek employment after transplantation may improve employment rates.


A serious complication late after mitral valve replacement: left ventricular rupture with pseudoaneurysm.
We report a left ventricular pseudoaneurysm, an unusual complication of mitral valve replacement (MVR) in a 65-year-old man who had undergone coronary artery bypass grafting and MVR surgery two years ago. The patient was referred to our clinics because of progressive exertional dyspnea and palpitations. Transthoracic and transesophageal echocardiography showed a large pseudoaneurysm of the posterolateral left ventricular wall and computerized tomographic angiography (CTA) demonstrated the location and the size of the pseudoaneurysm and its neck. Urgent surgical repair was accomplished without complications.


Hydrogen bonding and coordination bonding in the electronically excited states of Cu2(L)2 (L=5-(4-pyridyl)tetrazole)MeOH: a TDDFT study.
The luminescent metal organic framework (MOF), Cu2(L)2·MeOH (L=5-(4-pyridyl)tetrazole), was studied using time-dependent density functional theory (TDDFT). A combination of frontier molecular orbitals and electronic configuration analysis revealed that the emission mechanism was a ligand to metal charge transition (LMCT) rather than a metal to ligand charge transfer (MLCT). Hydrogen bonding significantly changed the nature of the frontier orbital and the luminescence. Electronic transition energies predicted that the hydrogen bonding in excited state would become weaker with an electronic spectral blue-shift. The bond lengths, frequencies, and binding energies indicated weakening of the hydrogen bonding in the excited state, which can affect emissions in two ways, including: (i) a decrease in the electronic coupling between methanol and the motif and suppressing the occurrence of the photo-induced electron transfer (PET); and (ii) increasing the energy gap between S1 and S0, leading to radiative transition. Coordination bonding was also investigated in the excited state through bond lengths, frequencies, and bond orders. Coordination bonds were found to become stronger in the excited state leading to an enhancement of the luminescence.


Evolving progress in oncologic and operative outcomes for esophageal and junctional cancer: lessons from the experience of a high-volume center.
Modern series from high-volume esophageal centers report an approximate 40% 5-year survival in patients treated with curative intent and postoperative mortality rates of less than 4%. An objective analysis of factors that underpin current benchmarks within high-volume centers has not been performed. Three time periods were studied, 1990 to 1998 (period 1), 1999 to 2003 (period 2), and 2004 to 2008 (period 3), in which 471, 254, and 342 patients, respectively, with esophageal cancer were treated with curative intent. All data were prospectively recorded, and staging, pathology, treatment, operative, and oncologic outcomes were compared. Five-year disease-specific survival was 28%, 35%, and 44%, and in-hospital postoperative mortality was 6.7%, 4.4%, and 1.7% for periods 1 to 3, respectively (P < .001). Period 3, compared with periods 1 and 2, respectively, was associated with significantly (P < .001) more early tumors (17% vs 4% and 6%), higher nodal yields (median 22 vs 11 and 18), and a higher R0 rate in surgically treated patients (81% vs 73% and 75%). The use of multimodal therapy increased (P < .05) across time periods. By multivariate analysis, age, T stage, N stage, vascular invasion, R status, and time period were significantly (P < .0001) associated with outcome. Improved survival with localized esophageal cancer in the modern era may reflect an increase of early tumors and optimized staging. Important surgical and pathologic standards, including a higher R0 resection rate and nodal yields, and lower postoperative mortality, were also observed.


Namibia's way to Marine Spatial Planning - Using existing practices or instigating its own approach?
The territorial waters and EEZ of Namibia are part of the Benguela Current Large Marine Ecosystem in the South-East Atlantic. Growing demands and conflicts emerge although the area is not as intensely used as marine areas elsewhere. Namibia has chosen Marine Spatial Planning (MSP) as an integrated approach to facilitate sustainable ocean development and improved ocean governance. The paper explores the reality of the Namibian MSP process to date by investigating two guiding research questions: (1) What makes the Namibian approach to MSP distinct? and (2) What are the opportunities and difficulties of the Namibian MSP process in that particular context? The country's approach to MSP features a series of distinct attributes, not least due to its unique environmental and socio-economic context. Namibian MSP is highly precautionary and forward-looking given the relatively low intensity of current uses, has a strong ecosystem-based perspective due to the fairly pristine environment, is driven by a social equity and distributive justice agenda, and features a strong collaborative process governance. Whilst challenges such as limited financial resources, lacking legislation and weak links to broader ocean governance exist, the MSP process, which was linked to a systematic conservation planning process from the outset, has however resulted in a clear framework for the development of the first marine plan.


Role of surgery in the treatment of patients with high-risk neuroblastoma who have a poor response to induction chemotherapy.
In instances of high-risk neuroblastoma that do not show a clinical response to induction therapy, whether it is worth performing surgical resection or not and whether gross total resection (GTR) is more important than subtotal resection (STR) remain controversial. We retrospectively analyzed the data of patients with stage 4 neuroblastoma aged 18 months or older at diagnosis. Primary tumor volumes were measured both at diagnosis and at the first tumor response evaluation (after 6 cycles of induction chemotherapy). If the tumor volume at the first response evaluation was > 50% of the initial tumor volume, the patient was categorized as a poor responder. Otherwise, the patient was categorized as a good responder. Only poor responders were included. Patients were evaluated for event-free survival (EFS), overall survival (OS), and complications of surgery based on extent of surgical intervention. Sixty-five patients were included in this study. The 41 patients who underwent surgical intervention had a higher 3-year OS than the 24 patients who had a biopsy only (55.4% ± 8.1% vs. 31.3% ± 10.2%, P=0.02). However, there was limited improvement in 3-year EFS following surgical intervention. Three-year EFS rates of BX group (biopsy only) and OP group (surgical resection) were 24.2% ± 9.3% and 37.7% ± 7.9%, respectively (P=0.063). The extent of resection had no impact on 3-year OS (P=0.631) and 3-year EFS (P=0.796). Patients in the GTR group trended to have more severe surgical complications than patients in the STR group (P=0.105). For high-risk neuroblastomas that do not show a clinical response to induction therapy, surgical resection is important in predicting outcome, but the extent of resection is not.


Sinuleptolide inhibits proliferation of oral cancer Ca9-22 cells involving apoptosis, oxidative stress, and DNA damage.
Sinuleptolide, a soft corals-derived bioactive norditerpenoid, is a marine natural product with a potent anti-inflammatory effect. We evaluate the potential anti-oral cancer effects of sinuleptolide and investigate the possible mechanisms involved. Cell viability, cell cycle, apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and DNA damage analyses were performed. In a cell viability assay, we found that sinuleptolide is dose-responsively antiproliferative against oral gingival cancer Ca9-22 cells but less harmful to normal human gingival fibroblast (HGF-1) cells (P<0.001). In cell cycle analysis, sinuleptolide induced subG1 accumulation at a higher dose and led to G2/M arrest of Ca9-22 cells (P<0.005). Apoptosis was significantly increased in sinuleptolide-treated Ca9-22 cells based on annexin V and poly(ADP-ribose) polymerase (PARP) expressions (P<0.05-0.0001). Based on flow cytometer analysis, sinuleptolide also induced the generation of ROS and decreased MMP in a dose-responsive manner (P<0.05-0.0001). DNA damage increased dose-responsively after sinuleptolide treatments (P < 0.001) based on comet and γH2AX assays. Sinuleptolide can induce an antiproliferation of oral cancer Ca9-22 cells involving apoptosis, oxidative stress and DNA damage, suggesting that sinuleptolide represents a potential chemotherapeutic drug for oral cancer treatment.


Contribution of the peripheral 5-HT 2A receptor to mechanical hyperalgesia in a rat model of neuropathic pain.
We investigated the effect of 5-HT receptor antagonists on mechanical hyperalgesia observed in a neuropathic pain rat model prepared by chronic constriction injury of the sciatic nerve. NAN-190, a 5-HT 1A receptor antagonist, (-)-pindolol, a 5-HT 1A/1B receptor antagonist, and tropisetron, a 5-HT(3/4) receptor antagonist, did not affect the pain threshold in the hyperalgesic hind limb to the same extent as in the normal hind limb. However, sarpogrelate and ketanserin, 5-HT 2A receptor antagonists, significantly elevated the pain threshold in the hyperalgesic hind limb, but not in the normal hind limb. In spite of its high affinity for the 5-HT 2A receptor, methysergide only slightly elevated the pain threshold in the hyperalgesic hind limb. Pre-treatment with methysergide significantly antagonized the inhibitory effect of sarpogrelate on hyperalgesia. Furthermore, the 5-HT 2A receptor specific binding activity of 3H-ketanserin determined for the hyperalgesic hind limb did not differ from that of the normal hind limb. From these results, we propose that the 5-HT 2A receptor in the hyperalgesic hind paw function as an agonist-independent active receptor following constriction of the sciatic nerve, and that sarpogrelate and ketanserin act as inverse agonists of this receptor and suppress its activation. Methysergide may act as a neutral antagonist that blocks the effect of inverse agonists on the 5-HT 2A receptor.


Effect of Medium pH on Rhodosporidium toruloides NCYC 921 Carotenoid and Lipid Production Evaluated by Flow Cytometry.
The effect of the culture medium pH (3.5-6.0) on the carotenoid and lipid (as fatty acids) production by the yeast Rhodosporidium toruloides NCYC 921 was studied. Flow cytometry was used to evaluate the yeast's physiological response to different culture medium pH values. The yeast biomass concentration and lipid content were maxima at pH 4.0 (5.90 g/L and 21.85 % w/w, respectively), while the maximum carotenoid content (63.37 μg/g) was obtained at pH 5.0. At the exponential phase, the yeast cell size and internal complexity were similar, at different medium pH. At the stationary phase, the yeast cell size and internal complexity decreased as the medium pH increased. At the exponential phase, the proportion of cells with polarized membranes was always high (>80 %) but at the stationary phase, the proportion of yeast cells with depolarized membranes was dominant (>65 %) and increased with the medium pH increase. The results here reported may contribute for yeast bioprocesses optimization. For the first time, multiparameter flow cytometry was used to evaluate the impact of medium pH changes on the yeast cell physiological status, specifically on the yeast membrane potential, membrane integrity, cell size and internal complexity.


[Bronchiolitis caused by influenza type A virus. An emerging infectious disease].
To prospectively study the emergence and diagnostic problems of bronchiolitis caused by influenza A virus among children durign the 1999-2000 influenza epidemic. Negative respiratory syncitial virus (RSV) specimens (ELISA dot-blot) were seeded in the MDCK cell line for the isolation of influenza A virus, by the shell-vial technique. Vials were revealed by indirect immunofluorescence with antibodies directed against the influenza A virus nucleoprotein (Monofluookit IA, Pasteur Diagnostics). The clinical and epidemiologic features of patients with viral recovery were studied. A theoretical cost/benefit study was performed on the usefulness of the rapid antigenic detection of the influenza A virus. A total of 117 cases of respiratory infection caused by influenza A virus were detected. In 62 cases (52.9%) the diagnosis was bronchiolitis. Of them, 80.6% of cases were aged less than 6 years. Subtype H3N2 predominated in all respiratory infections, paticularly in bronchiolitis. During the 1999-2000 season, a significant emergence of bronchiolitis caused by influenza A virus was observed (week 3, 30% cases of influenza A versus 24% of RSV). The cost/benefit study disclosed that the antigenic detection of RSV and influenza A virus in all respiratory specimens would amount up to 30.83 Euros/specimen. During the last influenza epidemic, an emergence of bronchiolitis caused by influenza A virus among children was observed and confirmed. Based upon this observation, a dual strategy should be followed. On the one hand, a prophylactic approach (immunization of pregnant women); on the other hand, a diagnostic approach with a rapid antigenic detection of the influenza A virus.


Health-related quality of life of adolescents with type 1 diabetes in the context of resilience.
Adolescents with type 1 diabetes (T1D) can be faced with deterioration in glycemic control (GC), reduced health-related quality of life (HRQoL), and other psychosocial problems. It is important to understand how the disease and its clinical conditions influence HRQoL and how adolescents are able to overcome the life adjustment difficulties. To assess HRQoL of adolescents with T1D from demographic, clinical, personal, and behavioral point of view. A total of 229 adolescents with T1D (51.2% males) with a mean age of 15.35 (2.29) years old were recruited from three diabetes centers. The mean diabetes duration was 7.48 (3.87), the mean hemoglobin A1C (HbA1c) level was 10.3 (1.76) mmol/L. A multicenter quantitative correlational design study was applied to investigate the influence of sex, age, diabetes duration, GC expressed by HbA1c, intensive insulin regimen, physical activity (PA), resilience (RS), and socioeconomic background on HRQoL. Presence of the diabetes symptoms and worry about the disease has negative impact on the patients' HRQoL. Stepwise multiple regression analyses indicated that insulin pump therapy, male sex, and higher level of RS were significantly related to an increase in HRQoL, whereas the higher level of PA, male sex, and better HRQoL was significantly related to positive change in RS. Patients treated with insulin pump therapy had significantly better HRQoL. Significant association can be observed between HRQoL and RS. Supposedly, higher level of PA promotes higher level of RS that in turn helps increase HRQoL in adolescents with T1D. Treatment with insulin pump therapy also promotes better HRQoL.


Evolution: radiotracking sexual selection.
Why are members of one sex bigger than those of the other? A new study in which male giant weta were radiotracked found that smaller, longer legged males win the race to inseminate females.


Intermediate results of health related quality of life after vertical banded gastroplasty.
The purpose of this study is to evaluate (a) health-related quality of life (HRQL) after vertical banded gastroplasty (VBG) (Mason) and (b) predictors of HRQL. Eighty-two consecutive patients were assessed preoperatively and then after 6, 12 and 24 months. Patients filled out questionnaires for subjective appraisal of HRQL (physical well-being, mood, physical performance, perceived health, social support and coping/adjustment). The greatest improvement in weight and HRQL was seen within 6 months of surgery. Twenty-four months after VBG weight reduction (P<0.05), perceived health (P<0.05), physical well-being (P<0.05), physical performance (P<0.05), mood (P<0.05), coping/adjustment (P<0.05) continued to be better than before surgery. Preoperative binge eating was the most important predictor of HRQL. Two years after VBG weight loss and a significant improvement of HRQL can be found. HRQL and weight loss are not associated in terms of outcome, indicating that weight loss alone may not be enough to improve HRQL.


Impact of IDH1 and IDH2 mutation detection at diagnosis and in remission in patients with AML receiving allogeneic transplantation.
Somatic mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML). The prognostic impact of the presence of IDH mutations may be influenced by the comutational status, the specific location of the mutation (ie, IDH1 R132, IDH2 R140, and IDH2 R172) at diagnosis, and the dynamics of the mutation burden during disease course. Even though many patients with IDH-mutated AML are consolidated by hematopoietic stem cell transplantation (HSCT), the underlying biology and prognostic consequences remain largely unknown. Here, we present a large analysis of 292 patients with AML who received HSCT in complete remission (CR) or CR with incomplete peripheral recovery (CRi), in which we assessed the IDH mutation status at diagnosis and HSCT as a potential marker for measurable residual disease (MRD). About a quarter of all patients were IDH-mutated at diagnosis. The diagnostic presence of IDH mutations in AML did not have a significant prognostic impact when consolidated with HSCT. However, IDH1 R132 and IDH2 R172 MRD positivity in remission at HSCT associated with an increased risk of relapse, while IDH2 R140 mutations did not. The IDH2 R140 variant allele frequency (VAF) at diagnosis was higher, clustering around 50%, and the mutation clearance at HSCT in morphologic remission was much lower compared with IDH1 R132 and IDH2 R172. In our cohort, IDH2 R140 mutations behaved more like a clonal hematopoiesis-related aberration, while IDH1 R132 and IDH2 R172 harbored AML disease-specific features.


Antigen shedding by human breast-cancer cells in vitro and in vivo.
Human breast cancer cells were adapted to chemically defined medium in order to recover naturally shed glycoproteins. Sephadex G-150 chromatography of these glycoproteins revealed 1 major and 2 minor peaks. When the cells were grown in the presence of 3H-leucine, the radioactive shed proteins had a Sephadex profile identical to the unlabelled shed glycoproteins. PAGE analysis of these proteins showed 5 major bands. Antigenically similar proteins were found in the serum of female nude mice bearing BOT-2 tumours, but not in controls.


At what age can human oocytes be obtained?
To determine whether oocyte retrieval and in vitro maturation (IVM) is effective in girls undergoing fertility preservation before cancer treatment. Cohort study. Tertiary university medical center. Patients <or=20 years old before gonadotoxic chemotherapy undergoing ovarian cortex cryopreservation. Before ovarian cortex cryopreservation, oocytes in all observed follicles were aspirated, matured in vitro, and cryopreserved. Maturation of oocytes. One hundred seventy-nine oocytes were detected in 17/19 patients (89%) aged 5-20 years. We found 7, 8, and 17 oocytes in patients 5, 8, and 10 years old, respectively. The median number of oocytes per patient was 9 (0-37). Maturation rate was 45/133 oocytes (34%). In total, 81 oocytes were cryopreserved. We cryopreserved 4 of 12 detected, 4 of 9 detected, 1 of 8 detected, and 4 of 9 detected IVM oocytes for patients aged 5-10, 11-14, 15-17, and 18-20 years old, respectively. Patients undergoing ovarian cryopreservation could benefit from supplementary oocyte aspiration from the cortex. Surprisingly, oocytes were detected even in young premenarcheal girls. The number of oocytes detected, matured, and cryopreserved was not age dependent. Retrieved oocytes can be matured in vitro and cryopreserved. Because no pregnancy has yet resulted from this procedure it should be considered to be experimental. We describe the youngest patients to undergo ovum collection, IVM, and oocyte cryopreservation.


Valve pathology in heart failure: which valves can be fixed?
Heart transplantation has evolved to become the gold standard treatment for patients who have symptoms of severe congestive heart failure associated with end-stage heart disease. From an epidemiologic perspective, this treatment is "trivial" because less than 2800 patients in the United States are offered transplantation because of limitations of age, comorbid conditions, and donor availability. New surgical strategies to manage patients who have severe end-stage heart disease have therefore evolved to cope with the donor shortage in heart transplantation and have included high-risk coronary artery revascularization, cardiomyoplasty, and high-risk valvular repair or replacement.


Time of fusion of epiphyses at the elbow and wrist joints in girls of northwest India.
A radiological examination of both elbows and wrists of 149 Northwest Indian schoolgirls between the ages of 11 and 19 years, of middle socio-economic status, was undertaken to determine the time of fusion of the epiphyses with the metaphyses of the medial epicondyle of the humerus, the proximal end of the radius and the distal ends of both radius and ulna. The data were subjected to discriminant function tests as well as sensitivity and specificity tests. If the epiphysis of the medial epicondyle of the humerus or that of the head of the radius has not fused with metaphysis completely, the age of the girl would be < 16 years. However, the age of the girl should be > 16 years if the distal epiphyses of the radius and the ulna show complete fusion with their respective metaphyses. Discriminant function tests show that 91.95% of girls can be correctly classified as being above or below the age of 16 years.


Durability of Linear Small-Intestinal Growth Following Treatment Discontinuation of Long-Acting Glucagon-Like Peptide 2 (GLP-2) Analogues.
Short-bowel syndrome is the leading cause of pediatric intestinal failure, resulting in dependency on long-term parenteral nutrition (PN). To promote enteral autonomy in neonates, a key outcome may be intestinal growth in length. The purpose of this study was to determine if intestinal lengthening persists following discontinuation of treatment with 1 of 2 GLP-2 analogues with different pharmacokinetic profiles. Neonatal short-bowel piglets were assigned to saline control (S), 7-day treatment with teduglutide (T) (0.05 mg/kg twice daily), or 7-day treatment with apraglutide (A) (5 mg/kg twice weekly). Comparisons were made between day 7 and day 14 endpoints using analysis of variance. Data included small-intestine length, weight, histology, and quantitative polymerase chain reaction analysis of mucosal transcripts for peptide growth factors and their receptors, nutrient transporters, and tight-junction proteins. Compared with control, 7 days of GLP-2 analogue treatment induced mucosal adaptation based on villus hyperplasia (P = .003), which was not durable 7 days after treatment cessation (day 14; P = .081). Treatment increased intestinal growth in length by day 7 (P = .005), which was maintained (by T) or further increased (by A) at day 14 (P < .001). No significant differences in mucosal transcripts were detected. Unlike mucosal adaptation, intestinal growth appears to be a lasting outcome of treatment with long-acting GLP-2 analogues in a neonatal piglet short-bowel model. This has significant clinical implications for neonates, given their potential for intestinal growth. Intestinal lengthening varies between analogues with different half-lives; however, molecular mechanisms require further elucidation.


Aggressive approach in a case of cancer cervix with uremia.
Carcinoma of cervix is the most common cancer in developing countries. Majority of them present in locally advanced stages. A 36-year-old lady presented with bleeding and white discharge per vagina since four months, vomiting and reduced urine output since two weeks. Patient had an exophytic cervical growth. Investigation revealed elevated serum creatinine. Patient received single fraction radiation and underwent percutaneous nephrostomy. At one month follow-up, serum creatinine returned to almost normal level. Patient underwent bilateral ante grade stenting and completed concurrent chemoradiotherapy. In selected subsets of patients, aggressive management offered longer palliation and good quality of life.


Parallel Functionalization of DNA Origami.
DNA origami enables the creation of large supramolecular structures, with precisely defined features at the nanoscale. The concept thus naturally lends itself to the concept of molecular patterning, i.e., the positioning of molecular moieties and functional features. Creation of nanoscale patterns was already disseminated by Rothemund in 2006, in which DNA hairpins were used to produce nanoscale patterns on the flat origami canvases (Rothemund PWK, Nature 440(7082):297-302, 2006). For this type of application, it is often desired to produce multiple different patterns using the same origami canvas by reusing existing origami staple strands, rather than ordering new, custom oligonucleotides for each unique pattern. This chapter presents a method where the enzyme terminal deoxynucleotidyl transferase (TdT) is used in a parallelized reaction to add functional moieties to the end of a selected pool of unmodified staple strand oligonucleotides, which are then incorporated at precisely defined positions in the DNA origami canvas. Introducing arrays of functional features using this enzymatic functionalization of origami staple strands offers a very high degree of flexibility, versatility, and ease of use and can often be obtained faster than custom synthesis. For small synthesis scales, typically employed during initial functional screening of many different molecular patterns, the method also offers a significant advantage in terms of cost. During the past years, we have utilized this to incorporate a large variety of molecules including bulky proteins (Sørensen RS, Okholm AH, Schaffert D, Kodal ALB, Gothelf KV, Kjems J, ACS Nano 7:8098-8104, 2013) in designed patterns from modified nucleotide triphosphate (NTP) building blocks (Jahn K, Tørring T, Voigt NV, Sørensen RS, Kodal ALB, Andersen ES, Bioconjug Chem 22:819-823, 2011). The near-quantitative yields obtained by enzymatic functionalization allow synthesis of a large set of oligonucleotides in a one-pot reaction from commercial starting materials without the need for individual post-purification. Based on the chosen subset of staple strand, it is possible to create any designed functionality, array, or pattern. Here we describe the process going from an idea/design of a DNA origami-specific molecular pattern to nucleotide synthesis and subsequent parallel functionalization of the DNA origami, assembly, and the final characterization.


Early Substance Use Initiation And Psychological Distress Among Adolescents In Five ASEAN Countries: A Cross-Sectional Study.
The study aimed to assess the associations between substance use early initiation (<12 years) (smoking cigarettes, alcohol and drug use) with psychological distress among adolescents in five ASEAN countries. Cross-sectional data were analysed from 33,184 school adolescents, with a median age of 14 years, from Indonesia, Laos, Philippines, Thailand and Timor-Leste that took part in the "Global School-Based Student Health Survey (GSHS)" in 2015. The overall prevalence of pre-adolescent (<12 years) cigarette use was 10.6%, 8.1% pre-adolescent current alcohol use, and 4.2% pre-adolescent drug use initiation. In adjusted multinomial logistic regression analysis, pre-adolescent initiation of cigarette smoking, pre-adolescent initiation of alcohol use, pre-adolescent initiation of drug use and multi-substance pre-adolescent initiation were highly associated with medium (=1) and high (=2-5) psychological distress (of five psychological distress items: no close friends, loneliness, anxiety, suicidal ideation and suicide attempt). Late initiation of cigarette use and late initiation of drug use were not associated with medium and/or high psychological distress. Early prevention programmes should target concurrent early substance use initiation in order to prevent possible subsequent psychological distress.


Liver lipid metabolism in T-2 toxicosis. I. Effects of a single dose feeding of T-2 toxin to rats.
The acute effects of oral administration of a single dose of T-2 toxin (2.0 mg/kg body wt) to rats on whole liver lipid metabolism were studied at 8, 16 and 24 h post-treatment. Administration of T-2 toxin significantly increased liver and microsomal total lipids, free cholesterol, esterified cholesterol and triglycerides initially at 8 h, which subsequently returned to control values at 24 h. However, no significant alterations were observed in the contents of whole liver and liver microsomal total phospholipids and phosphatidyl choline, except that phosphatidyl ethanolamine and sphingomyelin + lysophosphatidyl ethanolamine contents in liver at 16 and 24 h and sphingomyelin + lysophosphatidyl ethanolamine content in liver microsomes at all three periods were significantly lower. The incorporation of 1-14C-acetate into whole liver and liver microsomal total lipids was reduced at 16 and 24 h post feeding. However, the incorporation of 1-14C-acetate into liver and microsomal free cholesterol, esterified cholesterol and triglycerides was significantly higher at 8 h, subsequently returning to the control value at 24 h; incorporation was significantly lower even into microsomal triglycerides. The incorporation of 1-14C-acetate into liver and its microsomal total phospholipids, phosphatidyl choline, phosphatidyl ethanolamine and sphingomyelin + lysophosphatidyl ethanolamine, was significantly decreased at all three periods post toxin treatment. The results suggested that T-2 toxin inhibited the incorporation of 14C-acetate mainly into liver and its microsomal phospholipids and their subfractions in rats.


The safety and efficacy of formoterol (Oxis) turbuhaler plus budesonide (Pulmicort) turbuhaler in mild to moderate asthma: a comparison with budesonide Turbuhaler alone and current non-corticosteroid therapy in Russia.
Current therapy in Russia for long-term management of asthma is mainly non-steroidal. This provided the opportunity to compare the efficacy and safety of formoterol (Oxis) Turbuhaler plus budesonide (Pulmicort) Turbuhaler with budesonide Turbuhaler alone in adults (n=338) with mild to moderate asthma who had little previous exposure to inhaled corticosteroids. The 12-week study followed a randomised, double-blind, parallel group design and included an open control group of patients who were treated with conventional non-corticosteroid therapy. Patients treated with formoterol plus budesonide benefited from a significantly greater improvement in their pulmonary function and asthma symptoms compared with budesonide alone (95% Cl of difference in mean morning peak expiratory flow [PEF] 8.7-36.3 l/min, p=0.0015). Non-corticosteroid treatment was significantly less effective than formoterol plus budesonide and budesonide alone (95% CIs of differences in mean morning PEF were 36.4-63.6 l/min and 14.1-41.1 l/min, respectively, both p=0.0001). Although the incidence and frequency of adverse events was not significantly different between the groups, formoterol plus budesonide and budesonide alone were better tolerated than non-corticosteroid treatment, and there were fewer incidences of asthma deterioration. Overall, formoterol Turbuhaler plus budesonide Turbuhaler was the safest and most effective treatment.


Patient's age modifies the impact of the proposed predictors of sustained virological response in chronic hepatitis C patients treated with PEG-interferon plus ribavirin.
The aim of this study was to investigate the effect of patient's age on the impact of typically proposed predictors of sustained virological response (SVR) in treatment-naïve, high-pretreatment viral load (>700.000 IU/ml), chronic hepatitis C (CHC) patients treated under real-life conditions in Greece. We retrospectively analyzed 185 CHC patients (14.4% cirrhotics) who had been treated with weight-adjusted dosing (1.5 microg/kg per week) of pegylated interferon-a2b (PEG) plus genotype-based ribavirin (RIB) for 24 or 48 weeks of treatment, based on viral genotype. SVR was confirmed by undetectable serum HCV-RNA 6 months after the end of treatment. Overall, 68.5% of patients exhibited SVR and 31.5% were non-responders (non-SVRs). Among the non-SVRs, 71.4% were infected with HCV genotype-1. Importantly, 71.4% of genotype 4-infected treated patients exhibited SVR. In the multivariate analyses, only the early histological stage of liver disease (p=0.015) and the presence of genotype non-1 infection (p=0.003) were independent predictors of SVR. For patients younger than 35 years, none of the baseline parameters and neither viral genotype (p=0.284) nor the stage of liver disease (p=0.351) was an independent predictor of non-SVR, whereas for patients between 35 and 55, only the presence of genotype-1 infection independently predicted non-SVR (p=0.008). For older patients (>55 years), only the histological stage of liver disease (p=0.047) and not the viral genotype (p=0.275) independently predicted non-SVR. The impact of the typical predictors of SVR, such as viral genotype and liver histopathology, is modified according to patient's age in currently approved combination treatment.


Effect of atorvastatin on AGEs-induced injury of cerebral cortex via inhibiting NADPH oxidase -NF-κB pathway in ApoE-/- mice.
Advanced glycation end products (AGEs) are a group of modified proteins and/or lipids with damaging potential. AGEs-RAGE pathway plays a critical role to induce neurodegenerative encephalopathy. Statins can reduce the expression of AGEs-induced AGEs receptor (RAGE) in the aorta. It is not clear whether statins have potential benefits on AGEs-induced cognitive impairment. In this study, the effects of atorvastatin (ATV) on inflammation and oxidation stress in the cerebral cortex were investigated, and the underlying mechanisms were explored. Apolipoprotein E (ApoE)-/- male mice were divided into four groups: control, AGEs, AGEs + ALT711 (Alagebrium chloride) and AGEs + ATV. β-amyloid (Aβ) formation in the cerebral cortex was assessed through Congo red staining and the functional state of neurons was evaluated by Nissl's staining. Immunostaining was performed to assess the accumulation of AGEs in the cerebral cortex. The expressions of mRNA and protein of RAGE, Nuclear factor kappa B (NF-κB) p65 and Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) p47phox were detected by real-time polymerase chain reaction (PCR) and western blot. There were significant increases in AGEs deposit, Aβ formation, and the expressions of RAGE, NF-κB p65, and NADPH oxidase p47phox, and a decrease Nissl body in AGEs group compared with control group. ALT711 group recovered above change compared with AGEs group. Atorvastatin reduced Aβ formation and suppressed AGEs-induced expressions of NF-κB p65 and NADPH oxidase p47phox. Atorvastatin has little effects on AGEs deposit and RAGE expressions. Atorvastatin alleviates AGEs-induced neuronal impairment by alleviating inflammation and oxidative stress via inhibiting NADPH oxidase-NF-κB pathway.


Laser fusion of selected dental casting alloys.
Laser-fused precious, nonprecious, and mixed metal welds were investigated for optimum weld energy requirement as determined by tensile strength tests. These strengths were compared to soldered unions. Laser fusion is as good as, or better than, unions created by conventional dental joining methods.


Renal tumor biopsy does not increase the risk of surgical complications of minimally invasive partial nephrectomy.
For patients with cT1 renal lesions, Partial Nephrectomy (PN) is the gold standard treatment. However, 20% of small renal masses are benign, situation in which the PN is an overtreatment. The percutaneous Renal Tumor Biopsy (RTB) may lower the risk of overtreatment as there is a 90% concordance rate on histotype between the RTB and the final pathology. It has been suggested that the RTB could increase the difficulty of the PN and increase the risk of surgical complications. To compare surgical outcomes and complications of PN with or without previous RTB. monocentric retrospective review of patients who underwent laparoscopic or robotic-assisted PN between January 2012 and December 2019. perioperative complications were recorded using Clavien-Dindo classification, peroperative data included operative time, clamping time and blood loss, and histological outcomes of RTB and PN. In total, 163 patients were included in our study. There were significantly less benign lesions in PN with prior RTB: 7% (4/56) vs. 20% (22/107) without prior RTB (P=0.03). There were no significant differences regarding Clavien-Dindo>2 perioperative complications with respectively 7% (4/56) vs. 10% (11/107) (P=0.57). Same goes for peroperative data such as duration of surgery (P=0.81), warm ischemia (P=0.07) and blood loss (P=0.13). RTB does not increase the risk of surgical complications of PN and may reduce the risk of small renal masses overtreatment.


Computational fluid dynamics of developing avian outflow tract heart valves.
Hemodynamic forces play an important role in sculpting the embryonic heart and its valves. Alteration of blood flow patterns through the hearts of embryonic animal models lead to malformations that resemble some clinical congenital heart defects, but the precise mechanisms are poorly understood. Quantitative understanding of the local fluid forces acting in the heart has been elusive because of the extremely small and rapidly changing anatomy. In this study, we combine multiple imaging modalities with computational simulation to rigorously quantify the hemodynamic environment within the developing outflow tract (OFT) and its eventual aortic and pulmonary valves. In vivo Doppler ultrasound generated velocity profiles were applied to Micro-Computed Tomography generated 3D OFT lumen geometries from Hamburger-Hamilton (HH) stage 16-30 chick embryos. Computational fluid dynamics simulation initial conditions were iterated until local flow profiles converged with in vivo Doppler flow measurements. Results suggested that flow in the early tubular OFT (HH16 and HH23) was best approximated by Poiseuille flow, while later embryonic OFT septation (HH27, HH30) was mimicked by plug flow conditions. Peak wall shear stress (WSS) values increased from 18.16 dynes/cm(2) at HH16 to 671.24 dynes/cm(2) at HH30. Spatiotemporally averaged WSS values also showed a monotonic increase from 3.03 dynes/cm(2) at HH16 to 136.50 dynes/cm(2) at HH30. Simulated velocity streamlines in the early heart suggest a lack of mixing, which differed from classical ink injections. Changes in local flow patterns preceded and correlated with key morphogenetic events such as OFT septation and valve formation. This novel method to quantify local dynamic hemodynamics parameters affords insight into sculpting role of blood flow in the embryonic heart and provides a quantitative baseline dataset for future research.


Thymoquinone protects against 5-Fluorouracil-induced mucositis by NF-κβ and HIF-1 mechanisms in mice.
Mucositis is among the most common side effects of 5-Fluorouracil (5-FU) and other cancer therapeutic drugs. Thymoquinone (TQ), a bioactive constituent extracted from Nigella sativa, has antioxidant and anti-inflammatory properties and can modify acute gastrointestinal injury. To investigate the effects of TQ on mucositis induced by 5-FU, studied animals were divided into four groups: control, 5-FU unit dose (300 mg/kg) to cause oral and intestinal mucositis (OM and IM), TQ (2.5 mg/kg) and TQ (2.5 mg/kg) plus 5-FU. Due to The molecular mechanisms, it was confirmed that the expression of NF-κβ and HIF-1 increases in OM. The serum levels of malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD), as well as pathological parameters, were assessed. Based on our results, the nuclear factor-kappa β gene expression in the tongue was downregulated significantly in the 5-FU + TQ compared to the 5-FU. TQ treatment can diminish MDA, and a reduction in oxidative stress was shown. TQ could also reduce the severity of tissue destruction and damaging effects induced by 5-FU on the tongue and intestine. We also observed lower villus length and width in the intestine of the 5-FU group compared to the control group. According to our research's pathological, biochemical, and molecular results, treatment with TQ as an anti-inflammatory and antioxidant compound may be the potential to improve and treat 5-FU-induced OM and IM, and TQ could be used against cancer treatment drugs and exhibit fewer adverse effects.


Frequency of bovine viral diarrhea virus (BVDV) in Argentinean bovine herds and comparison of diagnostic tests for BVDV detection in bovine serum samples: a preliminary study.
Bovine viral diarrhea (BVD) is a major worldwide disease with negative economic impact on cattle production. Successful control programs of BVD require the identification and culling of persistently infected (PI) animals with bovine viral diarrhea virus (BVDV). A variety of diagnostic tests are available to detect BVDV, but no comparison has been performed among those tests in Argentina. Sera collected from 2864 cattle, belonging to 55 herds from three Argentinean provinces, were analyzed by nested RT-PCR (RT-nPCR) to detect BVDV for diagnostic purposes. Additionally, this study evaluated the agreement of the RT-nPCR along with virus isolation, antigen-capture ELISA, and real-time RT-PCR for BVDV detection in archived bovine serum samples (n = 90). The RT-nPCR was useful for BVDV detection in pooled and individual serum samples. BVDV was detected in 1% (29/2864) of the cattle and in 20% (11/55) of the herds. The proportion of BVDV-positive sera was not statistically different among the tests. In addition, comparisons showed high agreement levels, with the highest values between both RT-PCR protocols. The frequency of BVDV infection at individual and herd level was lower than the reported values worldwide. Since follow-up testing was not performed, the frequency of PI cattle was unknown. Also, this study demonstrated that the four diagnostic tests can be used reliably for BVDV identification in individual serum samples. Further epidemiologically designed studies that address prevalence, risk factors, and economic impact of BVDV in Argentina will be necessary to implement effective control programs.


Muciliary transport in newt lungs: the ultrastructure of the ciliary apparatus in isolated epithelial sheets and in functional triton-extracted models.
High voltage and conventional electron microscopy were used to investigate the ultrastructure of the ciliary apparatus in intact and in Triton-extracted, reactivated sheets of mucociliary epithelium isolated from newt lung. Each long (about 13 microns) ciliary axoneme terminates on a barrel-shaped basal body which is anchored in the apical cytoplasm by a variety of accessory structures. A basal foot is associated with the midpoint of each basal body and acts as a focal point for numerous microtubules (MTs). In many cases MTs can be seen to interconnect the feet of neighbouring basal bodies. Attached to the proximal end of each basal body and extending in a direction opposite the basal foot is a large 'ciliary root'. Each ciliary root is associated with a distinct bundle of 6-7 nm microfilaments which appear to stain with the specific F-actin probe NBD-phallacidin. A single 3-4 microns long striated rootlet inserts into each ciliary root and extends toward the cell nucleus through an extensive network of microfilaments. At the level of the basal plate 'Y-shaped' structures appear to connect each axonemal outer doublet MT to the plasma membrane. All of these ciliary accessory structures are present in the same relationship in Triton-extracted models. Their morphology and distribution indicates that they serve to anchor the cilia in the apical cytoplasm. In addition some of these structures appear to be responsible for maintaining the structural and functional integrity of the ciliary field in the demembranated and reactivated models.


Beneficial effects of diclofenac therapy on serum lipids, oxidized low-density lipoprotein and antioxidant defenses in rats.
To study the effects of diclofenac, a nonselective nonsteroidal anti-inflammatory drug (NSAID), on lipid profile, oxidized low-density-lipoprotein (Ox-LDL), serum antioxidant defenses and markers of oxidative stress, male Wistar rats were divided into two groups (n=10): (C) receiving intramuscularly a single daily dose of saline (NaCl 0.9%), and (AI) receiving intramuscularly a single daily dose of 10 mg/kg diclofenac sodium (C14H10Cl2NNaO2). After 28 days diclofenac-treated rats had lower Ox-LDL, apoprotein B (apo-B), apo-B/LDL-cholesterol and lipid hydroperoxide than C. Total antioxidant substances and superoxide dismutase were increased in diclofenac-treated rats, while no significant changes were observed in catalase, glutathione peroxidase and nitric oxide. A perincubation test done to examine the possibility of mechanism-based activation showed that diclofenac had no effect on maximal superoxide dismutase velocity, but significantly reduced the Michaelis-Menten (KM) constant, indicating that diclofenac induced SOD activation increasing substrate linkage affinity to the enzyme-catalytic site. In conclusion, diclofenac had beneficial effects decreasing Ox-LDL and improving antioxidant defense. It appears that the application of this agent may be feasible and beneficial for serum antioxidant protection, which certainly would bring new insights on dyslipidemia control.


Amphiregulin activates regulatory T lymphocytes and suppresses CD8+ T cell-mediated anti-tumor response in hepatocellular carcinoma cells.
CD8+ T cell-mediated immune response plays an important role in inhibiting progression of hepatocellular carcinoma (HCC). For strategic immunotherapy, it is critical to understand why some of the tumor cells escape from this immune attack. In this study, we investigated how HCC cells alter endogenous anti-tumor immunity and their related signaling pathways. We found that HCC cells, both in vitro and in vivo, substantially secret and express amphiregulin (AR). AR in turn activates immunosuppressive function of intratumoral CD4+Foxp3+ regulatory T cells (Tregs), a major inhibitor of CD8+ T cells. Using either lentiviral siRNA, or AR neutralizing antibody, we blocked the expression and function of AR to test the specificity of AR mediated activation of Tregs, Biochemical and cell biology studies were followed and confirmed that blocking of AR inhibited Tregs activation. In addition, we found that AR can trigger the activation of rapamycin complex 1(mTORC1) signaling in Tregs. The mTORC1 inhibitor rapamycin treatment led to compromise Treg function and resulted in enhancing anti-tumor function of CD8+ T cells. Blocking AR/EGFR signaling in Tregs with Gefitinib also enhanced anti-tumor immunity and decreased tumor size in a mouse xenograft tumor model. Taken together, our study suggested a novel mechanism of functional interaction between HCC and Tregs for regulating anti-tumor function of CD8+ T cells.


Female infertility--effect of perinatal xenoestrogen exposure on reproductive functions in animals and humans.
Environmental chemicals with inherent estrogenic activity are supposed to be responsible for the decrease of quantity and quality of human sperms during the past 40 years. The current hypothesis is that estrogenic agents acting during fetal life may lead to impaired development of the testes and of the male reproductive tract in the human as well as in several wildlife species. However, from clinical and experimental data it is known, that estrogens may also lead to impairment of female reproductive functions. Perinatal application of DDT, octylphenol and benzylbutylphthalate resulted in persistent estrus in rats, in- and subfertility, respectively, and impaired sexual behaviour. Epidemiological and experimental data speak in favour of environmental estrogens to be one cause for the development of polycystic ovaries, being the most important reason for female infertility in the human.


On the mechanisms underlying cardiac standstill: factors determining success or failure of escape pacemakers in the heart.
The mechanisms underlying cardiac standstill in health and disease are considered. Ventricular standstill results from failure of impulse formation or transmission in the ventricles. In the healthy heart, idioventricular automaticity is not brought into play and instead is suppressed by the sinus node by virtue of its faster rate (overdrive suppression). However, should the sinus node activity be suppressed or atrioventricular (AV) conduction blocked, overdrive suppression no longer persists. For this reason, the ventricular pacemakers activate the ventricles at a slow rate and under the regulatory activity of the sympathetic system. In the diseased heart, the idioventricular pacemakers or the regulatory mechanism can be altered structurally or functionally. This can be the result of the disease, compensatory mechanisms or therapeutic interventions. Disease may affect the idioventricular pacemakers directly or indirectly through anoxia, a change in ionic environment or an alteration of sympathetic innervation. Compensatory mechanisms may affect reflex actions, blood supply or heart rate. Drug administration may alter autonomic balance, block the action of neuromediators on their receptors or modify diastolic depolarization or its ability to attain the threshold. Because of these different direct and indirect actions, a sudden cessation of sinus node activity or sudden AV block may result in the diseased heart in a prolonged and even fatal cardiac standstill, especially if the tolerance to ischemia of other organs (notably the brain) is decreased.


Celebrating 20 years of open access publishing at BMC Musculoskeletal Disorders.
Twenty years ago, on October 23, the first article published by BMC Musculoskeletal Disorders appeared free online. Over 5700 publications later, we celebrate our anniversary as the largest Open Access journal in the 'Orthopaedics and Sports Medicine' and 'Rheumatology' fields. Our 'open, inclusive, and trusted' ethos, along with our efficient and robust peer review services, are recognized by the musculoskeletal field.The early pioneers of BMC Musculoskeletal Disorders pushed the Open Access publishing model, in order to better support the needs of both the clinical and research communities. We pride ourselves on the continual innovation of author services, data transparency, and peer review models. These advances would not have been possible without your efforts - so a massive thank you to all the authors, editorial teams, and reviewers who have contributed to our success. Excellent reviewers are the nucleus of any thriving journal, and we have been lucky to collaborate with so many talents.


Evaluation of the anti-proliferative activity of three new pyrazole compounds in sensitive and resistant tumor cell lines.
In previous papers we demonstrated that the activity of short heteroretinoids as anti-proliferative and pro-apoptotic compounds was deeply linked to their heterocyclic moiety and that ionone-derived 1,5-pyrazoles had the highest anti-proliferative activity in our preliminary experiments. We then demonstrated the high and pharmacologically significant anti-proliferative and apoptotic activities of the pyrazole compounds 2-(1-(4-chlorophenyl)-1H-pyrazol-5-yl)-5-methoxyphenol (EN12-4), 5-methoxy-2-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)phenol (EN12-2A) and 2-(5-(4-methoxyphenyl)-1H-pyrazol-1-yl)pyridine (EN7-2) establishing, especially for EN12-2A, a possible mechanism of action involving the cell microtubular system. Here, the anti-proliferative activity of these pyrazole compounds was analyzed in vitro by the MTT assay in six drug-resistant cell lines, five of which were selected after exposure to increasing concentrations of cisplatin (L1210/DDP), doxorubicin (A2780/DX3), 5-fluorouracil (HCT-8/5FU), taxol (A549/T24) and etoposide (MCF-7/VP), and one was obtained by transfection of the ABCG2 membrane transporter (HEK-293/R2). Our data show that these compounds have a similar anti-proliferative activity in nearly all resistant and sensitive cell lines, demonstrating their ability to overcome the most common mechanisms of drug resistance with two exceptions regarding the MCF-7/VP cell line over-expressing the ABCC1 (MRP1) transporter, and the MDR1 over-expressing A2780/DX3 cells, with a calculated RI = 3.2 for EN12-2A, relative to their sensitive cellular counterpart. On the other hand, the taxol-resistant A549/T24 cell line showed a significantly increased sensitivity to our compounds. Our data suggest that our pyrazole compounds are able to overcome in vitro the most common drug-resistance mechanisms demonstrating a significant anti-proliferative activity and confirming a mechanism of action involving the depolymerization of microtubules.


An assessment of surgical and 10-year follow-up vertical changes after contemporary Class II and III orthognathic surgery.
There has been little quantification of long-term vertical facial changes that might occur after contemporary orthognathic surgery. The aim was to assess ≥10-year follow-up vertical facial changes in patients after Class II and III orthognathic surgery. Sequential lateral cephalograms of 162 former orthognathic patients had been gathered during routine clinical follow-up before any consideration was given to this current project. For this study, facial patterns were classified according to the Frankfort-mandibular plane and ANB angles and the horizontal distance from the pogonion to the nasion-perpendicular line. Chosen Class II and III groups were divided into longer and shorter-face subgroups on either side of the average FMP angle (longer face >25°). The assessment was made from already-available lateral cephalograms taken before treatment, at debanding, and ≥10-year clinical follow-up. After obvious improvement with orthodontics and orthognathic surgery, mean FMP angles seemed to move back toward the preexisting vertical dimensions in both Class II and III longer and shorter-face groups over the next decade. However, there was considerable individual variation around the means. Similar posttreatment changes were seen with the ANB angle and the distance from pogonion to the nasion-perpendicular line. Significant correlations were found between the amount of preexisting discrepancy for these variables and their changes during and after treatment. Significant planned vertical mandibular changes are achieved with Class II and III surgery. However, in the longer term, it would seem that, in general, there is a tendency for postsurgical vertical facial proportions to revert somewhat toward the pretreatment proportions. Wide individual variation in posttreatment musculoskeletal behavior should be expected. Despite these changes, it does not necessarily mean that there should be an expectation of long-term dentofacial collapse after such treatment.


Cellulolytic enzyme production and enzymatic hydrolysis for second-generation bioethanol production.
Second-generation bioethanol made from lignocellulosic biomass is considered one of the most promising biofuels. However, the enzymatic hydrolysis of the cellulose component to liberate glucose for ethanol fermentation is one of the major barriers for the process to be economically competitive because of the recalcitrance of feedstock. In this chapter, the progress on the understanding of the mechanisms of lignocellulose degradation, as well as the identification and optimization of fungal cellulases, cellulolytic strains, and cellulase production is reviewed. The physiologic functions and enzymatic mechanisms of two groups of enzymes involved in lignocellulose degradation, cellulases and hemicellulases, are discussed, and the synergism of the cellulase components during lignocellulose degradation is addressed. Furthermore, the methods for screening filamentous fungal strains capable of degrading lignocellulose are evaluated and the production of cellulases by these fungal strains is discussed. Aside from traditional mutagenesis for improving the secretion level and enzymatic activities of cellulases from filamentous fungal species, genetic engineering of strains and protein engineering on cellulase molecules are also highlighted.


Slowing of EEG correlates with CSF biomarkers and reduced cognitive speed in elderly with normal cognition over 4 years.
Cerebrospinal fluid (CSF) biomarkers and quantitative EEG show particular patterns of change in Alzheimer's disease (AD) and reflect neuropathologic processes and cerebral function, respectively. The changes precede cognitive decline and should be visible already in preclinical stages. We therefore aimed to investigate their relationship in cognitively healthy individuals. Thirty-three (33) elderly individuals with repeated normal scores on cognitive tests over 4.5 years underwent EEG recording with quantitative frequency analysis and analysis of CSF total tau (T-tau), phosphorylated tau (P-tau) and beta-amyloid(1-42) (Abeta42). CSF T-tau and P-tau correlated with relative EEG theta power (r(s)>0.545; p<0.01), but not with relative alpha, beta or delta power. The combined P-tau/Abeta42 ratio exhibited an even stronger correlation with relative theta power (r(s)=0.622; p<0.001), especially in the right posterior quadrant of the head (r(s)=0.643; p<10(-4)). Slowing of cognitive speed correlated with increased relative theta power, foremost in the posterior quadrants (r(s)>0.503; p<0.01), and high P-tau/Abeta42 ratio (r(s)>0.462; p<0.01). Our results suggest that already in cognitively healthy elderly subjects, biochemical changes in CSF, and the possible underlying neuropathologic processes it reflects, have an effect on cerebral function as visualized by the EEG rhythm and cognitive speed. It hereby suggests that CSF biomarkers and EEG theta activity might indicate early abnormal degenerative changes in the brain.


Fractionation and characterization of hemicelluloses from young bamboo (Phyllostachys pubescens Mazel) leaves.
Bamboo leaves are considered as an important source of bioactive molecules. In this work, leaves from young bamboo (Phyllostachys pubescens Mazel) aged 3 months were subjected to aqueous extraction and 2% NaOH solution extraction followed by precipitation in ethanol-water medium with different ethanol concentrations. The dissolved hemicellulosic polysaccharides presented a total recovery of 67.83% based on the total hemicellulose content in bamboo leaves. Chemical analysis of the fractions was performed by sugar composition analysis, Fourier-transform infrared spectrometry, and 1D nuclear magnetic resonance imaging. The results revealed that all polysaccharide fractions contained xylose, arabinose, glucose, galactose, ribose, and uronic acid. The polysaccharides from young bamboo leaves mainly consisted of arabinoxylans, arabinogalactans, and non-cellulosic β-D-glucans having (1→3)- and (1→4)-glucosidic linkages. The content of these polysaccharides was found to vary among the fractions depending on the separation method. Finally, the thermal behavior was also discussed.


A Scoping Review of Aging Experiences Among Culturally and Linguistically Diverse People in Australia: Toward Better Aging Policy and Cultural Well-Being for Migrant and Refugee Adults.
Australia's population is growing, aging, and becoming more ethnically diverse, resulting in barriers and challenges around social inclusion for non-English-speaking migrants and refugees. This scoping review investigates the experiences of aging within Australia among older adults from culturally and linguistically diverse (CALD) migrant and refugee backgrounds to identify barriers to social integration. A scoping review of English language literature and gray literature on the experiences of aging among CALD migrants and refugees living in Australia was conducted from January 2000 to January 2021, according to Arksey and O'Malley's review process. A total of 34 studies were identified for analysis. Three primary themes were identified: (a) sociocultural similarities in settlement experiences, (b) engagement with technology for social connection, and (c) engagement with family and community networks. Aging, language, sociocultural, and technology contexts shape attitudes to belonging, as well as access to sociomedical services. We argue a cultural well-being framework may assist in developing policy for improved social integration of older CALD adults. As the focus is on social and cultural experiences, all studies with a primary focus on medical and other chronic conditions were excluded. Future studies could include health-related articles to present a more comprehensive approach regarding older CALD adult needs. Follow-up research could focus on the impact of the coronavirus disease 2019 pandemic on the experiences of older adults in Australia, in particular those of CALD backgrounds.


Surviving "Payment by Results": a simple method of improving clinical coding in burn specialised services in the United Kingdom.
Coding inpatient episodes plays an important role in determining the financial remuneration of a clinical service. Insufficient or incomplete data may have very significant consequences on its viability. We created a document that improves the coding process in our Burns Centre. At Yorkshire Regional Burns Centre an inpatient summary sheet was designed to prospectively record and present essential information on a daily basis, for use in the coding process. The level of care was also recorded. A 3-month audit was conducted to assess the efficacy of the new forms. Forty-nine patients were admitted to the Burns Centre with a mean age of 27.6 years and TBSA ranging from 0.5% to 65%. The total stay in the Burns Centre was 758 days, of which 22% were at level B3-B5 and 39% at level B2. The use of the new discharge document identified potential income of about 500,000 GB pound sterling at our local daily tariffs for high dependency and intensive care. The new form is able to ensure a high quality of coding with a possible direct impact on the financial resources accrued for burn care.


Capillary electrophoresis-mass spectrometry for direct structural identification of serum N-glycans.
Through direct coupling of capillary electrophoresis (CE) to mass spectrometry (MS) with a sheathless interface, we have identified 77 potential N-glycan structures derived from human serum. We confirmed the presence of N-glycans previously identified by indirect methods, e.g., electrophoretic mobility standards, obtained 31 new N-glycan structures not identified in our prior work, differentiated co-migrating structures, and determined specific linkages on isomers featuring sialic acids. Serum N-glycans were cleaved from proteins, neutralized via methylamidation, and labeled with the fluorescent tag 8-aminopyrene-1,3,6-trisulfonic acid, which renders the glycan fluorescent and provides a -3 charge for electrophoresis and negative-mode MS detection. The neutralization reaction also stabilizes the labile sialic acids. In addition to methylamidation, native charges from sialic acids were neutralized through reaction with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium to amidate α2,6-linked sialic acids in the presence of ammonium chloride and form lactones with α2,3-linked sialic acids. This neutralization effectively labels each type of sialic acid with a unique mass to determine specific linkages on sialylated N-glycans. For both neutralization schemes, we compared the results from microchip electrophoresis and CE.


The electrophysiologic effects of oral cibenzoline.
Five male patients with chronic stable ventricular arrhythmias underwent a placebo controlled ascending dose study with oral cibenzoline, a new type 1 antiarrhythmic drug. Ambulatory ECG (Holter) recordings and electrophysiologic studies were done while on placebo and on the maximum dose of cibenzoline. Drug toxicity, manifested by vomiting and QRS widening, accompanied by very high serum cibenzoline concentrations, was seen in two patients. A major reduction (greater than 85% in ventricular premature beats occurred in three patients including two in whom only relatively low serum concentrations had been achieved. Cibenzoline caused significant increases in AH (97 +/- 26 vs. 110 +/- 23 msec, p less than 0.01) and HV (59 +/- 7 vs. 78 +/- 7 msec, p less than 0.02), a major but statistically not significant increase in QRS (99 +/- 12 vs. 128 +/- 27 msec, NS) but QT (38 +/- 2 vs. 38 +/- msec) and QTc (42 +/- 1 vs. 44 +/- 3 msec) were essentially unchanged, even in toxic patients. Cibenzoline had no consistant effect on sinus cycle length, sinus node recovery time, or the relative, functional or effective refractory periods of the atrium and AV node. We conclude that cibenzoline has potent type 1 effects in prolonging HV but may be unique in not affecting QT or QTc, even at toxic levels. Its effects upon AH were unexpected and warrant further study.


Closing in on Mass Production of Mature Human Beta Cells.
Human pluripotent stem cell differentiation protocols based on mimicking developmental pathways are getting close to generating fully fledged pancreatic endocrine cells, including insulin-producing beta cells. However, challenges remain in identifying pathways to trigger the attainment of robust glucose responsiveness that occurs postnatally in beta cells.


Prostate MR imaging at high-field strength: evolution or revolution?
As 3 T MR scanners become more available, body imaging at high field strength is becoming the subject of intensive research. However, little has been published on prostate imaging at 3 T. Will high-field imaging dramatically increase our ability to depict and stage prostate cancer? This paper will address this question by reviewing the advantages and drawbacks of body imaging at 3 T and the current limitations of prostate imaging at 1.5 T, and by detailing the preliminary results of prostate 3 T MRI. Even if slight adjustments of imaging protocols are necessary for taking into account the changes in T1 and T2 relaxation times at 3 T, tissue contrast in T2-weighted (T2w) imaging seems similar at 1.5 T and 3 T. Therefore, significant improvement in cancer depiction in T2w imaging is not expected. However, increased spatial resolution due to increased signal-to-noise ratio (SNR) may improve the detection of minimal capsular invasion. Higher field strength should provide increased spectral and spatial resolution for spectroscopic imaging, but new pulse sequences will have to be designed for overcoming field inhomogeneities and citrate J-modulation issues. Finally, dynamic contrast-enhanced MRI is the method of imaging that is the most likely to benefit from the increased SNR, with a significantly better trade-off between temporal and spatial resolution.


Modeling ion-exchange adsorption of proteins in a spherical particle.
This paper presents a simple model of single- and multicomponent protein adsorption in a spherical particle. The model includes radial diffusion of salt and protein in the liquid phase coupled to adsorption by an ion-exchange mechanism described by the steric mass action isotherm. The molecular diffusivities of the protein and salt are reduced in the model by a factor which accounts for the tortuous nature of the pores and pore constrictions. The model parameters are selected from published values in the chromatographic literature. Of particular interest are the observations of induced salt gradients during protein adsorption and of multicomponent displacement when more that one protein is adsorbed simultaneously. These results cannot be predicted on the basis of the traditional Langmuir isotherm or other currently available descriptions of adsorption. The use of such a model during stationary phase design is discussed.


X-ray radiography of HPGe detectors for Monte Carlo simulations.
The results of the development of a radiographic installation that allows to control the size of the internal elements of HPGe detectors' cryostats for simulation by Monte Carlo method, are presented. Calibration and assessment of image quality value of the developed radiographic installation were carried out in accordance with ISO Standards 19232-1 and 19232-5. Simulation of the HPGe detector's registration efficiency in the range of 50 keV-3 MeV with the MCC-MT program showed that the discrepancy between the calculated and experimental results when adjusting the detector model using radiological measurement data does not exceed 3% in geometry for point sources and 5% for the Eu-152 source in the Marinelli beaker geometry.


Structures of tau and α-synuclein filaments from brains of patients with neurodegenerative diseases.
Intracellular accumulations and aggregates of abnormal protein, consisting of amyloid-like fibrils, are common neuropathological features of many neurodegenerative diseases. The distributions and spreading of these pathological proteins are closely correlated with clinical symptoms and progression. Recent evidence supports the idea that template-mediated amplification of amyloid-like fibrils and intracellular propagation of fibril seeds are the main mechanisms by which pathological features spread along the neural circuits in the brain. Here, we review recent developments in the structural analysis of amyloid-like fibrils from brains of patients with various types of tauopathy and α-synucleinopathy, focusing on cryo-electron microscopy and mass analysis, and we discuss their relevance to the mechanisms of template-mediated amplification and intracellular propagation.


Estradiol and testosterone levels in patients undergoing partial hepatectomy. A possible signal for hepatic regeneration?
In five adult male patients undergoing a 40-60% partial hepatectomy, serum sex hormone levels before and after hepatic resection were determined. Blood was drawn immediately prior to each surgical procedure and at specified time points postoperatively. Compared to hormone levels found prior to surgery, following major hepatic resection, estradiol levels increase at 24 and 48 hr, while testosterone levels decline, being significantly reduced at 96 and 144 hr. These data demonstrate that adult males who undergo a 40-60% partial hepatectomy experience alterations in their sex hormone levels similar to those observed in male rats following a 70% hepatectomy. These changes in sex hormone levels have been associated in animals with an alteration of the sex hormone receptor status of the liver that is thought to participate in the initiation of the regenerative response. These studies suggest, but do not prove, that in man, as in the case of the rat, sex hormones may participate in the initiation of or at least modulate in part the regenerative response that occurs following a major hepatic resection.


The effect of process control on the incidence of central venous catheter-associated bloodstream infections and mortality in intensive care units in Mexico.
To ascertain the effect of an infection control program including process control on intensive care unit (ICU) rates of intravascular device (IVD)-associated bloodstream infection (BSI). Two level III adult ICUs in one public university hospital in Mexico: one medical surgical ICU and one neurosurgical ICU. POPULATION STUDY: All adult patients admitted to study units who had a central venous catheter (CVC) in place for at least 24 hrs. A prospective before/after trial in which rates of IVD-associated BSI are determined during a period of active surveillance without process control (phase 1) were compared with rates of IVD-associated BSI after implementing an infection control program applying process control (phase 2). Six hundred five IVD-days were accumulated in phase 1, and 2824 IVD-days were accumulated during phase 2. Compliance with CVC site care and hand hygiene improved significantly from baseline during the study period: placing a gauze dressing over the catheter insertion site (99.24% vs. 86.69%, respectively; relative risk [RR] = 1.14; 95% confidence interval [CI] = 1.07-1.22; p = .0000), proper use of gauze for vascular catheter insertion site (97.87% vs. 84.21%, respectively; RR = 1.16; 95% CI = 1.09-1.24; p = .0000), documentation of the duration of the administration set of the vascular catheter (93.85% vs. 40.69%, respectively; RR = 2.34; 95% CI = 2.14-2.56; p = .0000), and hand hygiene before contact with the patient (84.9% vs. 62%, respectively; RR = 1.37; 95% CI = 1.21-1.51; p = .0000). Overall rates of IVD-associated BSI were lowered significantly from baseline rates after implementation of process control (19.5 vs. 46.3 BSIs per 1000 IVD-days, respectively; RR = 0.42; 95% CI = 0.27-0.66; p = .0001). Overall rates of crude unadjusted mortality were lowered significantly from baseline rates (48.5% vs. 32.8% per 100 discharges, respectively; RR = 0.68; 95% CI = 0.50-0.31; p = .01). Implementation of an infection control program utilizing education, process control, and performance feedback was associated with significant reductions in rates of IVD-associated BSI and mortality.


Genome-directed discovery of antiproliferative bafilomycins from a deepsea-derived Streptomyces samsunensis.
Genomic bioinformatics analysis identified a bafilomycin biosynthetic gene cluster (named bfl) in the deepsea-derived S. samsunensis OUCT16-12, from which two new (1 and 2, named bafilomycins R and S) along with four known (3-6) bafilomycins were targetly obtained. The structure of 3 was clearly identified for the first time, thus named bafilomycin T herein. Differ from the fumarate substitution at C-21 of known bafilomycins, its location on C-23 is a unique feature of 1 and 2. The stereochemistry of the compounds was established based on NOE correlations, ketoreductase (KR)-types in PKS modules of bfl, and ECD calculations. Moreover, a detailed biosynthetic model of 1-6 in S. samsunensis OUCT16-12 was provided based on the gene function prediction and sequence identity. Compared with the positive control doxorubicin, 1-6 showed more potent antiproliferative activities against drug-resistant lung cancer cell line A549-Taxol, with IC50 values ranging from 0.07 μM to 1.79 μM, which arrested cell cycle in G0/G1 phase to hinder proliferation.


Context and goals: Suicide notes from a linguistic point of view.
The article is a critique of a study of language of suicide notes. It raises the issue of the acontextual approach to language and suggests that suicide notes and their language must be seen within the social context in which they are written. Moreover, the article challenges the assumption that suicide notes have only a representational function. Instead, it argues that they can serve a host of other communicative purposes.


Daily 2% chlorhexidine gluconate bath wash in a tertiary adult intensive care and high dependency units to reduce risk of hospital acquired multi resistant organisms: a best practice implementation project.
There is growing evidence that the incidence of hospital acquired multi resistant organisms are increasing worldwide. Intensive care patients are particularly prone to hospital-acquired infections. In an effort to combat increasing nosocomial infections rates within the intensive care/high dependency unit setting, Canberra Hospital has implemented a daily 2% chlorhexidine gluconate bath wash in combination as part of a best practice policy to reduce hospital acquired multi resistant organism rates of colonization. This project focused on auditing the extent to which the protocol was implemented and on promoting its implementation. The primary aim of this evidence implementation project was to promote best practice in the use of 2% chlorhexidine gluconate body cleansing in the Canberra Hospital intensive care unit and high dependency unit settings. A secondary aim was to improve intensive care/high dependency unit patient outcomes and resource utilization. The project used the Joanna Briggs Institute's Practical Application of Clinical Evidence System and Getting Research into Practice audit tools for promoting change in 2% chlorhexidine gluconate wash health practice. A baseline audit was conducted followed by a three-prong education approach strategy targeted at clinicians and finalized using a follow-up audit. There was an improvement in best practice for all criteria monitored in the follow-up audit compared to the initial audit. The most significant improvement was education and allergy assessment with 90% and 46% improvements respectively. Wipe application compliance improved by 28% to 55%, suggesting a need for continual education. Minor decreases in compliance were also noted in allergy documentation and application technique by 2% and 7% respectively. The project was successful in increasing knowledge surrounding 2% chlorhexidine gluconate wash administration and has provided a future direction for sustaining evidence-based practice change. Further audits will need to be carried out in order to maintain the practice change and support sustained implementation of the best practice protocol.