The Global Impact of the COVID-19 Pandemic on In-Center Hemodialysis Services: An ISN-Dialysis Outcomes Practice Patterns Study Survey.
To assess the impact of the COVID-19 pandemic impact on hemodialysis (HD) centers, The Dialysis Outcomes and Practice Patterns Study and ISN collaborated on a web-survey of centers. A combined approach of random sampling and open invitation was used between March 2020 and March 2021. Responses were obtained from 412 centers in 78 countries and all 10 ISN regions. In 8 regions, rates of SARS-CoV-2 infection were <20% in most centers, but in North East Asia (NE Asia) and Newly Independent States and Russia (NIS & Russia), rates were ≥20% and ≥30%, respectively. Mortality was ≥10% in most centers in 8 regions, although lower in North America and Caribbean (N America & Caribbean) and NE Asia. Diagnostic testing was not available in 33%, 37%, and 61% of centers in Latin America, Africa, and East and Central Europe, respectively. Surgical masks were widely available, but severe shortages of particulate-air filter masks were reported in Latin America (18%) and Africa (30%). Rates of infection in staff ranged from 0% in 90% of centers in NE Asia to ≥50% in 63% of centers in the Middle East and 68% of centers in NIS & Russia. In most centers, <10% of staff died, but in Africa and South Asia (S Asia), 2% and 6% of centers reported ≥50% mortality, respectively. There has been wide global variation in SARS-CoV-2 infection rates among HD patients and staff, personal protective equipment (PPE) availability, and testing, and the ways in which services have been redesigned in response to the pandemic.


Hepcidin destabilizes atherosclerotic plaque via overactivating macrophages after erythrophagocytosis.
To explore a direct and causal relationship between vascular hepcidin and atherosclerotic plaque stability. Accelerated atherosclerotic lesions were established by perivascular collar placement in apolipoprotein E-deficient (ApoE(-/-)) mice. Adenoviral overexpression of hepcidin in the carotid artery during plaque formation enhanced intraplaque macrophage infiltration and suppressed the contents of collagen and vascular smooth muscle cells, whereas hepcidin shRNA treatment exerts opposite effects. The overexpression or knockdown of hepcidin did not affect plaque lipid deposition but increased or decreased oxidized low-density lipoprotein (ox-LDL) levels within intraplaque macrophages. In cultured macrophages, ox-LDL not only increased reactive oxygen species formation, inflammatory cytokine production, and apoptosis but also upregulated hepcidin expression. However, hepcidin did not exaggerate the ox-LDL-induced activation of macrophages until an onset of erythrophagocytosis. Whereas hepcidin was critical for the upregulation of L-ferritin and H-ferritin in both ox-LDL-treated erythrophagocytosed macrophages and atherosclerotic plaques, the adding of iron chelators suppressed the intracellular lipid accumulation, reactive oxygen species formation, inflammatory cytokine expression, and apoptosis in erythrophagocytosed macrophages. Hepcidin promotes plaque destabilization partly by exaggerating inflammatory cytokine release, intracellular lipid accumulation, oxidative stress, and apoptosis in the macrophages with iron retention.


Inoculation of BALB/c mice with fish-pathogenic nodaviruses.
To investigate the pathogenicity of fish-pathogenic nodaviruses (betanodaviruses) in mammals, weanling mice were inoculated with striped jack nervous necrosis virus (SJNNV; the type species of the genus Betanodavirus) or redspotted grouper nervous necrosis virus (RGNNV), which belong to different genotypes. After inoculation with 10(7.5) TCID50, either intramuscularly or intraperitoneally, mice remained clinically normal for the 14-day observation period. In a subsequent short-term (72 h) experiment, mice inoculated intramuscularly with 10(7.5) TCID50 yielded virus (10(6) to 10(5) TCID50/g) from muscle at the site of injection at 3, 24 and 72 h post-infection; they also yielded virus from the kidneys (10(5) TCID50/g) at 3 and 24 h post-infection, but by 72 h virus had become almost undetectable at this site. Throughout the experiment, no virus was detected in the sites that are target organs of betanodaviruses in fish, namely, the brain, spinal cord and eye. The results indicate that the mouse is not susceptible to betanodaviruses.


Reinterpretation of the results of a pooled analysis of dietary carotenoid intake and breast cancer risk by using the interval collapsing method.
A pooled analysis of 18 prospective cohort studies reported in 2012 for evaluating carotenoid intakes and breast cancer risk defined by estrogen receptor (ER) and progesterone receptor (PR) statuses by using the "highest versus lowest intake" method (HLM). By applying the interval collapsing method (ICM) to maximize the use of the estimated information, we reevaluated the results of the previous analysis in order to reinterpret the inferences made. In order to estimate the summary effect size (sES) and its 95% confidence interval (CI), meta-analyses with the random-effects model were conducted for adjusted relative risks and their 95% CI from the second to the fifth interval according to five kinds of carotenoids and ER/PR status. The following new findings were identified: α-Carotene and β-cryptoxanthin have protective effects on overall breast cancer. All five kinds of carotenoids showed protective effects on ER- breast cancer. β-Carotene level increased the risk of ER+ or ER+/PR+ breast cancer. α-Carotene, β-carotene, lutein/zeaxanthin, and lycopene showed a protective effect on ER-/PR+ or ER-/PR- breast cancer. The new facts support the hypothesis that carotenoids that show anticancer effects with anti-oxygen function might reduce the risk of ER- breast cancer. Based on the new facts, the modification of the effects of α-carotene, β-carotene, and β-cryptoxanthin should be evaluated according to PR and ER statuses.


Flow behavior of periodical electroosmosis in microchannel for biochips.
This paper presents an analytical solution for periodical electroosmotic flows in two-dimensional uniform microchannel based on Poisson-Boltzmann equations for electric double layer (EDL) and Navier-Stokes equation for incompressible viscous fluid. Analytical results indicate that the velocity of periodical electroosmosis strongly depends on Reynolds number Re=omegah(2)/nu, as well as on EDL properties and applied electric field. Slip velocity of EDL decreases as the Reynolds number increases. Electroosmotic velocity outside the EDL decreases, and lag phase angle of velocity increases as distance away from the channel wall increases. A wavelike velocity profile across the channel is found. An asymptotic solution for low Reynolds number is given in this paper. Periodical electroosmosis with low Reynolds has same velocity amplitude and a pluglike velocity profile as that of steady electroosmosis. Based on Debye-Hückel approximation, this paper also obtains a solution of periodical electroosmosis applicable to cases where the thickness of EDL is of the same order as half of channel width.


A novel clinically-oriented classification of fine-needle aspiration cytology for salivary gland tumors: a 20-year retrospective analysis of 1175 patients.
When determining treatment strategy for a salivary gland tumor, assessing histology and malignancy grade before surgery is essential. Several new diagnostic classification systems for salivary gland cytology have recently been proposed. However, none incorporate histology and grade of malignancy. We developed a new cytology classification system that incorporates histology and grade of malignancy of salivary gland tumors (OMC classification), consisting of 11 categories. Our OMC classification was applied to 1175 patients who had preoperative cytology and confirmed final pathological diagnosis available from the past 20 years at our hospital (benign tumor: 981 patients, malignant tumor: 194 patients). Based on the cytology, 729 patients (62.0%) had benign histology (Category 4-1), and 87 patients (7.4%) were diagnosed with grade of malignancy (Category 6-3 + 6-4). Based on the final pathological diagnosis, the accuracy rate of Category 4-1 and Category 6-3 + 6-4 of our classification system was 93.4% and 88.5%, respectively. Based on the correct diagnosis rate, the inclusion of histology and grade of malignancy in the salivary gland cytology classification was considered feasible. Thus, the OMC classification system is considered a useful tool when determining the treatment strategy for a salivary gland tumor.


Nephronophthisis with massive proteinuria.
A 23-year-old male whose uncle died of nephronophthisis, and whose pathology is also discussed, presented with 5 g of protein in a 24-hour urine collection. Nephrogenic diabetes insipidus and salt wasting were present in addition to azotemia. Characterization of the proteinuria, including elevated alpha globulins by electrophoresis and markedly elevated urinary beta-microglobulins by radioimmunoassay (49.55 mg/L) indicated predominantly tubular proteinuria. A percutaneous renal biopsy showed normal glomeruli, interstitial inflammation and fibrosis, and tubular atrophy. Electron microscopy revealed notable alterations of the tubular basement membrane.


Sonographic determination of renal volumes in normal neonates.
Renal diseases that affect renal size without altering renal architecture require a quantitative means of detection. A prospective study was undertaken to establish normal values for renal volumes in healthy neonates using sonography. Volumes were determined by two methods; (1) the serial area-volume method using parallel transverse images; and (2) the prolate ellipsoid model of the kidney using orthogonal diameters taken from ultrasound images. Renal volumes for both the right and left kidneys in both sexes were found to be approximately 10 ml. There was no significant difference between the results obtained by either method, nor were there significant differences between the volumes of the right and left kidneys within either sex. No difference in renal volume was noted between sexes. The mean greatest renal length was also computed for right and left kidneys in both sexes. Knowledge of normal renal volumes may aid in the diagnosis of urinary system disorders in neonates.


Simultaneous M-mode echoesophagram and manometry in the sheep esophagus.
We report the simultaneous measurement of esophageal wall layer thickness and intraluminal pressure in the sheep esophagus using a miniature suction device incorporating a high-frequency ultrasound transducer and a manometry system. Transnasal placement of the device into the distal esophagus of a conscious sheep allowed observation of 133 swallowing events during three trials, each lasting from 45 to 60 minutes. In a fourth trial, 11 sequential dry and 23 sequential wet swallows were compared. Maximum manometric pressure, esophageal wall layer thickness, and duration of contraction were measured. All swallowing events produced simultaneous increases in intraluminal pressure and esophageal wall thickness. Mean maximal pressures were lower for dry swallows (18 +/- 2.1 mm Hg) than wet swallows (22 +/- 3.0 mm Hg) (p < .01). Thickness of the inner (circular) muscle layer increased above baseline by 124% for dry swallows and 161% for wet swallows (p < .01). We conclude that thickening of the esophageal inner (circular) muscle layer may be important in the generation of intraluminal esophageal pressure in the sheep esophagus.


Temporal variations of PM2.5 in the ambient air of a suburban site in Athens, Greece.
Twenty-three hour measurements of PM(2.5) particulate matter have been carried out during the period between the 1st April and the 13th November 2003 in a suburban area of Athens. The monitoring site was located in the National Research Center "DEMOKRITOS", on the foot of Hemittos Mountain and about 12 km away from the center of Athens. The site covers an area of 600 acres in a forest of pine trees close enough to the newly constructed Hemittos Mountain peripheral highway. PM(2.5) samples were collected on 47 mm filters, with the use of low volume gravimetric samplers while a meteorological station recorded meteorological data 6 m above the ground, nearby the sampling instrumentation. The daily average PM(2.5) concentration reached 21.1 microg m(-3) and all measurements were below U.S. Environmental Pollution Agency daily limit (65 microg m(-3)). A regression analysis was used to investigate the relationship among PM(2.5) concentrations and meteorological parameters. Additionally, PM(2.5) mass concentrations were correlated with other inorganic gaseous pollutants (O(3), NO, NO(2), SO(2)) while weekly and seasonal PM(2.5) variations were also investigated.


Microplastic serves as a potential vector for Cr in an in-vitro human digestive model.
Microplastics (MPs), polymer particles capable of adsorbing heavy metals from ambient environment, have been found in diverse human food resources. Through the consumption of MPs, heavy metals adsorbed on MPs might be transported into human body. This study aims to explore the behavior of heavy metal-contaminated MPs in human digestive system which is not previously researched. Firstly, a chromium (Cr) adsorption/desorption study was conducted with four commonly used nondegradable MPs [polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) and polystyrene (PS)] as well as one degradable MP (polylactic, PLA). Then, the whole digestive system in-vitro method (WDSM), a systematic model including mouth, gastric, small intestine, and large intestine digestive phases, was conducted on the Cr-loaded MPs. Additionally, the bioaccessibilities and hazard quotients (HQs) of Cr(VI) and Cr(III) were evaluated. Among five MPs, although PLA showed the weakest adsorption capacity for Cr, the Cr(VI) bioaccessibilities for PLA reached the highest values of 19.9%, 15.6% and 3.9% in gastric, small intestinal and large intestinal phases, respectively. The bioaccessibilities of Cr(VI) in gastric phase were significantly higher than those in other phases, while no Cr release from MPs was detected in the mouth phase. In gastric phase, the bioaccessibilities of Cr(VI) were significantly higher than those of Cr(III) in the gastric phase, and both of them approached to a similar level in intestinal phases. In the WDSM, the HQs of Cr(VI) and Cr(III) on MPs were lower than the critical level for both adults and children. Based on the measured bioaccessibilities, the maximum daily total Cr intake for different human groups (female children, male children, female adults and male adults) through MP consumption was estimated from 0.50 to 1.18 μg/day. In general, the five tested MPs were potential to serve as Cr vectors in the WDSM.


Application of modified supercritical carbon dioxide extraction to microbial quinone analysis.
Supercritical carbon dioxide (scCO2) was applied to extract microbial quinones from activated sludge. Identification and analysis was then performed using high-performance liquid chromatography (HPLC) equipped with ultraviolet-visible (UV-Vis) detector and photodiode array detector (PDA). Extracted microbial quinones were trapped and separated as menaquinones (MK) and ubiquinones (Q) species using two Sep-Pak Plus Silica cartridges joined in series. Four ubiquinones and 12 menaquinones species were identified in 0.1 g dried activated sludge based on retention time and spectrum analysis. Among the tested various polar solvents, methanol showed to be the best modifier, based on the highest total quinone content extracted and the lowest dissimilarity index. The diversity index of quinone and the number of quinone species using methanol-modified scCO2 were similar to that of the conventional method (organic solvent extraction).


Alleles of the major histocompatibility complex play a role in the pathogenesis of pancreatic acinar atrophy in dogs.
Exocrine pancreatic insufficiency (EPI) is a disease wherein pancreatic acinar cells fail to synthesize and secrete sufficient amounts of digestive enzymes for normal digestion of food. EPI affects many dog breeds, with a dramatically higher prevalence in the German shepherd dog (GSD) population. In this breed and perhaps others, EPI most often results from degeneration of the acinar cells of the pancreas, a hereditary disorder termed pancreatic acinar atrophy (PAA). Evidence of lymphocytic infiltration indicates that PAA is an autoimmune disease, but the genetic etiology remains unclear. Data from global gene expression and single nucleotide polymorphism profiles in the GSD suggest the involvement of the major histocompatibility complex [MHC; dog leukocyte antigen (DLA)]. To determine if alleles of the MHC influence development of EPI, genotyping of polymorphic class I (DLA-88) and II loci (DLA-DRB1, DLA-DQA1, and DLA-DQB1) was carried out for 70 affected and 63 control GSDs, and four-locus haplotypes were determined. One haplotype containing a novel allele of DLA-88 is very highly associated with EPI (OR > 17; P = 0.000125), while two haplotypes were found to confer protection from EPI (P = 0.00087 and 0.0115). Described herein is the genotyping of MHC class I and II loci in a GSD cohort, establishment of four-locus haplotypes, and association of alleles/haplotypes with EPI.


First-In-Human Phase 1 Study of a Nonwoven Fabric Bioabsorbable Spacer for Particle Therapy: Space-Making Particle Therapy (SMPT).
Surgical spacer placement (SSP) is useful in particle therapy (PT) for patients with abdominal or pelvic tumors located adjacent to normal organs. We developed a nonwoven fabric bioabsorbable spacer made of polyglycolic acid (PGA) sutures that degrades via hydrolysis. We then conducted this first-in-human phase 1 study of the combination of SSP and PT using the PGA spacer, which we termed space-making PT (SMPT). This study aimed to evaluate the safety and efficacy of SMPT in patients with unresectable malignant tumor located adjacent to normal organs. The eligibility criteria included histologically proven malignant abdominal or pelvic tumor adjacent to the intestines, no metastasis, and no previous radiation therapy. Periodic computed tomography (CT) images were obtained before SSP and before, during, and after PT until the spacer disappeared. Treatment planning was performed for each CT image set until the end of PT, and doses for the planning target volume and organs at risk were analyzed. The thickness and volume of the PGA spacer were measured in each CT image set. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. Five patients were enrolled in this study. All patients received 70.4 Gy (relative biological effectiveness) of irradiation. V95% of the planning target volume before SSP, at the beginning of PT, and at the end of PT was 82.1% ± 11.3%, 98.1% ± 1.1%, and 97.1% ± 0.8%, respectively. The PGA spacers maintained enough thickness (≥1 cm) until the end of PT and disappeared within 8 months after SSP in all patients. No grade ≥3 acute adverse events were observed. The SMPT is feasible and useful for abdominal or pelvic tumors adjacent to the intestines. This method may be applicable to unresectable tumors located adjacent to normal organs and may expand the indications of PT.


"Exterritorial" lymphocytic hypophysitis within an ovarian teratoma during pregnancy: a possible sentinel lesion?
Pituitary tissue is rarely to be found among the constituents of ovarian teratomas (dermoid cysts). In some exceptional cases, however, such ectopic pituitary anlagen may even give rise to secondary organ-specific pathologies. Akin to those of the pituitary in its natural location, these tend to be adenomas. We describe a unique example of lymphocytic hypophysitis incidentally encountered in a mature left ovarian teratoma from a 30-year-old woman in the 19th week of pregnancy. Amidst various fully differentiated derivatives of all three embryonic layers, the cyst wall also included a miniature replica of the anterior pituitary lobe 0.5 cm in diameter. While a full set of adenohypophyseal hormone-producing cell types could be identified, there was characteristic pregnancy-related hyperplasia of lactotrophs. This was further overlaid by prominent mononuclear inflammation, including infiltration by T lymphocytes, follicular aggregates of B cells, and attendant destruction of parenchyma. There was no significant inflammatory reaction elsewhere. Discounting the non-standard location, the ensemble of the clinical setting and histology were felt to be indistinguishable from the classical paradigm of lymphocytic hypophysitis complicating pregnancy. To date, lymphocytic thyroiditis is the sole form of organ-specific inflammatory process within an ovarian teratoma on record. By analogy, we hypothesize that this ectopic manifestation of immune-mediated inflammation of pituitary parenchyma may possibly be read as a preclinical sentinel lesion of lymphocytic hypophysitis.


Radiotherapy versus radiotherapy combined with temozolomide in high-risk low-grade gliomas after surgery: study protocol for a randomized controlled clinical trial.
It has been reported that radiation therapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy could improve progression-free survival (PFS) and overall survival (OS) in patients with high-risk World Health Organization (WHO) grade 2 gliomas after surgery. However, procarbazine is not available in China. In clinical practice, Chinese doctors often use radiotherapy combined with temozolomide (TMZ) to treat these patients, although large-scale prospective studies are lacking. This trial aims to confirm whether RT combined with temozolomide can improve PFS and OS in high-risk patients with low-grade gliomas (LGGs). This is a two-group, randomized controlled trial (RCT) enrolling patients who have LGGs (WHO grade 2) and are aged 40 years or older without regard to the extent of resection or are aged younger than 40 years old with subtotal resection or biopsy. An estimated 250 patients will be enrolled. Eligible participants will be randomly assigned to receive RT alone or RT plus TMZ chemotherapy in a 1:1 ratio. The same RT will be given to all eligible participants regardless of whether they are randomly assigned to the RT group or the chemoradiotherapy (CRT) group. While in the CRT group, patients will receive adjuvant TMZ with or without concurrent radiochemotherapy. The primary outcome of this trial is PFS, and it will be analyzed by the intention-to-treat approach. Secondary outcomes include OS, adverse events, and cognitive function. The objective of our research is to assess the effect of radiotherapy coupled with TMZ in high-risk patients with LGGs after surgery, compared with RT alone. Different histological types and molecular subtypes will be examined, and a corresponding subgroup analysis will be conducted. Our data can provide evidence for postoperative adjuvant therapy in patients with high-risk LGGs in China. Chinese Clinical Trial Registry, ChiCTR1800015199. Registered on 13 March 2018.


Neural networks and nonlinear regression modelling and control of depth of anaesthesia for spontaneously breathing and ventilated patients.
Various attempts have been made to control the depth of anaesthesia by observing different variables. In some studies, depth of anaesthesia has been correlated with inferential parameters and the control has been made through these inferred parameters. No single system has been reported which provides a fully developed architecture to control the depth of anaesthesia. This study is concerned with the development of controllers and patient models via Artificial Neural Networks and regression analysis. Two types of data sets were used for the training and development of models and controllers. The first set was for spontaneously breathing and the second set for ventilated patients. All of the controllers and patient models gave satisfactory results when tested individually. Later these two sets of controllers and patient models were studied in closed-loop modes. The robustness to the sensitivity of the regression patient model was also investigated. Various tests were performed with these closed-loop situations. Results and performance of these tests are discussed in the paper.


Emotional responding to hyperventilation as a predictor of agoraphobia status among individuals suffering from panic disorder.
Some data suggest that panic patients with extensive agoraphobia (PDA) display more intense respiratory distress during their panic attacks than Panic disorder (PD) patients. However, no studies have determined if PDA patients also show heightened sensitivity to a respiratory challenge compared to PD patients. The current study examined the differential emotional responding to hyperventilation among PDA patients, PD patients, and a non-clinical group with a history of panic attacks. Response to hyperventilation challenge did not distinguish non-clinical panickers from panic patients; however, behavioral tolerance to hyperventilation challenge significantly predicted agoraphobia status among panic disorder patients, even after controlling for demographic and clinical status variables.


Diagnostic Test Accuracy of First-Void Urine Human Papillomaviruses for Presence Cervical HPV in Women: Systematic Review and Meta-Analysis.
First-void urine usually contains exfoliated cells of the debris and mucus from the female genital organs and cervix, i.e., high concentration of human papillomavirus deoxyribonucleic acid (HPV DNA). We conducted a meta-analysis of published data and determined an accuracy of HPV detection in first-void urine compared to the women's cervix. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we carried out a comprehensive literature search. Eligible articles published from 2011 until 2021 were gathered by searching Embase, PubMed and Cochrane Library Central databases. The patient selection, index test, standard test, and patient flow were the factors involved in quality evaluation. A meta-analysis of 15 studies (3412 women) based on 5054 potential records was conducted. Pooled sensitivity for high-risk HPV detection in urine of 78% (70-84%) and specificity of 89% (81-94%) were calculated. Any HPV detection in urine of 87% (74-94%) and 91% (83-96%) were pooled sensitivity and specificity, respectively. HPV 16 and 18 had a pooled sensitivity of 77% (76-77%) and specificity of 98% (98-98%). Meta-analysis indicated variations between the pooled specificities and sensitivities. In meta-regression analysis, a heterogeneity in accuracy by using covariates (bias in patient selection, purpose, sample timing, storage temperature and HPV detection method) were not detected. Our meta-analysis demonstrates the accuracy of detection of HPV in urine for the presence of cervical HPV. Although progress is continuously made in urinary HPV detection, further studies are needed to evaluate and to improve the accuracy of the first-void urine test in order to be comparable with other screening methods.


Effect of temporal and nasal unsutured limbal tunnel incisions on induced astigmatism after phacoemulsification.
To compare the surgically induced corneal astigmatism after unsutured temporal and nasal unsutured limbal tunnel incisions. Departments of Ophthalmology, Marienhospital, Aachen, and Johann Wolfgang Goethe-University, Frankfurt am Main, Germany. In a prospective clinical study, 42 eyes of 21 patients with a mean age of 75.1 years had phacoemulsification and implantation of a foldable hydrophobic acrylic intraocular lens using a 3.6 to 3.8 mm unsutured limbal tunnel incision. The right eye always received a temporal incision and the left eye, a nasal incision. Computerized videokeratography was performed preoperatively and 2 weeks and 6 months postoperatively. Surgically induced astigmatism was calculated by vector analysis using the Holladay-Cravy-Koch formula. The 2 groups were compared using a paired Wilcoxon test. The mean surgically induced corneal astigmatism in the temporal incision group was 0.62 diopters (D) +/- 0.48 (SD) 2 weeks postoperatively and 0.47 +/- 0.32 D at 6 months and in the nasal incision group, 1.55 +/- 0.84 D and 1.05 +/- 0.57 D, respectively. The difference between the groups was statistically significant (P <.05). There was a highly statistically significant difference in surgically induced corneal astigmatism after temporal and nasal unsutured limbal tunnel incisions. The degree of induced astigmatism and the difference between the temporal and the nasal incisions decreased over time. A nasal tunnel incision is not appropriate for astigmatism-neutral surgery.


Reimplantation approach for an anomalous aortic origin of the right coronary artery with an aberrant right subclavian artery.
Anomalous aortic origin of the right coronary artery is a rare disease. Although there are various reports on its treatment, the method of the surgical approach is still controversial. Here, we present a rare case of a 17 year-old man who had an anomalous aortic origin of the right coronary artery with an aberrant right subclavian artery. As a treatment, he underwent reimplantation of the right coronary artery. The surgical approach for the anomalous aortic origin of the right coronary artery should be selected by considering the age of the patient and size of the right coronary artery.


Design and syntheses of novel N'-((4-oxo-4H-chromen-3-yl)methylene)benzohydrazide as inhibitors of cyanobacterial fructose-1,6-/sedoheptulose-1,7-bisphosphatase.
Cyanobacterial fructose-1,6-/sedoheptulose-1,7-bisphoshatase (Cy-FBP/SBPase) is an important target enzyme for finding inhibitors to solve harmful algal bloom (HAB). In this study, as potential inhibitors of Cy-FBP/SBPase, a series of novel chromone-connecting benzohydrazone compounds (Novel N'-((4-oxo-4H-chromen-3-yl)methylene)benzohydrazide) were designed and synthesized. Their inhibitory activities against Cy-FBP/SBPase were further examined in vitro. Some of these compounds, such as f6-f8, f11, f12 and f16, exhibit higher inhibitory activities (IC50=11.2-16.1 μM), especially, the compound f7 was identified as the most potent inhibitor with IC50 value of 11.2 μM. The probable binding-mode of compound f7 was further analyzed carefully by molecular docking methods. These results indicate that compound f7 could be used as a lead compound for further optimization and might have potential to be developed as a new algicide.


Exogenous l-arginine reduces matrix metalloproteinase-2 and -9 activities and oxidative stress in patients with hypertension.
Increased matrix metalloproteinases activity and reduced nitric oxide (NO) bioavailability contributes to development of hypertension and this may be associated with a defective l-arginine-NO pathway. Exogenous l-arginine improves endothelial function to prevent the onset of cardiovascular disease, but the mechanism by which this is accomplished remains unclear. We determined the effects of exogenous l-arginine infusion on vascular biomarkers in patients with hypertension. Venous blood samples were obtained from seven patients with hypertension (45±5yrs., HT group) and eleven normotensive men (37±3yrs., CT group) before and during a 30-min intravenous l-arginine or saline infusion. Nitrite concentration was evaluated by ozone-chemiluminescence method; metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) activities were detected by zymography; tissue inhibitor of metalloproteinases-1 (TIMP-1) and 8-isoprostane concentrations were measured by enzyme-linked immunosorbent assay (ELISA); and thiobarbituric acid reactive substances (TBARS) were determined by colorimetric assay. At baseline, nitrite, TIMP-1, and MMP-2 activity were similar between the groups (P>0.05), but MMP-9, TBARS and 8-isoprostane were higher in HT group (P≤0.03). During l-arginine infusion, nitrite increased only in control group (P=0.01), while MMP-2, MMP-9 activities, MMP-9/TIMP-1 ratio and 8-isoprostane decreased in HT group (P≤0.02). There were no significant changes in vascular biomarkers between groups during the saline infusion (P>0.05). Exogenous l-arginine diminished metalloproteinase-2 and -9 activities and MMP-9/TIMP-1 ratio along with restoring the oxidative stress balance in patients with hypertension.


Familial aggregation in chronic obstructive pulmonary disease: use of the loglinear model to analyze intermediate environmental and genetic risk factors.
To examine the contribution of environmental and genetic risk factors to familial aggregation in chronic obstructive pulmonary disease (COPD), 325 first-degree (1d) relatives and 56 spouses of 150 COPD patients were compared with 222 1d relatives and 49 spouses of 107 nonpulmonary patient controls for the prevalence of two clinical outcomes: 1) airways obstruction (AO; 1-sec forced expiratory volume less than 68% of forced vital capacity) and 2) chronic bronchitis (CB; cough and sputum for 3+ months per year for 2+ years). The loglinear model was used to study direct and indirect (ie, those mediated by other risk factors) components of familial aggregation. Three risk factors were found to be independently associated with CB and/or AO: alpha 1-antitrypsin deficiency (PiZ allele), personal cigarette smoking, and parental cigarette smoking. Because 1d relatives of COPD patients were more likely to have a PiZ allele, be heavy smokers (1+ packs per day), and be exposed to parental smoking than 1d relatives of controls, these three factors also constitute indirect components of familial aggregation. However, after controlling for the three factors, 1d relatives of COPD patients were more likely to have AO and CB than 1d relatives of controls (direct component). This direct component might have a genetic basis, because no such association was found when spouses instead of 1d relatives were compared. Thus, both shared environmental factors (personal and passive smoking) and shared genetic factors (alpha 1-antitrypsin and a possible direct genetic component) contribute to familial aggregation in COPD. The loglinear model provides a useful tool for analyzing familial aggregation in diseases of multifactorial etiology.


Effects of mammalian ACTH on potential fuels and gluconeogenic substrates in the plasma of the spiny dogfish shark (Squalus acanthias).
The effects of mammalian ACTH on plasma beta-hydroxybutyrate, glucose, alanine, and lactate levels were determined in the unfed spiny dogfish shark (Squalus acanthias). Serial blood samples were collected from a cannula implanted in the dorsal aorta. The metabolite levels were estimated by standard enzymatic procedures for 4 days before treatment and for 4 days after treatment. Plasma glucose, alanine, and lactate, but not beta-hydroxybutyrate, declined after the surgery, but the metabolites were relatively stable for at least 48 hr before treatment. ACTH (40 units/kg) or the control solution were infused via the cannula after the morning blood sample on postoperative Day 4 and again after the 12-hr blood sample. Control plasma beta-hydroxybutyrate, glucose, and lactate did not change significantly, but alanine levels increased approximately 29% by 96 hr when sampling ended. Plasma beta-hydroxybutyrate levels were not significantly changed by ACTH treatment. Plasma glucose levels increased approximately 36% by 3 hr after ACTH infusion, remained elevated following the second ACTH treatment, and then declined to approximately the initial levels by 96 hr. Plasma alanine levels increased approximately 53% by 0.75 hr after ACTH treatment, were still approximately 15% greater than the initial levels by 12 hr, rose again after the second ACTH infusion at 12 hr, and then declined to near the control levels by 96 hr. Plasma lactate levels increased approximately 107% by 1.5 hr after ACTH infusion and then decreased to approximately 22% greater than the initial levels by 12 hr. Lactate levels increased after the second ACTH infusion and remained approximately 58% greater than the initial levels when sampling ended at 96 hr. The results indicate that the pituitary-adrenocortical axis hormones do not directly influence plasma beta-hydroxybutyrate levels. However, the data support the suggestion that the hyperglycemic action of the pituitary-adrenocortical axis hormones is mediated, at least in part, by the provision of alanine and lactate substrates for gluconeogenesis.


Regulating the expression of therapeutic transgenes by controlled intake of dietary essential amino acids.
Widespread application of gene therapy will depend on the development of simple methods to regulate the expression of therapeutic genes. Here we harness an endogenous signaling pathway to regulate therapeutic gene expression through diet. The GCN2-eIF2α signaling pathway is specifically activated by deficiencies in any essential amino acid (EAA); EAA deficiency leads to rapid expression of genes regulated by ATF4-binding cis elements. We found that therapeutic genes under the control of optimized amino acid response elements (AAREs) had low basal expression and high induced expression. We applied our system to regulate the expression of TNFSF10 (TRAIL) in the context of glioma therapy and found that intermittent activation of this gene by EEA-deficient meals retained its therapeutic efficacy while abrogating its toxic effects on normal tissue. The GCN2-eIF2α pathway is expressed in many tissues, including the brain, and is highly specific to EAA deficiency. Our system may be particularly well suited for intermittent regulation of therapeutic transgenes over short or long time periods.


Single neuron activity in the dorsomedial frontal cortex during smooth pursuit eye movements.
This report describes the behavior of neurons in the dorsomedial frontal cortex during smooth pursuit eye movements. Single neurons were recorded from monkeys while they tracked a small target that moved from the center of a screen outward. The firing rate of most cells was modulated during smooth pursuit eye movements, and often the activity peaked around pursuit initiation. Visual motion of the small target with the eyes fixed could activate pursuit neurons, but did not account for the total pursuit response. Neurons were also selective for the direction in which the animal was tracking, indicating that they were linked to the generation of the eye movements, and not to non-specific arousal effects. The results suggest that the dorsomedial frontal cortex participates in initiating smooth pursuit. It is proposed that the dorsomedial frontal cortex is part of a partial alternative path to the classic pursuit pathway that might be used to facilitate the initiation or control of eye movements beyond a simple reflexive response to retinal slip.


Associations between household solid fuel use and activities of daily living trajectories: A nationwide longitudinal study of middle and older adults in China.
More studies focus on reporting the effects of ambient air pollution on physical activity while ignoring the hazards of indoor air pollution caused by household solid fuel use. Moreover, the impact of individual cognitive and depressive status on the health effects of air pollution is often overlooked. We examined the association between household solid fuel and activities of daily living (ADL) trajectories, and further examined this association in homogeneous subgroups of cognitive or depressive trajectories. Participants were from the China Health and Retirement Longitudinal Study, which conducted four waves of surveys from 2011 to 2018. We collected information on participants' household fuel use, then the ADL, cognitive and depressive performances were assessed in each wave. The latent growth mixture model (LGMM) was used to identify the optimal trajectory class for ADL, cognition, and depression. Then, the multinomial logistic regression was used to assess the association between solid fuel use and ADL trajectories in total population, as well as subgroups with different cognitive or depression trajectories. Furthermore, we examined the association between switching household fuel types and ADL trajectories across the four-wave survey. The study sample included 7052 participants. We identified three ADL trajectory classes in total population: "Low-stable", "Moderate-anterior rise", and "Moderate-posterior rise". The multinomial logistic regression results showed that solid fuel use was associated with elevated odds for the adverse ADL trajectories, and this association was still shown in homogeneous subgroups of cognitive or depressive trajectories, while some effects were less significant. In addition, the risk of adverse ADL trajectories generally increases with the times of solid fuel use across the four-wave survey. For middle and older adults in China, household solid fuel use was not conducive to physical activity development, which inspires that a further transformation to cleaner fuels is an important intervention.


Preparation, characterization, and pharmacokinetics of tilmicosin taste-masked formulation via hot-melt extrusion technology.
Tilmicosin (TMS) is a macrocyclic antibiotic specially used in veterinary clinics, but its extreme bitterness limits its use. This study aimed to obtain a taste-masked formulation of TMS by hot melt extrusion (HME) technology and to investigate the formulation's characterization, stability, and effects in vitro/in vivo. Eudragit® E PO was selected as the carrier, and TMS dissolution in artificial saliva was used as a reference. The HME parameters were optimized via an orthogonal design. The optimized results were as follows: 135 ℃ extrusion temperature, 100 rpm screw speed and 30 % drug load. The masking efficiency of the formulation was evaluated by both simulated oral drug release in vitro and electronic tongue tests. The release of the taste-masked formulation in artificial saliva medium was significantly reduced within 60 s (less than 2%), while the release in 0.1 M HCl buffer was fast (more than 80 %) within 30 min. As suggested by the results of the electronic tongue, the taste-masked formulation had a better taste-masked effect than the commercial premix and the commercial enteric granules. Finally, a pharmacokinetic study was performed. Analysis of variance demonstrated that the pharmacokinetic behavior of the TMS taste-masked formulation was similar to that of the commercial premix, while the absorption effect was better than that of the commercially available enteric granules. This research indicates that the taste-masked formulation has the potential for future commercialization.


Concurrent replication of a papovavirus and a C-type virus in the CCL 33 porcine cell line.
A papovavirus, CCL 33 PV, isolated from a porcine cell line, CCL 33 (GT), was characterized. Based on a comparison of four isoenzyme systems, CCL 33 (GT) and CCL 33 (ATCC), obtained directly from the American Type Culture Collection, appeared to be the same. In addition to the previously characterized C-type virus of CCL 33 cultures, CCL 33 (GT) produced CCL 33 PV in high quantity, but CCL 33 (ATCC) produces a papovalike virus, presumably the same as CCL 33 PV, in barely detectable amounts. Serological results showed that CCL 33 PV is apparently identical to a papovavirus (SPV) isolated by Newman and Smith after inoculation of CCL 33 with concentrated porcine trypsin. These studies extend the characterization of this papovavirus, demonstrating that CCL 33 PV is weakly hemagglutinating after neuraminidase treatment, has a high affinity for a component of fetal bovine serum and is highly infectious in appropriate porcine cell systems rather than very defective as reported previously. Moreover, it was concluded from the data that CCL 33 PV is probably indigenous to the CCL 33 porcine cell line.


Three cases of AVM at eloquent areas finally treated with conventional microsurgical method.
Three special cases of AVM finally treated with conventional microsurgical method are presented. Two cases of medium sized AVMs were located at the central region, one of them was primarily treated with Gamma-knife followed by endovascular embolization having been complicated with growing cyst formation followed ultimately by microsurgical removal. The AVM of another case was embolized three times, followed by removal of the residual nidus under awake surgery. The third AVM located at the hypothalamus in the vicinity of the optic nerve was considered unsuitable for embolization and Gamma-knife therapy, and therefore removed by microsurgery using special approaches after a trial of embolization. In terms of microsurgical removal, preoperative embolization, embolization material, awake surgery and selection of special approaches are discussed.


Reversible acute unilateral diminished pulmonary ventilation and perfusion caused by a mucous plug.
A case of acute unilateral decreased pulmonary ventilation and perfusion caused by a mucous plug documented by bronchoscopy is presented, and the literature is reviewed.


Complementary and Synergistic Design of Bi-Layered Double Hydroxides Modified Magnesium Alloy toward Multifunctional Orthopedic Implants.
Magnesium (Mg)-based alloys have been regarded as promising implants for future clinic orthopedics, however, how to endow them with good anti-corrosion and biofunctions still remains a great challenge, especially for complicated bone diseases. Herein, three transition metals (M = Mn, Fe, and Co)-containing layered double hydroxides (LDH) (LDH-Mn, LDH-Fe, and LDH-Co) with similar M content are prepared on Mg alloy via a novel two-step method, then systematic characterizations and comparisons are conducted in detail. Results showed that LDH-Mn exhibited the best corrosion resistance, LDH-Mn and LDH-Co possessed excellent photothermal and enzymatic activities, LDH-Fe revealed better cytocompatibility and antibacterial properties, while LDH-Co demonstrated high cytotoxicity. Based on these results, an optimized bilayer LDH coating enriched with Fe and Mn (LDH-MnFe) from top to bottom have been designed for further in vitro and in vivo analysis. The top Fe-riched layer provided biocompatibility and antibacterial properties, while the bottom Mn-riced layer provided excellent anti-corrosion, photothermal and enzymatic effects. In addition, the released Mg, Fe, and Mn ions have a positive influence on angiogenesis and osteogenesis. Thus, the LDH-MnFe showed complementary and synergistic effects on anti-corrosion and multibiofunctions (antibacteria, antitumor, and osteogenesis). The present work offers a novel multifunctional Mg-based implant for treating bone diseases.


Association of Down syndrome with periodontal diseases: Systematic review and meta-analysis.
Down syndrome (DS) is distinguished by cognitive disability, a concave profile, and systemic complications. Oral diseases have been reported to be common in DS patients. To investigate the association between DS and periodontal diseases. Two independent reviewers searched six bibliographic databases up to January 2023 and used additional search methods to identify published studies on gingivitis or periodontitis in people with and without DS. Meta-analysis, risk of bias, sensibility analysis, publication bias, and evidence grading were all carried out. Twenty-six studies were included for analysis. There was a tendency for increased plaque accumulation, periodontal probing, periodontal attachment level, bleeding on probing and indices in DS individuals. Meta-analysis of 11 studies showed a significant association between DS and periodontitis (OR 3.93; 95% CI 1.81-8.53). Probing depth was significantly high in individuals with DS as compared to controls (mean difference 0.40 mm; 95% CI 0.09-0.70). Gingivitis was significantly associated (OR 1.93; 95% CI 1.09-3.41) with DS in four studies. The evidence was classified as 'moderate certainty'. Medium/low-quality studies demonstrate that Down syndrome is strongly associated with periodontitis and moderately associated with gingivitis.


Behçet's disease with slowly enlarging midbrain mass on MRI: resolution following steroid therapy.
We describe a case of Behçet's disease with a slowly enlarging midbrain mass on magnetic resonance imaging, which resolved after 4 months of oral steroids.


Mining tailings and alkali activation: a comprehensive bibliometric review.
Significant amounts of mining tailings are generated and disposed of every year in dams, leading to potentially serious environmental and safety problems. To identify alternatives for the disposal of these wastes, research works involving their potential application as precursors in the development of alkaline-activated materials have been published in recent years. In this context, the objective of this paper is to present an overview of the main contributions already made on the subject, identified through a bibliometric review and content analysis in the Scopus and Web of Science databases. There was an exponential growth of interest in the subject in the period 2019-2021, when more than 50% of the papers were published. The most used tailings and sub-areas of research were also identified.


The role of gastrin in congenital hypertrophic pyloric stenosis.
A study was designed and carried out to determine if the canine model of hypertrophic pyloric stenosis is applicable to other species and to demonstrate the transplacental passage of gastrin. Results of the study show that (1) pentagastrin does not induce hypertrophic pyloric stenosis in the rabbit; (2) human gastrin does not cross the canine placenta, and (3) gastrin has no documented and little inferred role in the etiology of CHPS.


Evaluation of CD86/CD28 and CD40/CD154 pathways in regulating monocyte-derived CD80 expression during their interaction with allogeneic endothelium.
This study was designed to examine the role of monocyte-derived CD80 in providing costimulation to CD4+ cells, and to determine whether monocyte-derived CD80 expression is regulated by CD86/CD28 and CD40/CD154 pathways during allogeneic immunoresponses. Human endothelial cells (EC) and purified monocytes cocultured with or without CD4+ cells were analyzed by real-time quantitative polymerase chain reaction (RT-PCR) and florescence-activated cell scanning (FACS). Peripheral blood mononuclear cells (PBMC)-EC cocultures with or without costimulation blockade were analyzed by FACS. The effects of CD154 and CD28 blockade to inhibit lymphocyte proliferation were evaluated by mixed lymphocyte-EC reaction (MLER). RT-PCR demonstrated upregulation of CD80 transcripts in EC-stimulated monocytes in the absence of CD4+ cells. However, the surface expression of CD80 was undetectable. The expression of CD80 was restored in the presence of CD4+ cells. Additionally, CD80 blockade partially inhibited CD4+ cell proliferation induced by EC-conditioned monocytes. Monocytes demonstrated upregulation of CD80 on the surface during PBMC-EC interaction. CD86, CD28, and CD154 blockade did not prevent upregulation of monocyte-derived CD80 expression. CD28 and CD154 blockade partially inhibited lymphocyte proliferation of MLER. In summary, EC-stimulated monocytes upregulated CD80 expression at the transcript level but not on their surface in the absence of T cells. The surface expression of monocyte-derived CD80 is upregulated on EC-stimulated monocytes in the presence of T cells. CD154/CD40 and CD28/CD86 blockade cannot prevent monocyte-derived CD80 expression, suggesting that CD80 upregulation is through a CD154- or CD86-independent pathway. Specific therapy to prevent monocyte activation may be required for successful allograft transplantation.


Application of the ADM1 model to advanced anaerobic digestion.
In this paper the ADM1 model that has been developed by the IWA Task Group for Mathematical Modelling of Anaerobic Digestion Processes is summarized. The model was applied to a variety of anaerobic digestion scenarios that are presented in the literature and for each data set the model predictions were compared to experimental values. Based upon the model applications it was apparent that for accurate model simulations the influent sludge should be well characterized in terms of biodegradable and recalcitrant COD and also nitrogenous compounds. In almost all cases the model was able to reflect the trends that were observed in the experimental data however the concentrations of VFAs were consistently over-predicted in digesters with short SRTs. It would appear that the inhibition functions associated with low pH values tend to overestimate the impact of pH on biokinetic rates for the acid-consuming bacteria. Application of the model with flow through of active biomass between digesters in series in temperature-phased systems needs to be further evaluated in the future.


MicroRNA panels as disease biomarkers distinguishing hepatitis B virus infection caused hepatitis and liver cirrhosis.
An important unresolved clinical issue is to distinguish hepatitis B virus (HBV) infection caused chronic hepatitis and their corresponding liver cirrhosis (LC). Recent research suggests that circulating microRNAs are useful biomarkers for a wide array of diseases. We analyzed microRNA profiles in the plasmas of a total of 495 chronic hepatitis B (CHB) patients, LC patients and healthy donors and identified 10 miRNAs that were differentially expressed between CHB and LC patients. Our logistic models show that three panels of miRNAs have promising diagnostic performances in discriminating CHB from LC. Blinded tests were subsequently conducted to evaluate the diagnostic performances in clinical practice and a sensitivity of 85% and specificity of 70% have been achieved in separating CHB from LC pateints. The expression levels of some circulating miRNAs were significantly correlated with HBV DNA load and liver function, such as prothrombin activity (PTA) and levels of alanin aminotransferase (ALT), albumin (ALB) and cholinesterase (CHE). Our results provide important information for developing novel diagnostic tools for distinguishing chronic HBV hepatitis and their corresponding cirrhosis.


Keratinophilic fungi isolated from Antarctic soil.
In the present study, 10 soil samples were collected aseptically from an equal number of areas of the Antarctic in the zone occupied by the 1986-1987 Italian expedition for research on keratinophilic fungi. Of particular interest was the isolation of a pathogenic fungus, Microsporum gypseum, from two sites in the base camp occupied by men and by skuas. Trichophyton terrestre was isolated from a site in which people worked and through which penguins and skuas passed. The most widespread fungal species were members of the genus Chrysosporium. Some of these species were isolated but not identified and this part of the study was still be completed. Another significant finding was the absence of fungi in one sample, while in another the widespread and abundant growth in all the seeded dishes of a single species of Chrysosporium. Other species in genera of general diffusion in many environments were also isolated: Aspergillus spp., Malbranchea sp., Mycelia sterilia spp., Paecilomyces sp., Penicillium spp. and Scopulariopsis spp.


Unicentric Castleman's disease presenting as a pulmonary mass: a diagnostic dilemma.
Castleman's disease, or angiofollicular lymphoid hyperplasia, is a rare disorder and can be easily misdiagnosed as lymphoma, neoplasm, or infection. The diagnosis is challenging due to the nonspecific signs and symptoms as well as the rarity of the disease. We present an unusual case of a young girl presenting with an enlarging pulmonary mass that was believed to be infectious in origin. A 16-year-old Native American female from Arizona initially presented with occasional non-productive cough and chest pain. Imaging revealed a 3-cm left upper lobe lobulated mass. This mass was thought to be due to coccidioidomycosis and was treated with fluconazole. Follow-up imaging demonstrated growth of the mass to 4.8 cm. The patient underwent a left video-assisted thoracoscopic left upper lobectomy and mediastinal lymphadenectomy. Histopathological examination revealed Castleman's disease. Pulmonary masses in young patients can be easily misdiagnosed as infections or cancer. We present the case of a 16-year-old female misdiagnosed as having a fungal infection of the lung, which was later revealed to be Castleman's disease of the left upper lobe.


Progression of Device-Detected Atrial High-Rate Episodes and the Risk of All-Cause Mortality.
Atrial high-rate episodes (AHREs) are prevalent in approximately 1/3 of patients with cardiac implanted electronic devices and are associated with an increased risk of several adverse outcomes. This study aimed to explore the factors associated with AHRE progression and the risk of all-cause mortality. At least 1 day with AHRE burden ≥15 minutes was identified in 124 of 343 recipients (36.2%) of an implantable cardioverter defibrillator or cardiac resynchronization therapy device. We included patients whose AHRE burden at the time of first detection was ≥15 minutes but <24 hours (n = 107). Various cut-off values (15 minutes, 6 hours, and 24 hours) of daily AHRE burden were analyzed. During an average follow-up of 4.2 years, 60 patients (56.1%) experienced ≥1 progression to greater AHRE burden. Patients with hypertension or greater AHRE burden at first detection were associated with faster progression. In addition, 27 deaths (45%) occurred among 60 patients with AHRE progression, compared with 25.5% (12 of 47) for those without progression. After multivariable adjustment, AHRE progression was independently associated with all-cause mortality (hazard ratio 2.56, 95% confidence interval 1.23 to 5.35, p = 0.012). Notably, AHRE progression within 1 month after their first detection was associated with an increased risk for all-cause mortality (hazard ratio 4.01, 95% confidence interval 1.76 to 9.16, p = 0.001) compared with patients without progression. However, a similar risk was not observed among patients with AHRE progression occurring after 1 month after their first detection. In conclusion, >1/2 of the patients with AHRE progressed to a greater burden over time. Continuous monitoring of the AHRE burden may help identify patients at great risk for death.


The occurrence and zoonotic potential of Cryptosporidium species in freshwater biota.
Protozoan pathogens from the genus Cryptosporidium cause the diarrhoeal disease cryptosporidiosis in humans and animals globally. Freshwater biota could act as potential reservoirs or zoonotic sources of Cryptosporidium infections for livestock and people, but Cryptosporidium occurrence in aquatic biota is largely unexplored. The aim of this study was to investigate the occurrence of Cryptosporidium in a range of freshwater organisms in upland rivers across England and Wales. Fish were sampled by electrofishing, invertebrate larvae by kick sampling and the otter Lutra lutra and mink Mustela vison through faecal samples collected opportunistically as part of a nation-wide study. PCR targeting the small subunit ribosomal RNA gene was used to detect Cryptosporidium species. Cryptosporidium occurred in just 0.8% of all the samples and in none of 73 samples from nine invertebrate genera. Cryptosporidium was detected in two of 2/74 fish samples (2.7%), both salmonids, and in 2/92 otter faecal samples (2.17%), but there were no positive samples in mink (0/24) or the bullhead Cottus gobio (0/16). Low detection rate of human-infective Cryptosporidium species in aquatic fauna indicates they may present a low risk of contamination of some upland freshwaters.


Plasma membrane glycoproteins of cultured rheumatoid synovial fibroblasts.
Fibroblast cultures were started from synovial tissue samples of 12 rheumatoid arthritic, 9 non-rheumatoid synovitic and 6 control patients. External galactose units of plasma membrane glycoproteins of confluent cells were labelled using the galactose oxidase-tritiated borohydride method. These surface-labelled cells were analyzed for possible differences in their glycoproteins by electrophoresis in SDS-containing polyacrylamide gradient gels. Total cell lysates were separated into 50-60 polypeptide bands. Fluorography of the gels revealed about 20 labelled plasma membrane glycoproteins. Some strain-specific differences were detected between the samples in all the groups, but no correlation with rheumatoid arthritis could be demonstrated.


Thrombin regulation of cell function through protease-activated receptors: implications for therapeutic intervention.
The serine protease thrombin is well recognized as being pivotal to the maintenance of hemostasis under both normal and pathological conditions. Its cellular actions are mediated through a unique family of protease-activated receptors (PARs). These receptors represent a novel family of G protein-coupled receptors that undergo proteolytic cleavage of their amino terminus and subsequent autoactivation by a tethered peptide ligand. This paper reviews the consequences of PAR activation in thrombosis, vascular injury, inflammation, tissue injury, and within the tumor microenvironment.


Ultraviolet-C-Based Mobile Phone Sanitisation for Global Public Health and Infection Control.
Mobile phones act as fomites that pose a global public health risk of disseminating microorganisms, including highly pathogenic strains possessing antimicrobial resistances. The use of ultraviolet-C (UV-C) to sanitise mobile phones presents an alternative means to complement basic hand hygiene to prevent the cross-contamination and dissemination of microorganisms between hands and mobile phones. This study aimed to evaluate the germicidal efficacy of the Glissner CleanPhone UV-C phone sanitiser (Glissner) device. Two experimental trials were performed for the evaluation of the CleanPhone (Glissner). The first was a controlled trial, where the germicidal efficacy of the CleanPhone was evaluated against six different microorganism species that were inoculated onto mobile phones. The second was a field trial evaluating the germicidal efficacy of the CleanPhone on 100 volunteer mobile phones. Efficacy was determined based on colony counts of microorganisms on Columbia sheep blood agar before and after UV-C treatment. In the controlled trial, reduction in growth was observed for all microorganisms after UV-C treatment with ST131 Escherichia coli showing the highest growth reduction at 4 log10 CFU/mL followed by C. albicans and ATCC E. coli at 3 log10 CFU/mL. An overall reduction in microorganism growth after UV-C treatment was also observed for the field trial, with an average growth reduction of 84.4% and 93.6% in colony counts at 24 h and 48 h post-incubation, respectively. The findings demonstrated the capability of the CleanPhone (Glissner) to rapidly sanitise mobile phones, thereby providing a means to reduce the potential dissemination of microorganisms, including highly pathogenic strains with antimicrobial resistance.


The effect of bundle branch block on heart function and cardiac output in premature infant.
It is well known that hyperkalemia may cause arrhythmia, right bundle branch block, and cardiac conduction block. These dysrhythmias have the potential to affect cardiac function. We present a premature newborn with hyperkalemia and right bundle branch block causing left ventricular dyssynchrony with mitral regurgitation, which led to decreased pump function.


Antiamyloid β toxicity effect of genistein via activation of DAF-16 and HSP-16.2 signal pathways in Caenorhabditis elegans.
β-Amyloid toxicity (Aβ) is an important pathological factor of Alzheimer's disease (AD). Studies have shown that genistein can reduce the toxicity of Aβ to a certain extent; however, the specific mechanism is still uncertain. In the study, we applied Caenorhabditis elegans strains expressing Aβ peptides to evaluate the role of genistein inhibiting Aβ toxicity and the undying mechanism. Genistein influencing the sterol metabolism pathway, the HSP-16.2 pathway, and lipofuscin in different strains of C. elegans were studied using reverse transcription-polymerase chain reaction, fluorescence labeling, RNA interference (RNAi), and so forth. Our results showed that genistein alleviated the paralysis of transgenic C. elegans strains. Furthermore, in AD C. elegans, genistein reduced the fluorescence of lipofuscin, downregulated the messenger RNA (mRNA) level of vit-3 and vit-6 which were related to the sterol metabolism pathway, significantly increased the mRNA level and protein level of HSP-16.2, increased the nuclear translocation of the DAF-16 transcription factor and increased the survival rate after heat stress, which was closely associated with HSP-16.2 levels. However, the paralysis-alleviating effect of genistein was greatly reduced because of RNAi-mediated inhibition of hsp-16.2, indicating that the anti-Aβ toxicity effect of genistein was greatly dependent on HSP-16.2. The above results suggest that genistein inhibiting the toxicity of Aβ in C. elegans, is involved in the modulation of the sterol metabolism pathway by promoting transcription factor DAF-16 translocation into the nucleus, increasing the expression level of HSP-16.2, and reducing the levels of lipofuscin through its antioxidant activity.


Uptake and toxicity of safranine and triphenylmethylphosphonium ion in human tumour cells.
Despite having lower cell membrane potentials, four human melanoma cell lines and HeLa cells accumulated the membrane probe triphenylmethylphosphonium ion (TPMP, 2 microM) 2-10 fold more rapidly than human fibroblasts, and did not reach equilibrium during the 2 h incubation period studied. The difference was not due to drug toxicity, although at much higher levels of TPMP (greater than 20 microM) selective killing of melanoma cells compared with fibroblasts was observed. Some dependence of TPMP accumulation upon membrane potential was indicated by inhibition of uptake in fibroblasts depolarised by culture in calcium-deficient medium. Melanoma cells exhibited no change in TPMP uptake or membrane potential under these conditions. Uptake of safranine, an indicator of mitochondrial membrane potential, did not follow the TPMP pattern. Thus, the anomalous accumulation of TPMP by human tumour cells appeared to result from either carrier-mediated transport or rapid intracellular metabolism and could not be used to determine cell membrane potentials.


The cost of hospitalizations for treatment of hemodialysis catheter-associated blood stream infections in children: a retrospective cohort study.
Hospitalization costs for treatment of hemodialysis (HD) catheter-associated blood stream infections (CA-BSI) in adults are high. No studies have evaluated hospitalization costs for HD CA-BSI in children or identified factors associated with high-cost hospitalizations. We analyzed 160 HD CA-BSIs from the Standardizing Care to Improve Outcomes in Pediatric End-stage Kidney Disease (SCOPE) collaborative database linked to hospitalization encounters in the Pediatric Health Information System (PHIS) database. Charge-to-cost ratios were used to convert hospitalization charges reported in PHIS database to estimated hospital costs. Generalized linear mixed modeling was used to assess the relationship between higher-cost hospitalization (cost above 50th percentile) and patient and clinical characteristics. Generalized linear regression models were used to assess differences in mean service line costs between higher- and lower-cost hospitalizations. The median (IQR) length of stay for HD CA-BSI hospitalization was 5 (3-10) days. The median (IQR) cost for HD CA-BSI hospitalization was $18,375 ($11,584-$36,266). ICU stay (aOR 5.44, 95% CI 1.62-18.26, p = 0.01) and need for a catheter procedure (aOR = 6.08, 95% CI 2.45-15.07, p < 0.001) were associated with higher-cost hospitalization. Hospitalizations for HD CA-BSIs in children are often multiple days and are associated with substantial costs. Interventions to reduce CA-BSI may reduce hospitalization costs for children who receive chronic HD. A higher resolution version of the Graphical abstract is available as Supplementary information.


Effects of perfusion pressure during flushing on the viability of the procured liver using noninvasive fluorometry.
The influence of perfusion pressure and flow rate on hepatic cellular viability was investigated in the procured liver using noninvasive pyridine nucleotide fluorometry, in relation to other metabolic indices such as nicotinamide adenine dinucleotide (NAD) concentration, adenine nucleotides, tissue ketone bodies, and mitochondrial phosphorylative activity. Rat liver was perfused at a controlled flow rate through the portal vein with a nonrecirculating open-end-design perfusion system driven by a roller pump using cooled oxygenized Euro-Collins' solution. The maximum pressures (mean pressure in parentheses) of experimental groups were 8 (5) mmHg, 15 (9) mmHg, 40 (25) mmHg, 80 (50) mmHg, 120 (73) mmHg, 240 (152) mmHg. The amplitude between oxidation and reduction levels (RxA) in the fluorometric trace, and the gradient or velocity of the trace curve from oxidation to reduction (RxV) were determined by the measurement of fluorescence from NAD phosphate, reduced form (NADPH) using a new fluorometric device. Other metabolic indices were measured after attainment of a fully oxygenated state. RxA decreased in accordance with the increase of pressure. Similar results were obtained in the changes of NAD concentration, total adenine nucleotides, and total tissue ketone bodies, possibly due to the wash-out of these metabolites. RxV decreased in inverse proportion to the increase of pressure. There were close positive correlations between RxV and tissue ketone body ratio (acetoacetate/3-hydroxybutyrate) (r = 0.793, less than 0.01), RxV and respiratory control ratio in isolated mitochondria (r = 0.617, P less than 0.05), RxV and state 3 respiration (r = 0.792, P less than 0.01), and RxV and phosphorylation rate (r = 0.833, P less than 0.01). These results suggest that perfusion pressure and flow rate can easily deteriorate the energy metabolism of the procured liver, and that the gravity-induced hydrostatic pressure presently used in procurement perfusion should be reevaluated on the basis of energy metabolism.


Visceral larva migrans involving the myocardium: report of two cases and review of literature.
Two cases of asymptomatic visceral larva migrans (VLM) involving the myocardium, discovered during open heart surgery, are reported. Only 7 cases of VLM myocarditis were found in recent English publications. All 7 cases involved children, with most of the patients acutely ill. Our 2 asymptomatic cases, coupled with the high rate of positive serologic tests in the general population, stress the widespread nature of Toxocara canis infection in human and the large number of subclinical, undetected cases.


Cryopreservation of human mesenchymal stromal cells expressing TRAIL for human anti-cancer therapy.
Mesenchymal stromal cells (MSCs) are being extensively researched for cell therapy and tissue engineering. We have engineered MSCs to express the pro-apoptotic protein tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and are currently preparing this genetically modified cell therapy for a phase 1/2a clinical trial in patients with metastatic lung cancer. To do this, we need to prepare a cryopreserved allogeneic MSCTRAIL cell bank for further expansion before patient delivery. The effects of cryopreservation on a genetically modified cell therapy product have not been clearly determined. We tested different concentrations of dimethyl sulfoxide (DMSO) added to the human serum albumin ZENALB 4.5 and measured post-thaw cell viability, proliferation ability and differentiation characteristics. In addition, we examined the homing ability, TRAIL expression and cancer cell-killing capacities of cryopreserved genetically modified MSCs compared with fresh, continually cultured cells. We demonstrated that the post-thaw viability of MSCs in 5% DMSO (v/v) with 95% ZENALB 4.5 (v/v) is 85.7 ± 0.4%, which is comparable to that in conventional freezing media. We show that cryopreservation does not affect the long-term expression of TRAIL and that cryopreserved TRAIL-expressing MSCs exhibit similar levels of homing and, importantly, retain their potency in triggering cancer cell death. This study shows that cryopreservation is unlikely to affect the therapeutic properties of MSCTRAIL and supports the generation of a cryopreserved master cell bank.


Preexposure prophylaxis with albumin-conjugated C34 peptide HIV-1 fusion inhibitor in SCID-hu Thy/Liv mice.
PC-1505 is a C34 peptide derived from the heptad repeat 2 region of HIV-1 gp41 conjugated to human serum albumin for sustained in vivo activity. One single preexposure dose of PC-1505 reduced viral RNA in HIV-1-infected SCID-hu Thy/Liv mice by 3.3 log₁₀ and protected T cells from virus-mediated depletion. In contrast, a single preexposure dose of Truvada reduced viral RNA by only 0.8 log₁₀ and was substantially less effective in preventing T cell depletion.


[Problems of dermatology and venereology in conducting universal dispensary care of the population].
The author emphasizes the necessity of screening for sexually transmitted diseases within the frames of annual prophylactic check-ups of the population and describes methods for such screening.


The DAL10 gene from Norway spruce (Picea abies) belongs to a potentially gymnosperm-specific subclass of MADS-box genes and is specifically active in seed cones and pollen cones.
Transcription factors encoded by different members of the MADS-box gene family have evolved central roles in the regulation of reproductive organ development in the flowering plants, the angiosperms. Development of the stamens and carpels, the pollen- and seed-bearing organs, involves the B- and C-organ-identity MADS-box genes. B- and C-type gene orthologs with activities specifically in developing pollen- and seed-bearing organs are also present in the distantly related gymnosperms: the conifers and the gnetophytes. We now report on the characterization of DAL10, a novel MADS-box gene from the conifer Norway spruce, which unlike the B- and C-type conifer genes shows no distinct orthology relationship to any angiosperm gene or clade in phylogenetic analyses. Like the B- and C-type genes, it is active specifically in developing pollen cones and seed cones. In situ RNA localization experiments show DAL10 to be expressed in the cone axis, which carry the microsporophylls of the young pollen cone. In contrast, in the seed cone it is expressed both in the cone axis and in the bracts, which subtend the ovuliferous scales. Expression data and the phenotype of transgenic Arabidopsis plants expressing DAL10 suggest that the gene may act upstream to or in concert with the B- and C-type genes in the establishment of reproductive identity of developing cones.


Ceramide: an endogenous regulator of apoptosis and growth suppression.
The action of several cytokines is mediated via activation of the sphingomyelin cycle of signal transduction. Ceramide, the product of this pathway, is emerging as an intracellular messenger that mediates effects on terminal differentiation, apoptosis and cell-cycle arrest. Here, Marina Pushkareva, Lina Obeid and Yusuf Hannun discuss the regulation and mechanism of action of this stress-activated pathway.


Glomerular size and structure in diabetes mellitus. III. Early enlargement of the capillary surface.
The present electron microscopic study shows that the kidney hyperfunction in early diabetes can be due to a significant morphological change: an increased glomerular filtration surface. Applying standard stereological methods, the area of the peripheral wall of the glomerular capillaries was measured in biopsy specimens obtained from 7 patients with early diabetes and 7 controls.--An 80% enlargement of the capillary wall (the surface of the peripheral basement membrane) was found in the diabetics (2p=0.0096). Also the total area of the interface between the tuft and the urinary space was increased by 70% (2p=0.029). Since the thickness of the peripheral basement membrane is known to be unchanged in patients with early diabetes the finding of an increased area of the membrane implies that an increased quantity of basement membrane material is present in these patients. The significance of this phenomenon for the understanding of the metabolism of the basement membrane is discussed, and a working hypothesis is advanced for the pathogenesis of the diabetic microangiopathy.


Hyperammonemia induces transient GFAP immunoreactivity changes in goldfish spinal cord (Carassius auratus L.).
In this study we have demonstrated that high ammonia concentration in tank water induces changes in the glial fibrillary acidic protein (GFAP) of ependymal cells and radial astrocytes in the goldfish spinal cord. Hyperammonemia was induced by elevating the ammonia concentration in the tank water to 0.88 mM using ammonium chloride; ammonia in control water was less than 0.1 mM. Immunohistochemical methods were used for GFAP and vimentin, and levels were measured at 4, 8, 16, 30, 60, 90 and 120 days. GFAP quantification was made by means of a digital analysis system. The GFAP immunoreactivity was significantly lower at 30 and 60 days of treatment and at 90 days it had returned to control levels. However, no changes in vimentin immunoreactivity were appreciated in any case. GFAP loss was general and was not selective in any specific spinal cord region. To explain this transient generalized loss of GFAP and its posterior recuperation, a possible relation between glutamine synthetase distribution and GFAP changes is discussed.


Mutational analysis of ABC proteins.
The 49 human members of the ATP-binding cassette (ABC) family of proteins are involved in a wide range of activities such as active transport of compounds across membranes, extraction of compounds out of membranes, functioning as ion channels, or regulators of channel activity. Mutations and/or overexpression of many of the proteins can have adverse effects on health. A goal in the study of ABC proteins is to understand their mechanisms of action. This review will focus on the mutational approaches that have been used to study the structure and mechanisms of some ABC proteins.


Vasopressin effects on isolated non-pregnant myometrium and uterine arteries and their inhibition by deamino-ethyl-lysine-vasopressin and deamino-ethyl-oxytocin.
The contractile effects of lysine- (L) and arginine- (A) vasopressin (VP) on isolated non-pregnant myometrium and uterine arteries and the inhibition of these actions by two analogues of posterior pituitary hormones, deamino-ethyl-LVP (dE-LVP) and deamino-ethyl-oxytocin (dE-OXY) were investigated. Both AVP and LVP effectively stimulated the smooth muscle preparations. The threshold dose for both agonists was about 2 ng/ml of bath fluid and a maximal response was obtained with approximately 75 ng/ml. No distinguishable effect was produced by dE-LVP and dE-OXY alone, but when given before the agonists in concentrations of 150 or 300 ng/ml, dose-dependent inhibition of the contractions was seen. The inhibition of the uterine artery responses was always greater than the inhibition of the effects on myometrial activity and dE-LVP appeared to have stronger antagonistic effects than de-OXY on the myometrial responses to the agonists. The inhibition of the myometrial and uterine artery responses to AVP could explain the therapeutic effect of dE-OXY recently found in primary dysmenorrhoea, where increased VP secretion seems to be of aetiological importance.


[Quality of marginal sealing of Evicrol fillings when using dental adhesives in vitro].
The quality of the marginal sealing of fillings made from Evicrol in vitro was investigated by means of a couloured indicator. The close adherence of the composite filing to the surface of the tooth was ensured by the by micro retention treatment of the marginal enamel and different dentin adhesives. The thermal strain of filling materials and their combination with the tooth, corresponding roughly to conditions in the oral cavity, was modelled by cyclic temperature changes using a special apparatus designed by the authors.


Therapeutic administration of 3,4,5-trimethoxy-4'-fluorochalcone, a selective inhibitor of iNOS expression, attenuates the development of adjuvant-induced arthritis in rats.
We have previously investigated the effects of a series of dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, on nitric oxide production in LPS-stimulated murine RAW 264.7. The present study was designed to determine if 3,4,5-trimethoxy-4'-fluorochalcone (CH 17) could modulate the production of NO and/or prostaglandins in vivo. On the mouse macrophage cell line RAW 264.7 CH 17 inhibited dose-dependently NO production, with an IC(50) value in the nanomolar range, and reduced PGE(2) levels by a 58% at 10 microM. This compound had no direct inhibitory effect on iNOS and COX-2 activities. NO reduction was the consequence of inhibition of the expression of iNOS. In vitro experiments indicated that CH 17 is an inhibitor of the nuclear factor-kappaB (NF-kappaB) pathway of cellular activation in macrophages. This compound exhibited in vivo an inhibitory behaviour correlated with its in vitro results on nitrite and PGE(2) accumulation. In the rat adjuvant-induced arthritis, oral administration of CH 17 (25 mg/kg) on days 17-24 after adjuvant injection, significantly inhibited paw oedema, protected from weight loss and reduced the levels of inflammatory mediators (nitrites and PGE(2)) in paw homogenates, without affecting PGE(2) levels in stomach homogenates. The profile and potency of this compound, a selective inhibitor of iNOS expression that interferes with NF-kappaB activation, may have relevance for the inhibition of the inflammatory response, representing a new approach to the modulation of different inflammatory pathologies.


Treatment of striae distensae with non-ablative fractional laser: clinical and in vivo microscopic documentation of treatment efficacy.
The efficacy of NAFL in the treatment of striae distensae (SD) has been demonstrated. Nevertheless, the base for this improvement has not been clarified yet. The aim of this study is to describe in vivo variations occurring in the skin after the treatment, using reflectance confocal microscopy (RCM). Ten patients asking for the treatment of SD were enrolled. Clinical and RCM images were acquired before the treatment, immediately after 1 and 6 months after the first treatment. One thousand five hundred forty-nanometer laser treatments were performed every 4 weeks for 6 sessions. Efficacy was estimated through the evaluation of pre- and post-treatment clinical pictures by two expert and independent physicians and with GAIS. Improvement of SD was observed in 80% of patients. Temporary erythema and edema were reported. RCM revealed the dissolution of collagen bundles and the appearance of new papillae, as compared to baseline. NAFL represents an effective and safe treatment modality for SD. We report herein in vivo variations occurring in SD after NAFL treatment.


Ultrasonic gene and drug delivery to the cardiovascular system.
Ultrasound targeted microbubble destruction has evolved as a promising tool for organ specific gene and drug delivery. This technique has initially been developed as a method in myocardial contrast echocardiography, destroying intramyocardial microbubbles to characterize refill kinetics. When loading similar microbubbles with a bioactive substance, ultrasonic destruction of microbubbles may release the transported substance in the targeted organ. Furthermore, high amplitude oscillations of microbubbles lead to increased capillary and cell membrane permeability, thus facilitating tissue and cell penetration of the released substance. While this technique has been successfully used in many organs, its application in the cardiovascular system has dominated so far. Drug delivery using microbubbles has played a minor role in the cardiovascular system. In contrast, gene transfer has been successfully achieved in many studies. Both viral and non-viral vectors were used for loading on microbubbles. This review article will give an overview on studies that have applied ultrasound targeted microbubble destruction to deliver substances in the heart and blood vessels. It will show potential therapeutic targets, especially for gene therapy, describe feasible substances that can be loaded on microbubbles, and critically discuss prospects and limitations of this technique.


Multiple Aryne Insertions into Oxindoles: Synthesis of Bioactive 3,3-Diarylated Oxindoles and Dibenzo[b,e]azepin-6-ones.
An aryne insertion cascade reaction on oxindoles has been observed and constitutes a convenient "one pot" preparation of bioactive di- and triarylated oxindoles in good yields under mild conditions. A temperature controlled "reaction switch" enables ready access to dibenzo[b,e]azepin-6-one derivatives employing the same reaction regime. This tactic has been extended to a short synthesis of potent antiulcer agent darenzepine.


Investment in mailroom services produces better communications.
A survey of mailroom practices at Providence Medical Center, Seattle, revealed inadequate working conditions and a lack of supervision. This article explains how careful planning and management enabled the mailroom to control copying costs and to improve services to patients, physicians, and hospital staff.


A preliminary study of ALPPS procedure in a rat model.
Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) has been reported to be a novel surgical technique that provides fast and effective growth of liver remnant. Despite occasional reports on animal studies, the mechanisms of rapid liver regeneration in ALPPS remains unclear. In the present study, we intend to develop a reproducible rat model to mimick ALPPS and to explore the underlying mechanisms. Rats assigned to the portal vein ligation (PVL), left lateral lobe (LLL) resection, transection and sham groups served as controls. Results indicated that the regeneration rate in the remnant liver after ALPPS was two times relative to PVL, whereas rats with transection alone showed minimal volume increase. The expression levels of Ki-67 and PCNA were about ten-fold higher after ALPPS compared with the transection and LLL resection groups, and four-fold higher compared with the PVL group. The levels of TNF-α, IL-6 and HGF in the regenerating liver remnant were about three-fold higher after ALPPS than the controls. There was a more significant activation of NF-κB p65, STAT3 and Yap after ALPPS, suggesting synergistic activation of the pathways by PVL and transection, which might play an important role in liver regeneration after ALPPS.


Synthesis of defined oligohyaluronates-decorated liposomes and interaction with lung cancer cells.
In this work hyaluronic acid (HA) oligosaccharides with degree of polymerization (DP) 4, 6 and 8, obtained by enzymatic depolymerization of HA, were conjugated to a PEG-phospholipid moiety. The products (HA-DP4, HA-DP6 and HA-DP8) were used to prepare decorated liposomes. The cellular uptake of HA-DP4, HA-DP6 and HA-DP8-decorated fluorescently labelled liposomes was significantly higher (12 to 14-fold) in lung cancer cell lines with high CD44 expression than in those with low CD44 expression, suggesting a receptor-mediated entry of HA-conjugated formulations. Competition assays showed that the uptake followed this rank order: HA-DP8>HA-DP6>HA-DP4 liposomes. Moreover, they are capable of a faster interaction with CD44, followed by phagocytosis, than HA liposomes obtained from HA of higher molecular weight (4800 and 14800 Da). HA-DP4, HA-DP6 and HA-DP8-liposomes did not show cytotoxicity or inflammatory effects. Overall, we propose our new HA-DP oligosaccharides as biocompatible and effective tools for a potential drug delivery to CD44-positive cells.


Kainate Receptors Play a Role in Modulating Synaptic Transmission in the Olfactory Bulb.
Glutamate is the neurotransmitter used at most excitatory synapses in the mammalian brain, including those in the olfactory bulb (OB). There, ionotropic glutamate receptors including N-methyl-d-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) play a role in processes such as reciprocal inhibition and glomerular synchronization. Kainate receptors (KARs) represent another type of ionotropic glutamate receptor, which are composed of five (GluK1-GluK5) subunits. Whereas KARs appear to be heterogeneously expressed in the OB, evidence as to whether these KARs are functional, found at synapses, or modify synaptic transmission is limited. In the present study, coapplication of KAR agonists (kainate, SYM 2081) and AMPAR antagonists (GYKI 52466, SYM 2206) demonstrated that functional KARs are expressed by OB neurons, with a subset of receptors located at synapses. Application of kainate and the GluK1-selective agonist ATPA had modulatory effects on excitatory postsynaptic currents (EPSCs) evoked by stimulation of the olfactory nerve layer. Application of kainate and ATPA also had modulatory effects on reciprocal inhibitory postsynaptic currents (IPSCs) evoked using a protocol that evokes dendrodendritic inhibition. The latter finding suggests that KARs, with relatively slow kinetics, may play a role in circuits in which the relatively brief duration of AMPAR-mediated currents limits the role of AMPARs in synaptic transmission (e.g., reciprocal inhibition at dendrodendritic synapses). Collectively, our findings suggest that KARs, including those containing the GluK1 subunit, modulate excitatory and inhibitory transmission in the OB. These data further suggest that KARs participate in the regulation of synaptic circuits that encode odor information.


Evaluation and modification of commercial dry powder inhalers for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation.
The aim of this study was to evaluate and modify commercial dry powder inhalers (DPIs) for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation. The optimized device and formulation combination was then tested in a realistic in vitro mouth-throat - tracheobronchial (MT-TB) model. An optimized EEG submicrometer powder formulation, consisting of albuterol sulfate (drug), mannitol (hygroscopic excipient), l-leucine (dispersion enhancer) and poloxamer 188 (surfactant) in a ratio of 30:48:20:2 was prepared using a Büchi Nano spray dryer. The aerosolization performance of the EEG formulation was evaluated with five conventional DPIs: Aerolizer, Novolizer, HandiHaler, Exubera and Spiros. To improve powder dispersion, the HandiHaler was modified with novel mouth piece (MP) designs. The aerosol performance of each device was assessed using a next generation impactor (NGI) at airflow rates generating a pressure drop of 4 kPa across the DPI. In silico and in vitro deposition and hygroscopic growth of formulations was studied using a MT-TB airway geometry model. Both HandiHaler and Aerolizer produced high emitted doses (EDs) together with a significant submicrometer aerosol fraction. A modified HandiHaler with a MP including a three-dimensional (3D) array of rods (HH-3D) produced a submicrometer particle fraction of 38.8% with a conventional fine particle fraction (%<5 μm) of 97.3%. The mass median diameter (MMD) of the aerosol was reduced below 1 μm using this HH-3D DPI. The aerosol generated from the modified HandiHaler increased to micrometer size (2.8 μm) suitable for pulmonary deposition, when exposed to simulated respiratory conditions, with negligible mouth-throat (MT) deposition (2.6%).


Responses of various carbon to nitrogen ratios to microbial communities, kinetics, and nitrogen metabolic pathways in aerobic granular sludge reactor.
The role of different ammonia concentrations (mg N/L) (of 100 (carbon to nitrogen ratio (C/N) = 12; Stage I), 200 (C/N = 6; Stage II), 400 (C/N = 3; Stage III) and 200 (C/N = 6; Stage IV)) in nitrogen metabolic pathways, microbial community, and specific microbial activity were investigated in an aerobic granular sludge reactor. Heterotrophic ammonia oxidizing bacteria (HAOB) showed higher ammonia oxidation rates (AORs) than autotrophic ammonia oxidizing bacteria (AAOB) at higher C/N conditions (Stages I and II). Paracoccus was the dominant HAOB. AAOB, with only 0.2-0.3 % in relative abundance, showed 2.7-fold higher AORs than HAOB at elevated ammonia and free ammonia (FA) concentrations with C/N at 3. Nitrosomonas and a genus in Nitrosomondaceae family were the major AAOB. This study proposed that FA inhibition on heterotrophic bacteria might be the mechanism that contributes to the development of the autotrophic ammonia oxidation pathway and enrichment of AAOB.


Once-daily Mesalamine Formulation for Maintenance of Remission in Ulcerative Colitis: A Randomized, Placebo-controlled Clinical Trial.
To evaluate the efficacy and safety of mesalamine granules 1.5 g once daily for maintenance of ulcerative colitis (UC) remission. Mesalamine is a first-line treatment for induction and maintenance of UC remission. A phase 3, randomized, double-blind, placebo-controlled trial of patients with a history of mild to moderate UC, currently in remission, who received mesalamine granules once daily for 6 months. The primary efficacy endpoint was percentage of patients maintaining UC remission at 6 months. A significantly greater percentage of patients receiving mesalamine granules versus placebo were in remission at 6 months (79.9% vs. 66.7%; P=0.03). A greater percentage of patients receiving mesalamine granules maintained a revised Sutherland Disease Activity Index (SDAI)≤2 with no individual component of revised SDAI>1 and rectal bleeding=0 at 6 months (72.0% vs. 58.1%; P=0.04). No significant differences between groups were observed for change from baseline to 6 months for total SDAI score or its components (ie, stool frequency, rectal bleeding, mucosal appearance, physician's rating of disease). Mesalamine granules treatment resulted in a significantly longer remission duration versus placebo (P=0.02) and decreased patients' risk of relapse by 43% (hazard ratio=0.57; 95% confidence interval, 0.35-0.93; P=0.02). Mesalamine granules were well tolerated, and adverse events related to hepatic, renal, and pancreatic function-potential concerns with long-term treatment-occurred at a rate similar to placebo. Once-daily mesalamine granules are efficacious and safe for the maintenance of UC remission.


Synthetic salmon calcitonin is not diabetogenic in patients with normal or impaired glucose metabolism.
The effects of short term administration of 200 MRC U of synthetic salmon calcitonin (sCT) daily on carbohydrate metabolism were investigated in 10 patients with various bone diseases, 3 of whom had type II diabetes mellitus and 3 of whom had impaired glucose tolerance. Blood glucose levels during the nocturnal postabsorptive period, blood glucose and blood insulin (IRI) levels and the ratio of the area under the insulin curve to the area under the glucose curve (AI/AG) after a mixed meal were determined before and after 15 days of treatment. The values before and after sCT treatment were not significantly different, suggesting that high doses of sCT are not diabetogenic and can be given to patients with impaired glucose tolerance or to diabetics, without any risk of deteriorating metabolic control.


Clinical classification of age-related macular degeneration.
To develop a clinical classification system for age-related macular degeneration (AMD). Evidence-based investigation, using a modified Delphi process. Twenty-six AMD experts, 1 neuro-ophthalmologist, 2 committee chairmen, and 1 methodologist. Each committee member completed an online assessment of statements summarizing current AMD classification criteria, indicating agreement or disagreement with each statement on a 9-step scale. The group met, reviewed the survey results, discussed the important components of a clinical classification system, and defined new data analyses needed to refine a classification system. After the meeting, additional data analyses from large studies were provided to the committee to provide risk estimates related to the presence of various AMD lesions. Delphi review of the 9-item set of statements resulting from the meeting. Consensus was achieved in generating a basic clinical classification system based on fundus lesions assessed within 2 disc diameters of the fovea in persons older than 55 years. The committee agreed that a single term, age-related macular degeneration, should be used for the disease. Persons with no visible drusen or pigmentary abnormalities should be considered to have no signs of AMD. Persons with small drusen (<63 μm), also termed drupelets, should be considered to have normal aging changes with no clinically relevant increased risk of late AMD developing. Persons with medium drusen (≥ 63-<125 μm), but without pigmentary abnormalities thought to be related to AMD, should be considered to have early AMD. Persons with large drusen or with pigmentary abnormalities associated with at least medium drusen should be considered to have intermediate AMD. Persons with lesions associated with neovascular AMD or geographic atrophy should be considered to have late AMD. Five-year risks of progressing to late AMD are estimated to increase approximately 100 fold, ranging from a 0.5% 5-year risk for normal aging changes to a 50% risk for the highest intermediate AMD risk group. The proposed basic clinical classification scale seems to be of value in predicting the risk of late AMD. Incorporating consistent nomenclature into the practice patterns of all eye care providers may improve communication and patient care.


On the road to cancer: aneuploidy and the mitotic checkpoint.
Abnormal chromosome content - also known as aneuploidy - is the most common characteristic of human solid tumours. It has therefore been proposed that aneuploidy contributes to, or even drives, tumour development. The mitotic checkpoint guards against chromosome mis-segregation by delaying cell-cycle progression through mitosis until all chromosomes have successfully made spindle-microtubule attachments. Defects in the mitotic checkpoint generate aneuploidy and might facilitate tumorigenesis, but more severe disabling of checkpoint signalling is a possible anticancer strategy.