On modelling the impacts of phosphorus stripping at sewage works on in-stream phosphorus and macrophyte/epiphyte dynamics: a case study for the River Kennet.
A new model of in-stream phosphorus and macrophyte dynamics, 'The Kennet model', was applied to a reach of the River Kennet, southern England. The reach, which is 1.5 km long, is immediately downstream of Marlborough sewage treatment works, where phosphorus reduction by tertiary effluent treatment began in September 1997. The model is used to simulate the flow, water chemistry and macrophyte biomass within the reach, both before and after phosphorus removal from the effluent. Monte Carlo experiments coupled with a general sensitivity analysis indicate that the model offers a feasible explanation for the salient aspects of the system behaviour. Model simulations indicate that epiphyte smothering is an important limitation to macrophyte growth, and that higher stream and pore water soluble reactive phosphorus (SRP) concentrations allow the earlier onset of growth for the epiphytes and macrophytes, respectively. Higher flow conditions are shown to reduce the simulated peak epiphyte biomass; though at present, the effect of flow on the macrophyte biomass is unclear. Another simulation result suggests that phosphorus will not be released from the bed sediments in this reach following phosphorus removal from the effluent.


A comprehensive review on metal based active sites and their interaction with O3 during heterogeneous catalytic ozonation process: Types, regulation and authentication.
Heterogeneous catalytic ozonation (HCO) was a promising water purification technology. Designing novel metal-based catalysts and exploring their structural-activity relationship continued to be a hot topic in HCO. Herein, we reviewed the recent development of metal-based catalysts (including monometallic and polymetallic catalysts) in HCO. Regulation of metal based active sites (surface hydroxyl groups, Lewis acid sites, metal redox cycle and surface defect) and their key roles in activating O3 were explored. Advantage and disadvantage of conventional characterization techniques on monitoring metal active sites were claimed. In situ electrochemical characterization and DFT simulation were recommended as supplement to reveal the metal active species. Though the ambiguous interfacial behaviors of O3 at these active sites, the existence of interfacial electron migration was beyond doubt. The reported metal-based catalysts mainly served as electron donator for O3, which resulted in the accumulation of oxidized metal and reduced their activity. Design of polymetallic catalysts could accelerate the interfacial electron migration, but they still faced with the dilemma of sluggish Me(n+m)+/Men+ redox cycle. Alternative strategies like coupling active metal species with mesoporous silicon materials, regulating surface hydrophobic/hydrophilic properties, polaring surface electron distribution, coupling HCO process with photocatalysis and H2O2 were proposed for future research.


Repeated delirium from homatropine eye-drops. A case report.
The administration of homatropine eye-drops precipitated several episodes of delirium in a 69-year-old woman. The unusual susceptibility of this patient to the central anticholinergic effect of homatropine is perhaps related to a preexisting mild cognitive defect possibly related to a cholinergic neurotransmitter deficit.


Effect of Length Stability on Complications in the Treatment of Preadolescent Diaphyseal Femur Fractures Treated With Elastic Stable Intramedullary Nailing.
To examine the effectiveness and complication rates in age- and size-appropriate patients with either stable or unstable fracture patterns treated with elastic stable intramedullary nailing (ESIN). Retrospective case series. Academic tertiary care children's hospital. This was a consecutive series of 106 preadolescent children with femoral shaft fractures. The mean age of the patients was 8.0 years (range, 4.0-16.0 years). All children were treated by retrograde ESIN. Fractures were categorized as either length stable or unstable. Length stability and complications were assessed. A subset of patients with final full-length, standing x-rays was also evaluated. We analyzed 63 stable and 43 length unstable fractures. The mean age and weight of the patients with stable and unstable fractures were similar. There was no difference in complication rates between groups (χ2(1) = 0.00, P = 0.99). There was no difference (t(96.93) = 0.53, P = 0.59) in femoral shaft length change. Leg length discrepancies as assessed by full-length standing radiographs at follow-up were similar (χ2(2) = 1.52, P = 0.47). Preadolescent children younger than 10 years do not experience increased complications after ESIN of length unstable femur fractures [odds ratio (OR) = 1.68 (0.18-16.87), P = 0.65]. Length unstable femur fractures are not at increased risk of more complications [OR = 0.90 (0.26-2.92), P = 0.87], early femoral shortening [OR = (0.42-2.02), P = 0.85], or leg length discrepancy [OR = (0.13-1.56), P = 0.21] when treated with ESIN. Prognostic Level III. See Instructions for Authors for complete description of levels of evidence.


Transient BOLD responses at block transitions.
Block-design fMRI responses include sustained components present for the duration of each task block as well as transient components at the beginning and end of each block. Almost all prior block-design fMRI studies have focused on the sustained response components while the transient responses at block transitions have been largely ignored. These transients, therefore, remain poorly characterized. We here present a systematic study of block-transition transient responses obtained using four widely divergent tasks. We characterize transient response topography and examine the extent to which these responses vary across different tasks and between block onset and offset. Our analysis reveals that certain regions show transient responses regardless of task or transition type. However, our analysis also shows that specific task state transitions give rise to transient responses with unique spatial profiles. Relevance of the current findings to studies of exogenous attention, task shifting, and the BOLD overshoot is discussed.


Surgery of Cerebral Cavernous Angiomas With Navigational Support.
Accurate localization and removal of deep-seated cavernomas through a less invasive approach is still a challenge. The aim of this study is to compare the efficacy of neuronavigation and ultrasound in guiding surgery for resection of deep-seated cavernomas by transsulcal microsurgical approach. A total of 38 consecutive patients who suffered from deep-seated cavernomas underwent surgery via a transsulcal microsurgical approach in our hospital between September 2016 and March 2018. Patients were randomly divided into 2 groups (20 cases in neuronavigation group and 18 cases in ultrasound group). The clinical features, character of images, and surgical outcome were analyzed. There was no significant difference between the 2 groups in diameter (16.6 ± 2.7 mm versus 19.6 ± 2.0 mm, P > 0.05) and depth (19.2 ± 2.4 mm versus 22.0 ± 4.6 mm, P > 0.05) of lesions. The ultrasound group had a similar tumor resection rate (100% versus 80%, P = 0.11) and shorter operation time (119.7 ± 4.5 minutes versus 137.3 ± 4.9 minutes, P < 0.05) than that in the neuronavigation group. There was no significant difference between in the symptomatic improvement rate, complication, postoperative hospital stay, and period of follow-up (P > 0.05). No death and recurrence appeared in both groups. Ultrasound showed certain advantages than neuronavigation in guiding resection of deep-seated cavernomas by transsulcal microsurgical approach.


Promoter-specific lentivectors for long-term, cardiac-directed therapy of Fabry disease.
In Fabry disease a deficiency of α-galactosidase A (α-gal A) activity leads to accumulation of globotriaosylceramide (Gb3) in various tissues including the heart. A specific cardiac variant of Fabry disease has also been described. Previously we have demonstrated the feasibility of gene therapy for Fabry disease. Here, to provide efficient transfer and increased specificity of transgene expression, we synthesized lentiviral vectors (LVs) with myocardial-specific promoters including: α-myosin heavy chain (α-MHC), myosin light chain (MLC2v), and cardiac troponin T (cTnT). Initially, neonatal Balb/c mice were injected with such LV constructs engineering expression of luciferase. One month post-injection, we found specific expression of luciferase in hearts of recipient animals when compared with transgene expression driven by the standard EF1-α promoter. To examine the feasibility of long-term therapy specifically targeting the heart, recombinant LV/α-gal A therapeutic vectors with analogous cardiac promoters were generated and injected into numerous neonatal Fabry mice. No immune response against the corrective α-gal A hydrolase was observed in the treated mice. Serum α-gal A activity of 10-week-old Fabry mice was increased in LV/α-gal A-injected animals compared to controls. In 28-week-old Fabry mice we observed significantly decreased Gb3 accumulation. Neonatal injections with LVs harboring cardiac-specific promoters may thus be an effective long-term treatment strategy for heart manifestations and cardiac variant Fabry disease. These results can be also extended to other progressive pathologies of the heart.


Plasma trypsin in chronic pancreatitis and pancreatic adenocarcinoma.
We have used a simple and precise radioimmunoassay to measure trypsin in human plasma. Fasting plasma trypsin concentrations were extremely low in patients with chronic pancreatitis with steatorrhoea (5 +/- 2 ng/ml) when compared to healthy controls (86 +/- 7 ng/ml, p less than 0.001). In patients with chronic pancreatitis but no steatorrhoea basal plasma trypsin levels were similar to those of the normal controls (99 +/- 25 ng/ml). A small but significant postprandial rise in plasma trypsin concentrations was observed in normal subjects (mean increment 15 +/- 4%, p less than 0.005, paired t test) but was absent in patients with chronic pancreatitis with steatorrhoea. In contrast to exocrine deficient chronic pancreatitis, other malabsorptive conditions associated with steatorrhoea (active coeliac disease and acute tropical sprue) demonstrated mean fasting trypsin concentrations similar to controls. Patients with adenocarcinoma of the pancreas had basal trypsin concentrations similar to healthy subjects as did patients with adenocarcinoma of the stomach, colon, rectum, brochus, and breast. In some cases measurement of plasma trypsin may be of help in the differential diagnosis of steatorrhoea.


Maxillofacial trauma in the gulf countries: a systematic review.
The objective of this review was to determine the prevalence, major causative factors and the most common sites of Maxillofacial Trauma in the Gulf Cooperation Council (GCC) Countries. All articles that were published in the English language in the databases such as Google Scholar, EBSCO, PubMed, NCBI, Medline, COCHRANE, ELSEVIER and SCOPUS were reviewed for MFT from GCC during the last 23 years. A total of 19,151 patients (16,567 males and 2584 females) (86-14%) with an age range between 0 and 97 years were included in the study. In all of the Gulf countries males outnumber females in terms of maxillofacial injuries with a ratio of 6.4:1. The mandible was the most common site of trauma followed by the maxilla. Road Traffic Accidents (RTA) was the most common cause of injury in the GCC followed by falls. Maxillofacial injuries are highly prevalent, distributed among the Gulf countries, and is mainly caused by RTAs especially among males who are highly prone to MFT in the gulf. The reasons are due to lack of road safety culture and weak enactment of traffic legislation, other possible factors include intrinsic car safety features, high speed driving and the amount/use of highways in these societies.


Neuroprotective Effects of Rutin in Streptozotocin-Induced Diabetic Rat Retina.
Diabetic retinopathy is widely recognized as a neurodegenerative disease of the eye. Increased oxidative stress has been considered the central factor in damaging neural retina in diabetes. Flavonoids, being powerful antioxidants, play protective roles in several oxidative stress-mediated neurodegenerative diseases. In this study, we analyzed the neuroprotective effects of a potential flavonoid, rutin, in the diabetic rat retina. Diabetes was induced in male Wistar rats by single injection of streptozotocin (65 mg/kg). In age-matched control (non-diabetic) and 1 week of diabetic rats, rutin (100 mg/kg/day) was orally administered and continued for 5 weeks. In another group of diabetic rats, only saline was supplemented. After treatments, retinas from all the groups were isolated and analyzed for potential neurotrophic factors and apoptotic and oxidative stress markers using biochemical and immunoblotting techniques. Our results indicate that rutin possesses antidiabetic activity, as blood glucose level decreased and insulin level increased in diabetic rats. In the diabetic retina, rutin supplementation enhanced the reduced levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glutathione (GSH) (P < 0.05), and reduced the level of thiobarbituric acid-reactive substances (TBARS) (P < 0.05). In addition, rutin treatment showed antiapoptotic activity by decreasing the level of caspase-3 and increasing the level of Bcl-2 in the diabetic retina. These results suggest the effectiveness of rutin in ameliorating the levels of neuroprotective factors in diabetic retina. Therefore, rutin might be a potential flavonoid that can prevent the retinal damage and subsequently the development of diabetic retinopathy.


Blood-Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy.
Background Blood-based DNA methylation patterns are linked to types of diseases. FKBP prolyl isomerase 5 (FKBP5), a protein cochaperone, is known to be associated with the inflammatory response, but the regulatory mechanisms by leukocyte FKBP5 DNA methylation in patients with dilated cardiomyopathy (DCM) remain unclear. Methods and Results The present study enrolled patients with DCM (n=31) and age-matched and sex-matched control participants (n=43). We assessed FKBP5 CpG (cytosine-phosphate-guanine) methylation of CpG islands at the 5' side as well as putative promoter regions by methylation-specific quantitative polymerase chain reaction using leukocyte DNA isolated from the peripheral blood. FKBP5 CpG methylation levels at the CpG island of the gene body and the promoter regions were significantly decreased in patients with DCM. Leukocyte FKBP5 and IL-1β (interleukin 1β) mRNA expression levels were significantly higher in patients with DCM than in controls. The protein expressions of DNMT1 (DNA methyltransferase 1) and DNMT3A (DNA methyltransferase 3A) in leukocytes were significantly reduced in patients with DCM. In vitro methylation assay revealed that FKBP5 promoter activity was inhibited at the methylated conditions in response to immune stimulation, suggesting that the decreased FKBP5 CpG methylation was functionally associated with elevation of FKBP5 mRNA expressions. Histological analysis using a mouse model with pressure overload showed that FKBP5-expressing cells were substantially infiltrated in the myocardial interstitium in the failing hearts, indicating a possible role of FKBP5 expressions of immune cells in the cardiac remodeling. Conclusions Our findings demonstrate a link between specific CpG hypomethylation of leukocyte FKBP5 and DCM. Blood-based epigenetic modification in FKBP5 may be a novel molecular mechanism that contributes to the pathogenesis of DCM.


Aflibercept for pigment epithelial detachment for previously treated neovascular age-related macular degeneration.
Assess the efficacy of intravitreal aflibercept on pigment epithelial detachments (PED) associated with previously treated patients with neovascular age-related macular degeneration (AMD). Retrospective study. Sixty eyes. Patients with persistent PED who were treated with intravitreal aflibercept (2.0 mg) with ≥2 previous injections of bevacizumab (1.25 mg) or ranibizumab (0.5 mg) were analyzed. Mean number of prior injections was 24.8 during a mean of 32 months of management (range 3-77 months). Baseline mean PED height was 258 µm (range 80-687 µm), which decreased at 1, 6, and 12 months upon switching to aflibercept to 226 µm (-14%, range 34-701 µm), 215 µm (-18%, range 0-666 µm), and 208 µm (-22%, range 0-752 µm), respectively. The majority of eyes experienced a decrease in PED height after switching to aflibercept: 50/58 (86%), 38/47 (81%), and 37/47 (79%) at months 1, 6, and 12, respectively. Reduction in PED height was weakly correlated with improved visual acuity (R(2) = 0.11). Intravitreal aflibercept resulted in significant reduction in PED height in previously treated eyes with neovascular AMD.


Characteristics of staff victims of psychiatric patient assaults: updated review of findings, 1995-2001.
This paper examines the peer-reviewed, databased journal articles on the characteristics of staff victims of psychiatric patient assaults from 1995 to 2001. These studies partially confirm earlier findings in that patient assaults on staff victims continue across all disciplines. Unlike findings in earlier reviews, this review found that psychiatric residents and older, more experienced nurses were at highest risk for violence. Since there is little empirical data on staff victims of assaults by Alzheimer's and other dementia patients, this paper will explore the implications of the present findings for long-term care settings.


31P-MRS study of bio-energy recovering phenomenon.
The ATP and creatine phosphate (PCr) contents in isolated guinea-pig hearts were determined by 31P-MRS measurement at 80.75 MHz using the Langendorff technique. Reperfusion of post-ischemic hearts with adenosine for 180 minutes increased ATP to 117.4% and decreased PCr to 59.8% of the preischemic value. Reperfusion without adenosine did not increase ATP and did not decrease PCr. The depressed cardiac function due to ischemia was remarkably improved in post-ischemic hearts by the increase in ATP due to adenosine. We found that the loss of ATP due to ischemia is not necessarily proportional to the extent of myocardial ischemic injury.


Are intratumoral microbiota involved in the progression of intraductal papillary mucinous neoplasms of the pancreas?
Microbiota have been reported to influence the development of various gastrointestinal neoplasms through the mechanism of sustained inflammation; however, few data are available regarding their influence on intraductal papillary mucinous neoplasms. The aim of this study was to assess the association between specific microbiota and the clinicopathologic characteristics of intraductal papillary mucinous neoplasms of the pancreas. DNA was extracted from formalin-fixed, paraffin-embedded samples of 30 patients who underwent pancreatectomy for intraductal papillary mucinous neoplasm, and polymerase chain reaction was used to create sequence libraries using the primer set for the V3 and V4 region of 16S recombinant DNA. Filtered sequence reads were then processed into operational taxonomic units with a 97% identity threshold and the relative abundance of bacteria compared between the 2 groups using operational taxonomic units. There was a trend toward fewer Firmicutes and more Proteobacteria and Fusobacteria in the relative abundance of main duct operational taxonomic units than in branch duct operational taxonomic units. The relative abundances of Bacteroidetes (P < .01) and Fusobacteria (P = .04) were significantly higher in invasive intraductal papillary mucinous neoplasms than in noninvasive intraductal papillary mucinous neoplasms. The relative abundance of the intestinal type was significantly lower in Firmicutes than the relative abundance of the nonintestinal type (P = .04). Notably, main duct operational taxonomic units with the intestinal subtype were affected by increased proportions of Proteobacteria and Fusobacteria, and Fusobacteria were abundant in the intestinal type of invasive main duct operational taxonomic units. Intratumoral microbiota may be involved in the progression of operational taxonomic units.


Role of splenic stroma in the action of bacterial lipopolysaccharides on radiation mortality: a study in mice carrying the Slj allele.
Slj/+ mice display a slight macrocytic anaemia due to a defect in their haemopoietic organ stroma. They have a deficient endogenous spleen colony (CFU-end) formation following sublethal doses of gamma-radiation compared with their normal +/+ littermates, which is likely to be due to the low pre-irradiation CFU-S content of the Slj/+ spleen. CFU-S in these congenic mice do not differ in their sensitivity to gamma-irradiation or stem cell-activating factor. While injection of +/+ mice with 10 micrograms of lipopolysaccharide-W (LPS) one day prior to irradiation led to a substantial increase in their survival, the survival of Slj/+ mice was only slightly increased. Irradiation induced a similar dose-related reduction in the numbers of CFU-S in the spleen and femora of LPS-injected Slj/+ mice compared to similarly treated +/+ mice when measured directly after irradiation. At Day 9 after irradiation, injection of LPS led to a significantly higher CFU-end formation and higher numbers of CFU-S and nucleated cells in the Slj/+ spleens compared to LPS-injected +/+ mice. No such differences in the radioprotective effect of LPS were observed in the +/+ and Slj/+ mice with respect to the splenic and femoral 59Fe-incorporation and the femoral CFU-S numbers at Day 9. These data strongly suggest a contribution by immigrating CFU-S to the CFU-S numbers and endogenous colony formation in at least the Slj/+ spleen after LPS injection and subsequent sublethal irradiation. The observations also imply that the splenic organ stroma may play a mediatory role in the radioprotective action of LPS. In addition, the data represent an extreme example of a lack of correlation between animal survival and haemopoietic parameters. Caution should be taken when applying endogenous colony counts as a means of screening potential anti-radiation drugs.


Combination of media, biomaterials and extracellular matrix proteins to enhance the differentiation of neural stem/precursor cells into neurons.
The purpose of this study was to induce the differentiation of neural stem/precursor cells (NSPC) more towards neurons than glial cells by the combination of media, biomaterials and extracellular matrix (ECM) proteins. Considering the role of serum, 10% fetal bovine serum or its fractions were added to DMEM/F12 medium to examine the effect of the differentiation-promoting potential on cultured NSPC isolated from embryonic rat cerebral cortex. The NSPC were cultured for 7 days, after which differentiation was assayed using immunocytochemistry for lineage specific markers. It was demonstrated that molecules promoting neuron differentiation were present in serum with molecular weight <100 kDa, which could dominate the differentiation of NSPC principally into neurons in the presence of basic fibroblast growth factor. In contrast, NSPC were induced to differentiate predominantly into glial cell phenotypes in the presence of whole serum components. Based on medium containing serum fraction, semi-quantification showed that the MAP2-positive percentage of the immunoreactive ratio within migrated cells could be promoted over 85% by combining poly(ethylene-co-vinyl alcohol) biomaterial and fibronectin matrix protein. These results are very encouraging, since an environment favorable for neuronal differentiation should be useful in the development of strategies for controlling the behavior of NSPC in neuroscience research.


Hepatic triglyceride lipase deficiency in liver disease.
The activity of post-heparin lipases in patients with alcoholic hepatitis and viral hepatitis was evaluated. Lipoprotein lipase and hepatic triglyceride lipase were differentiated by assay under high and low salt conditions and also by separation on heparin-agarose affinity chromatography columns. The mean activity of hepatic triglyceride lipase in the sera of liver disease patients was only 21-24% of the mean of controls, but lipoprotein lipase in patients' sera was not different from normal levels. Hepatic triglyceride lipase deficiency may partially account for the accumulation of a triglyceride-rich low density lipoprotein in liver disease.


Molecular cloning of protamine-2 and expression with aging in Japanese monkey (Macaca fuscata).
In order to isolate genes relating spermatogenesis with postnatal development and aging, we have attempted to obtain genes showing differences in expression in testis of Japanese monkeys ( Macaca fuscata) by means of differential display PCR, and we have cloned, sequenced and characterized protamine-2 (PRM2) of Japanese monkey. The predicted open reading frame encoded a protein of 103 amino acid residues, most of which are common to those of other mammals. Northern analysis revealed that the PRM2 gene is expressed at adult and aged stages, but not at the juvenile stage. In situ hybridization revealed that the PRM2 gene is expressed mainly in late spermatids and its expressional potential is decreased from adult to aged stages. It suggests that PRM2 in spermiogenesis is mediated by the age of the animal.


A safe and efficient method for elimination of cell culture mycoplasmas using ciprofloxacin.
The antibacterial activity of ciprofloxacin, a 4-fluoroquinolone antibiotic, in the control of mycoplasma contamination in experimentally infected cell lines has been investigated. Seven mycoplasma species, including M. hyorhinis, M. gallisepticum, M. orale, M. salivarium, M. hominis, M. fermentans, and M. arginini, which had chronically infected the murine plasmocytoma line X63-Ag8 653, were eradicated with 10 micrograms/ml ciprofloxacin. Wild type laboratory infections of two human cell lines, HL-60 and U-937, were eliminated by 12 days of such treatment. Mycoplasma decontamination of cell cultures was monitored by the cultivation method 4 weeks after treatment. No side effects were seen in cell cultures and complex proliferation assays with cells of human and murine origin, using ciprofloxacin in doses up to 2.5 times the usual bactericidal concentration.


Selective recognition of ATP by multivalent nano-assemblies of bisimidazolium amphiphiles through "turn-on" fluorescence response.
Bisimidazolium receptors, tagged with chromophoric pyrene at one end and linked to an n-alkyl chain at the other, underwent self-assembly in aqueous media depending on the length of the alkyl segment. The amphiphilic derivatives having n-decyl or longer chains, formed nano-assemblies with cyanic-green emission resulting from the stacked pyrene chromophores in the aggregates. The presence of positive surface charges on the multivalent aggregates led to ATP binding which was accompanied by a significant increase in the excimeric emission intensity. This provided a convenient way of monitoring ATP binding in a "turn-on" mode and an efficient detection of ATP was achieved in aqueous buffer and also in buffer containing 150 mM NaCl at physiological pH value. Furthermore, the multivalent aggregates demonstrated a significant selectivity in ATP detection over ADP, AMP and pyrophosphate.


Deceased-Donor Kidney Biopsy Scoring Systems for Predicting Future Graft Function: A Comparative Study.
Deceased-donor kidney quality pretransplantation is considered critical for future graft function. Assessment of donor kidney quality considers clinical and histologic variables. Several models that incorporate a variety of these factors have been proposed to predict long-term graft survival. We compared the performance metrics of 4 scoring systems models---the Maryland Aggregate Pathology Index, Banff, Remuzzi, and Leuven---for predicting renal allograft survival. In this retrospective cohort study, we analyzed 173 renal allografts that underwent preoperative baseline biopsy. Donor demographics and donor baseline histopathology data were collected and correlated with graft survival posttransplant. Among the 4 scoring systems, none were significantly associated with posttransplant graft survival or early graft function. The Maryland Aggregate Pathology Index scoring system had better predictive capacity in receiver operating characteristic curve analysis; however, the utility as a predictor of graft survival was only slightly better than chance. Baseline histologic features were individually analyzed, and it was found that none were associated with graft survival in this cohort. Among donor demographics, none were significantly associated with graft survival. In our study none of the 4 previously proposed predictive models were associated with graft survival after transplantation. Further studies are needed to define new models with stronger predictive value for graft outcome that could help minimize organ discards.


Macroscopic hematuria in patient with myelofibrosis caused by extramedullary hematopoiesis of bladder.
Extramedullary hematopoiesis (EMH) is a physiologic process in fetal life. However, after birth, its occurrence is abnormal, and it develops when hematopoiesis in the bone marrow is disturbed, such as occurs in many hematologic disorders. EMH can become symptomatic, depending on its extent and location. We describe the case of a 67-year-old man with postpolycythemic myelofibrosis who presented clinically with macroscopic hematuria due to EMH in the bladder. EMH in the bladder is extremely rare but illustrates the importance of an adequate pathologic assessment of transurethral resection chips, especially in patients with underlying disease.


Fluoride sensitivity in freshwater snail, Bellamya bengalensis (Lamarck, 1882): An integrative biomarker response assessment of behavioral indices, oxygen consumption, haemocyte and tissue protein levels under environmentally relevant exposure concentrations.
There is limited information on fluoride toxicity and risk overview on ecotoxicological risks to aquatic invertebrate populations particularly molluscan taxa. This necessitated the assessment of toxicity responses in the freshwater snail, Bellamya bengalensis exposed to environmentally relevant concentrations of sodium fluoride. Under lethal exposures (150, 200, 250, 300, 400 and 450 mg/l), the median lethal concentrations (LC50) were determined to be 422.36, 347.10, 333.33 and 273.24 mg/l for B. bengalensis at 24, 48, 72 and 96 h respectively. The rate of mortality of the snails was increased significantly with elevated concentrations of the toxicant. The magnitude of toxicity i.e., toxicity factor at different time scale was also higher with increased exposure duration. Altered behavioural changes i.e., crawling movement, tentacle movement, clumping tendency, touch reflex and mucous secretion in exposed snail with elevated concentrations and exposure duration. Similarly, oxygen consumption rate of the treated snail also lowered significantly during 72 and 96 h of exposure. Under 30-day chronic exposures (Control-0.00 mg/L; T1-27.324 mg/L; T2-54.648 mg/L), protein concentrations in gonad and hepatopancreas of exposure groups was significantly lowered. Chronic exposures also revealed lowered haemocytes counts in exposure groups. The potential for loss of coordination, respiratory distress and physiological disruption in organisms exposed to environmentally relevant concentrations of fluoride was demonstrated by this study. The estimation and magnitude of toxicity responses are necessary for a more accurate estimation of ecological risks to molluscan taxa and invertebrate populations under acute and chronic fluoride exposures in the wild.


Hypoalbuminemia in children with cancer treated with chemotherapy.
Hypoalbuminemia is a well-recognized finding associated with cancer, but its prevalence and prognostic significance have not been well studied in children with cancer. To determine the prevalence of hypoalbuminemia prior to starting chemotherapy in children with cancer and its association with relapse-free survival (RFS) and overall survival (OS). We performed a single institution, IRB-approved, retrospective review of pediatric oncology patients diagnosed between 1998 and 2012. Five-year survival was estimated using the Kaplan-Meier method; groups were compared using Cox regression. We identified 659 pediatric patients with a first diagnosis of cancer and a serum albumin level prior to starting chemotherapy. Mean age was 8.6 years (SD = 5.8); 62% were male and 92% were non-Hispanic. Hypoalbuminemia prior to starting chemotherapy was present at least once in 302 (45.8%). The five-year RFS and OS of those with hypoalbuminemia and without hypoalbuminemia were not significantly different. However, patients with severe hypoalbuminemia (defined as a value 10% or more below the lower limit of normal) had inferior RFS and OS for patients with hematologic/lymphatic malignancies, and inferior RFS for patients with metstatic Ewing sarcoma. Hypoalbuminemia prior to starting chemotherapy in pediatric oncology patients is common (nearly half in this cohort). Severe hypoalbuminemia was associated with inferior 5-year RFS in some subgroups.


Development of a calibration protocol and identification of the most sensitive parameters for the particulate biofilm models used in biological wastewater treatment.
Biofilm models are valuable tools for process engineers to simulate biological wastewater treatment. In order to enhance the use of biofilm models implemented in contemporary simulation software, model calibration is both necessary and helpful. The aim of this work was to develop a calibration protocol of the particulate biofilm model with a help of the sensitivity analysis of the most important parameters in the biofilm model implemented in BioWin® and verify the predictability of the calibration protocol. A case study of a circulating fluidized bed bioreactor (CFBBR) system used for biological nutrient removal (BNR) with a fluidized bed respirometric study of the biofilm stoichiometry and kinetics was used to verify and validate the proposed calibration protocol. Applying the five stages of the biofilm calibration procedures enhanced the applicability of BioWin®, which was capable of predicting most of the performance parameters with an average percentage error (APE) of 0-20%.


Postoperative hyperbilirubinemia and graft outcome in living donor liver transplantation.
Little information is available on the characteristics and clinical significance of serum bilirubin level early after liver transplantation. The aim of this study was to clarify the risk factors for early graft loss and to assess the significance of postoperative hyperbilirubinemia as a predictor of graft outcome in living donor liver transplantation (LDLT). We retrospectively analyzed perioperative parameters in 68 patients who underwent LDLT. Graft loss within 1 year post-LDLT was confirmed in 9 patients (13.4%). Univariate analysis of risk factors showed that preoperative Model for End-Stage Liver Disease score, donor age, postoperative peak serum bilirubin level (p-BIL) within 28 days after LDLT, and surgical complications were significant determinants of early graft loss (<1 year post-transplant). Multivariate analysis identified p-BIL (odds ratio = 1.170, 95% confidence interval = 1.030-1.329, P = 0.016) as the only independent predictor of early graft loss. The incidence of such loss was high in patients with p-BIL over 27.0 mg/dL (area under the receiver operating characteristic curve = 0.988). In conclusion, serum bilirubin level is a useful predictor of short-term (<1 year) graft outcome and for considering retransplantation in a timely fashion.


Pili in Gram-negative and Gram-positive bacteria - structure, assembly and their role in disease.
Many bacterial species possess long filamentous structures known as pili or fimbriae extending from their surfaces. Despite the diversity in pilus structure and biogenesis, pili in Gram-negative bacteria are typically formed by non-covalent homopolymerization of major pilus subunit proteins (pilins), which generates the pilus shaft. Additional pilins may be added to the fiber and often function as host cell adhesins. Some pili are also involved in biofilm formation, phage transduction, DNA uptake and a special form of bacterial cell movement, known as 'twitching motility'. In contrast, the more recently discovered pili in Gram-positive bacteria are formed by covalent polymerization of pilin subunits in a process that requires a dedicated sortase enzyme. Minor pilins are added to the fiber and play a major role in host cell colonization.This review gives an overview of the structure, assembly and function of the best-characterized pili of both Gram-negative and Gram-positive bacteria.


Voltage-gated sodium channel activity mediates sea urchin larval skeletal patterning through spatial regulation of Wnt5 expression.
Defining pattern formation mechanisms during embryonic development is important for understanding the etiology of birth defects and to inform tissue engineering approaches. In this study, we used tricaine, a voltage-gated sodium channel (VGSC) inhibitor, to show that VGSC activity is required for normal skeletal patterning in Lytechinus variegatus sea urchin larvae. We demonstrate that tricaine-mediated patterning defects are rescued by an anesthetic-insensitive version of the VGSC LvScn5a. Expression of this channel is enriched in the ventrolateral ectoderm, where it spatially overlaps with posterolaterally expressed Wnt5. We show that VGSC activity is required to spatially restrict Wnt5 expression to this ectodermal region that is adjacent and instructive to clusters of primary mesenchymal cells that initiate secretion of the larval skeleton as triradiates. Tricaine-mediated Wnt5 spatial expansion correlates with the formation of ectopic PMC clusters and triradiates. These defects are rescued by Wnt5 knockdown, indicating that the spatial expansion of Wnt5 is responsible for the patterning defects induced by VGSC inhibition. These results demonstrate a previously unreported connection between bioelectrical status and the spatial control of patterning cue expression during embryonic pattern formation.


An open-safety study of dual antiviral therapy in real-world patients with chronic hepatitis C.
Treatment of patients with chronic hepatitis C with alpha-interferon and ribavirin usually produces adverse events within the first 3 months. We aimed to assess safety and predictors of discontinuation or dose modification of these drugs. Observational study of 312 patients with predominantly genotype 1 chronic hepatitis C treated openly along 5 years in a clinical practice setting. Eighty-four percent of patients experienced at least one adverse event (853 events in total, 3.3 per patient on average). Incidence rate was higher during the first 90 days and decreased thereafter (<5%). Discontinuation rates at 30 and 90 days and at end of treatment were 2, 4 and 8%, respectively. Seventy percent of discontinuation cases were due to adverse events rather than to laboratory abnormalities. Serious adverse events were rare (<1%). Dose modifications were made in 158 patients (51%) on 237 occasions. After adjusting for covariates, older age was a predictor of early discontinuation, whereas HCV genotypes 1-4 and daily ribavirin dose of 1000 mg or more were predictors of dose modification. The majority of real-world patients with chronic hepatitis C tolerate acceptably dual therapy and very few discontinue it. Subjective decisions on dose reduction of either compound appears to have a major impact on adherence of patients. There is a need to better define, collect and analyse clinical features which may predict adverse events and safety-related decisions during therapy of chronic hepatitis C.


[Macrophageal antigen in the prostatic adenocarcinoma cells].
The macrophageal antigen complex HAM56yu was found in the limited areas of adrenocarcinoma. The presence of antigen complexes on the epithelium should be considered when interpreting the results of immunohistochemical study of metastases without a detected primary focus.


Total laparoscopic hysterectomy and laparoscopy-assisted vaginal hysterectomy.
To compare the feasibility of total laparoscopic hysterectomy (TLH) and laparoscopy-assisted vaginal hysterectomy (LAVH) in the treatment of benign gynecologic diseases and to determine the selection criteria for each technique. This was a retrospective medical records review of 168 patients who underwent TLH or LAVH performed by one surgeon. A chi-square test was used to compare the difference between the TLH and LAVH groups. Pearson's correlation coefficient was calculated for the relationship between the clinico-demographic factors of the patients. There were no differences between the 2 groups with respect to age, parity, history of abdominal delivery, body mass index, and indication for hysterectomy. The operative time was similar between the 2 groups (P>.99). The uterine weight was greater in the LAVH group compared to the TLH group (P<.01). Ten patients were converted from TLH to LAVH, because of a large uterus and/or a lower segmental mass on the uterus, making it difficult to expose the Koh cup rim contour. TLH and LAVH are safe, feasible methods by which to perform a hysterectomy. LAVH is preferred in patients with a mass involving the lower segment or a relatively large uterus.


Nanoparticles in medicine: therapeutic applications and developments.
Nanotechnology is the understanding and control of matter generally in the 1-100 nm dimension range. The application of nanotechnology to medicine, known as nanomedicine, concerns the use of precisely engineered materials at this length scale to develop novel therapeutic and diagnostic modalities. Nanomaterials have unique physicochemical properties, such as ultra small size, large surface area to mass ratio, and high reactivity, which are different from bulk materials of the same composition. These properties can be used to overcome some of the limitations found in traditional therapeutic and diagnostic agents.


island biogeography of Day Geckos (Phelsuma) in the Indian Ocean.
Step-wise multiple regression was employed to probe the determinants of species diversity of day geckos (Phelsuma) in the Indian Ocean. Independent variables were area, elevation, and two measures of isolation. Distance from Madagascar and island height (an indicator of habitat diversity) were the two most important predictors of species richness. Similar studies on other taxa rarely find isolation to be a major factor. The relatively poor dispersal abilities of reptiles may explain why isolation, rather than attributes of the islands, are more important in this case. The regressions also indicate that habitat diversity (assumed to correlate with maximum island elevation) is more important than area per se in determining species diversity. These results agree with predictions of the equilibrium theory of island biogeography, but historical processes have also greatly influenced species richness.


Treatment Decision-Making Capacity in Children and Adolescents Hospitalized for an Acute Mental Disorder: The Role of Cognitive Functioning and Psychiatric Symptoms.
This study was conducted to assess treatment decision-making capacity (TDMC) in a child and adolescent psychiatric sample and to verify possible associations between TDMC, psychiatric symptom severity, and cognitive functioning. Twenty-two consecutively recruited patients hospitalized for an acute mental disorder, aged 11-18 years, underwent measurement of TDMC by the MacArthur Competence Assessment Tool for Treatment (MacCAT-T). The MacCAT-T interview focused on patients' current treatment, which comprised second-generation antipsychotics (45.5%), first-generation antipsychotics (13.6%), antiepileptic drugs used as mood stabilizers or lithium carbonate (45.5%), selective serotonin reuptake inhibitors (32%), and benzodiazepines (18%). We moreover measured cognitive functioning (Wechsler Intelligence Scale for Children III) and psychiatric symptom severity (Brief Psychiatric Rating Scale v 4.0). Patients' TDMC varied within the sample, but MacCAT-T scores were good in the sample overall, suggesting that children and adolescents with severe mental disorders could be competent to consent to treatment. The TDMC proved independent of psychiatric diagnosis while being positively associated with cognitive functioning and negatively with excitement. The MacCAT-T proved feasible for measuring TDMC in a child and adolescent psychiatric sample. TDMC in minors with severe mental disorders was not necessarily impaired. These results deserve reconsidering the interplay between minors and surrogate decision-makers as concerning treatment decisions.


Assessing cognition in the era of COVID19: Do we need methods to assess cognitive function virtually?
With an aging population, cognitive impairment has become increasingly prevalent. Early symptoms are often missed in primary care and may progress to clinical dementia before being noticed. Screening for dementia has been a challenge. No clear guideline describes how to assess for cognition in primary care despite the robust data suggesting that early identification of dementia allows for mobilization of resources to support patients and caregivers, and there is no harm in proactive assessing cognition in older patients. In addition, most of the cognitive assessment methods requires in-person cognitive testing in primary care practices, this may be affected by situations where the in-person visitations to the physician offices are limited such as in the COVID 19 pandemic. Our study aims to access performance of in-person cognitive assessment in primary care during COVID 19 pandemic. Cleveland Clinic implanted MiniCog as a cognitive screening tool in primary care at Cleveland Clinic Community Care (4C). Inclusion criteria are- Age 65+, Annual Wellness visit, no preexisting diagnosis of dementia, normal MiniCog in previous year. Data were registered from from January 2019 until November 2020. Figure 1 displays the number of MiniCog performed at 4C averaging 360 MiniCog every month. Total number of MiniCogs performed during the study period was 7126 out of which 6739 were normal (95%) and 387 were abnormal (5%). Figure 2 displays the impact of COVID 19 pandemic on in-person visits in 4C, resulting an impressive decline in cognitive assessment process leading to no cognitive testing in April and only two tests in May. Most of the cognitive assessment tools used in clinical practice requires in-person office based and are often needed to diagnose dementia. Telephonic cognitive interviews such as TICS and MoCA 5 minute protocol are available, but are difficult to administer in primary care. The substantial drop in the performance of in-person cognitive assessment during the COVID 19 pandemic raises the need of validated tools to virtually assess cognitive function and also highlights the negative impact of COVID 19 pandemic on already frail processes of assessing cognitive health of older adults in primary care.


Neurophysiological characterization of commissurally projecting dentate neurons in the rat.
Commissural neurons in the dentate hilus and in the deep dentate granule cell layer were recorded intracellularly in vivo, in conjunction with combined injection of the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L) at sites of electrical stimulation. Two hilar neurons responded with short latency antidromic spikes to stimulation of the contralateral dentate infrapyramidal molecular layer, but did not show any synaptic potentials, suggesting that these neurons do not receive commissural hilar input, either directly or indirectly, from the stimulating sites. On the other hand, 3 dentate-hilar border neurons responded to the contralateral hilar stimulation with antidromic spikes, excitatory postsynaptic potentials (EPSPs), orthodromic spikes, and inhibitory PSPs (IPSPs), suggesting a rich synaptic interaction both commissurally and locally in this region. No direct commissural inhibition was observed in any of the cells. PHA-L injection at the stimulation site indicated that commissural hilar axon terminals project to a limited region of the contralateral molecular layer in a lamellar fashion, and have only a sparse distribution in the contralateral hilus. The results indicate that rapidly conducting commissural neurons in the dentate gyrus are themselves inhibited in an indirect manner by commissural fibers.


Tracking and Resolving CT Dose Metric Outliers Using Root-Cause Analysis.
The aim of this study was to examine the frequency and type of outlier dose metrics for three common CT examination types on the basis of a root-cause analysis (RCA) approach. Institutional review board approval was obtained for this retrospective observational study. The requirement to obtain informed consent was waived. Between January 2010 and December 2013, radiation dose metric data from 34,615 CT examinations, including 26,878 routine noncontrast CT head, 2,992 CT pulmonary angiographic (CTPA), and 4,745 renal colic examinations, were extracted from a radiation dose index monitoring database and manually cleaned. Dose outliers were identified on the basis of the statistical distribution of volumetric CT dose index and dose-length product for each examination type; values higher than the 99th percentile and less than the 1st percentile were flagged for RCA. There were 397 noncontrast CT head, 52 CTPA, and 80 renal colic outliers. Root causes for high-outlier examinations included repeat examinations due to patient motion (n = 122 [31%]), modified protocols mislabeled as "routine" (n = 69 [18%]), higher dose examinations for patients with large body habitus (n = 27 [7%]), repeat examinations due to technical artifacts (n = 20 [5%]), and repeat examinations due to suboptimal contrast timing (CTPA examinations) (n = 18 [5%]). Root causes for low-outlier examinations included low-dose protocols (n = 112 [29%]) and aborted examinations (n = 8 [2%]). On the basis of examination frequency over a 3-month period, the 90th and 10th percentile values were set in the radiation dose index monitoring database as thresholds for sending notifications to staff members responsible for outlier investigations. Systematic RCA of dose outliers identifies sources of variation and dose excess and pinpoints specific protocol and technical shortcomings for corrective action.


Structural studies of inositol 1,4,5-trisphosphate receptor: coupling ligand binding to channel gating.
The three isoforms of the inositol 1,4,5-trisphosphate receptor (IP(3)R) exhibit distinct IP(3) sensitivities and cooperativities in calcium (Ca(2+)) channel function. The determinants underlying this isoform-specific channel gating mechanism have been localized to the N-terminal suppressor region of IP(3)R. We determined the 1.9 Å crystal structure of the suppressor domain from type 3 IP(3)R (IP(3)R3(SUP), amino acids 1-224) and revealed structural features contributing to isoform-specific functionality of IP(3)R by comparing it with our previously determined structure of the type 1 suppressor domain (IP(3)R1(SUP)). The molecular surface known to associate with the ligand binding domain (amino acids 224-604) showed marked differences between IP(3)R3(SUP) and IP(3)R1(SUP). Our NMR and biochemical studies showed that three spatially clustered residues (Glu-20, Tyr-167, and Ser-217 in IP(3)R1 and Glu-19, Trp-168, and Ser-218 in IP(3)R3) within the N-terminal suppressor domains of IP(3)R1(SUP) and IP(3)R3(SUP) interact directly with their respective C-terminal fragments. Together with the accompanying paper (Yamazaki, H., Chan, J., Ikura, M., Michikawa, T., and Mikoshiba, K. (2010) J. Biol. Chem. 285, 36081-36091), we demonstrate that the single aromatic residue in this region (Tyr-167 in IP(3)R1 and Trp-168 in IP(3)R3) plays a critical role in the coupling between ligand binding and channel gating.


Ciprofloxacin-resistant Salmonella enterica serotype Typhimurium, China.
We characterized 44 Salmonella enterica serotype Typhimurium isolates from Tongji Hospital outpatients in Wuhan, China, May 2002-October 2005. All 31 ciprofloxacin-resistant isolates were also resistant to > or = 8 other antimicrobial drugs and carried > or = 2 mutations in GyrA and 1 mutation in ParC. Class 1 integrons were identified in 37 isolates.


Influence of carbon chain length of dietary fat on intestinal alkaline phosphatase in chylous ascites.
The long-term effects of chain length of dietary fat on intestinal lymphatic transport of alkaline phosphatase were investigated in two patients with chylous ascites due to leakage of intestinal lymph into the peritoneal cavity. Substitution of a medium-chain triglyceride diet for long-chain triglyceride resulted in a parallel fall in triglyceride and the intestinal isoenzyme of alkaline phosphatase in chylous ascites. The concentrations of lymph triglyceride were linearly related to lymph intestinal alkaline phosphatase levels, suggesting a positive relation between absorption of long-chain triglycerides and transport of mucosal alkaline phosphatase into lymph.


Lactiplantibacillus plantarum ELF051 Alleviates Antibiotic-Associated Diarrhea by Regulating Intestinal Inflammation and Gut Microbiota.
Probiotics are widely recognized for their ability to prevent and therapy antibiotic-associated diarrhea (AAD). This study was designed to evaluate Lactiplantibacillus plantarum ELF051 ability to prevent colon inflammation and its effect on gut microbial composition in a mouse model of AAD. The mice were intragastrically administered triple antibiotics for 7 days and then subjected to L. plantarum ELF051 for 14 days. The administration of L. plantarum ELF051 ameliorated the pathological changes in the colon tissue, downregulated interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and upregulated IL-10, and increased the intestinal short-chain fatty acids (SCFAs) level. Lactiplantibacillus plantarum ELF051 also regulated the Toll-like receptor/myeloid differentiation primary response 88/nuclear factor kappa light chain enhancer of activated B cells (TLR4/MyD88/NF-κB) and the phosphatidylinositol 3-kinase/protein kinase B/ NF-κB (PI3K/AKT/ NF-κB) inflammatory signaling pathways. 16S rRNA analyses showed that L. plantarum ELF051 increased the abundance and diversity of gut bacteria, restoring gut microbiota imbalance. A Spearman's rank correlation analysis showed that lactobacilli are closely associated with inflammatory markers and SCFAs. This work demonstrated that L. plantarum ELF051 can attenuate antibiotic-induced intestinal inflammation in a mouse AAD model by suppressing the pro-inflammatory response and modulating the gut microbiota.


Characteristics of asthma patients admitted to an intermediate respiratory care unit.
Intermediate respiratory care units (IRCU) provide continuous monitoring and non-invasive mechanical ventilation (NIMV) in patients with severe respiratory failure who are usually admitted to intensive care units (ICU). The usefulness of IRCU in managing severe asthma exacerbations has never been evaluated. Clinical data were prospectively and systematically compiled from patients admitted to the IRCU with a principal diagnosis of bronchial asthma exacerbation. We assessed therapeutic failure (intubation or exitus) and patient evolution up until 6 months after discharge compared with a group of patients admitted to a conventional hospital ward, paired for age and sex, and with the same principal diagnosis. A total of 74 asthma patients were included (37 admitted to IRCU and 37 to the hospital ward) with a mean age (±SD) of 58±20, who were predominantly women (67%), with previous diagnosis of asthma and persistent asthma treatment. The main cause of admittance to the IRCU was severe respiratory failure. The patients who were admitted to the IRCU presented more radiological affectation (alveolar infiltrates) and had significantly higher pCO(2). Ten patients admitted to the IRCU required NIMV. There were no differences between the two groups regarding either therapeutic failure or the 6-month follow-up after discharge. Patients with severe asthma exacerbations can be managed in an IRCU while avoiding hospitalization in an ICU and demonstrating a prognosis similar to milder exacerbations treated in conventional hospital wards.


Mononeuropathy in diabetes mellitus: a phenomenon easily overlooked.
In patients with diabetes, a carefully taken history and meticulously performed neurologic examination enable the clinician to separate superimposed mononeuropathy from more generalized symmetric polyneuropathy. Recognition of mononeuroparhy is important, since often it is reversible.


Genetic manipulation strategies for ethanol production from bioconversion of lignocellulose waste.
Lignocellulose waste was served as promising raw material for bioethanol production. Bioethanol was considered to be a potential alternative energy to take the place of fossil fuels. Lignocellulosic biomass synthesized by plants is regenerative, sufficient and cheap source for bioethanol production. The biotransformation of lignocellulose could exhibit dual significance-reduction of pollution and obtaining of energy. Some strategies are being developing and increasing the utilization of lignocellulose waste to produce ethanol. New technology of bioethanol production from natural lignocellulosic biomass is required. In this paper, the progress in genetic manipulation strategies including gene editing and synthetic genomics for the transformation from lignocellulose to ethanol was reviewed. At last, the application prospect of bioethanol was introduced.


Non-collagen genes role in digenic Alport syndrome.
Alport syndrome is a clinically heterogeneous nephropathy characterized by severe symptomatology at kidney level due to ultrastructural lesions of the glomerular basement membrane (GBM) as consequence of mutations in COL4 genes. The disease has been linked to COL4A3/COL4A4/COL4A5 mutations, which impair GBM functionality and can be inherited in a dominant, recessive or X-linked transmission. Although a targeted Next Generation Sequencing approach has allowed identifying families with pathogenic mutations in more than one COL4 α3-α4-α5 heterotrimer encoding genes, leading to conclude for a digenic pattern of inheritance, the role of non-collagen genes in digenic Alport syndrome has not yet been established. We employed a whole-exome sequencing approach on three families in whom a digenic pattern of transmission could be suspected because of a likely biparental contribution or an unexplained phenotype in the proband. We identified in the three probands hypomorphic LAMA5 mutations co-inherited with pathogenic COL4 α4-α5 chains mutations. Segregation analysis revealed that the combination of LAMA5/COL4 variants co-segregate with a fully penetrant phenotype in line with a digenic inheritance. In one of the three probands an hypomorphic variant in NPHS2 was also found, suggesting that role of other kidney disease related-genes as modifiers. These findings validate the impact of LAMA5 mutations in digenic ATS and highlight the role of extracellular matrix's genes, basement membrane, slit diaphragm and podocyte cytoskeleton in ATS. This underline the need for a more extensive panel approach in the presence of a digenic ATS, in order to better define clinical severity and recurrence risk for family members.


Biphenylsulfonamide endothelin receptor antagonists. Part 3: structure-activity relationship of 4'-heterocyclic biphenylsulfonamides.
A number of 4'-heterocyclic biphenylsulfonamide derivatives, formally derived from BMS-193884 (1) by replacing the oxazole ring with other heterocyclic rings, are potent and selective endothelin A (ET(A)) receptor antagonists. Among the analogues examined, the pyrimidine derivative 18 is the most potent (K(i)=0.9 nM) and selective for the ET(A) receptor, approximately equivalent to 1.


Level of evidence supporting the Chinese cardiovascular disease clinical practice guidelines and its evolution in the past two decades.
Clinical practice is guided by guidelines in the era of evidence-based medicine to improve healthcare. The consistency between the strength of recommendations and the underlying quality of evidence in clinical guidelines and its evolution dynamically reflects the status of medical practice in important aspects. This study aimed to evaluate the levels of evidence (LOEs) supporting different classes of recommendations (CORs) in Chinese cardiovascular disease (CVD) guidelines between 2003 and 2021, and changes over time. Clinical guideline documents on cardiovascular topics issued by leading professional organizations were retrieved in the Databases of SinoMed and Wanfang Med Online from inception to June 2021. All guidelines were screened through abstract and full-text reading, and included if satisfying the pre-specified criteria. 79 Chinese guideline documents on 12 sub-topics including a total of 5195 recommendations and the designated CORs/LOEs, were abstracted. The number of recommendations of Class Ⅰ, Class Ⅱ, Class Ⅲ, LOE A, LOE B, and LOE C were identified for each guideline document. The proportion of CORs, LOEs, and COR-LOE combinations in guidelines and the changes among those with ≥2 versions. A total of 79 guidelines were included in the analysis. When examining the status of current guidelines, among the 3325 recommendations derived from 59 documents during 2011-2021, 735 recommendations (22.1%) were classified as LOE A, 1280 (38.5%) as LOE B, and 1310 (39.4%) as LOE C. 596 recommendations (17.9%) were characterized as Class Ⅰ-LOE A, accounting for the majority of LOE A recommendations but only one-third of Class I recommendations. Evidence levels varied greatly across different sub-topics and individual guidelines. There are 9 guidelines on 5 sub-topics having ≥2 versions. When analyzing the changes over time, although an increase was observed in the total number of recommendations, the proportion of recommendations designated as Class Ⅰ-LOE A did not significantly improve (19.1% [current] vs 19.0% [prior], p = 0.97). In current Chinese CVD guidelines, the high level of evidence lacks, and its alignment with strong recommendations is deficient. Although it shows moderate improvements in certain major topics (e.g., coronary artery disease, interventional therapy, surgery) in the past two decades, the overall proportion of Class I-LOE A recommendations remains small, suggesting that conduction, and particularly translation, of high-quality studies like RCTs addressing CVDs-related questions are still essential and demanded, especially for areas with less attention. This study was supported by Beijing Nova Program from Beijing Municipal Science & Technology Commission (Z211100002121063, Z201100006820002); Fundamental Research Funds for the Central Universities (3332022023); National Key R&D Program of China (2020YFC2004705); CAMS Innovation Fund for Medical Sciences (2021-I2M-5-003); National Natural Science Foundation of China (81825003, 91957123, 82270376).


Clinical and microbiological outcomes of photodynamic and systemic antimicrobial therapy in smokers with peri-implant inflammation.
To compare the effectiveness of two protocols in the treatment of peri-implant mucositis (p-iM) among cigarette smokers. Three groups were randomized into (i) single session of antimicrobial photodynamic therapy (aPDT) with mechanical debridement (MD) (Group-A), (ii) systemic AB with MD (Group-B), and (iii) MD alone (Group-C). Clinical peri-implant parameters including plaque scores (PS), bleeding on probing (BOP) and probing depth (PD) were measured at baseline, 6 weeks and 12 weeks. Microbiological parameters included the assessment of percentage level of Pseudomonas aeruginosa and Staphylococcus aureus at baseline and 12 weeks. All parameters were analyzed using Friedman test and multiple comparisons performed using Bonferroni tests. P-value less than 0.05 were considered statistically significant. At 6 weeks of follow-up, there was a statistically significant reduction in PS (p < 0.001), BOP (p < 0.01), and PD (p < 0.05) among patients in groups A and B on intragroup comparison. At 12 weeks of follow-up, there was a further significant reduction in PS (p < 0.001) and BOP (p < 0.01) among patients in groups A and B on intragroup comparison but this reduction was comparable with 6-week follow-up. On inter-group comparison, only Group-A showed statistically significant reduction in BOP compared to Group-B and C at 6 weeks (p < 0.05). The levels of both P. aeruginosa and S. aureus in Group-A and Group-B showed statistically significant reductions at 12 weeks compared with baseline (p < 0.01). On inter-group comparison, Group-A and B showed no significant differences at follow-up (p > 0.05). This short term clinical study suggests that aPDT as an adjunct to MD is as efficacious as adjunctive antibiotic therapy. However, additional benefits in the reduction of bleeding scores were observed for aPDT in peri-implant inflammation among cigarette smokers.


Bilateral vestibular loss after caloric irrigation: clinical application of vestibular rehabilitation.
Bilateral vestibular loss is a rare diagnosis among patients with dizziness and imbalance. Nevertheless, symptoms are often disabling and therapy has yet to be established. To evaluate and describe the clinical outcome of patients with imbalance due to bilateral vestibular loss after a caloric test treated with vestibular rehabilitation. Retrospective case report. Pre- and post-treatment outcomes were evaluated in 8 individuals suffering from post-caloric bilateral vestibular paresis who were submitted to vestibular rehabilitation. Clinical improvement after vestibular rehabilitation was observed in 7 (87.5%) of the 8 patients. Although complete compensation for bilateral vestibular loss is not expected, vestibular rehabilitation may be used as a therapeutic method in these patients.


Captive-born cotton-top tamarins (Saguinus oedipus) respond similarly to vocalizations of predators and sympatric nonpredators.
What types of cues do callitrichid primates use to detect and respond to predators? Do they respond to predator-specific cues or to more general cues? The evidence for these questions remains conflicting. We presented captive-born and reared cotton-top tamarins with no previous exposure to predators (or predator cues) with vocalizations from three potential predators of cotton-top tamarin in the wild (white hawk, jaguar, and tayra) and with vocalizations from sympatric nonpredators (black-faced antthrush and red howler monkey). Vocalizations from predators and from nonpredator mammals elicited equivalent arousal, fear, and vocal responses. Howler monkey roars produced the strongest responses. The results suggest that predator-naïve cotton-top tamarins do not recognize specific predator vocalizations, but may respond to vocal qualities (low-frequency, noisy sounds) that indicate large body size, threat, or aggression. On the other hand, tamarins responded much more strongly to the higher frequency calls from the hawk than the antthrush, suggesting another mechanism must also be involved. The failure of captive-reared tamarins to distinguish between vocalizations of predators and nonpredator mammals has important implications for reintroduction studies.


Connectedness underlies the underestimation of the horizontal vertical illusion in L-shaped configurations.
L-shaped configuration is a commonly used stimulus configuration in studying horizontal vertical illusion. Here, we report that the horizontal vertical illusion is substantially underestimated when the L-shaped configuration is used for evaluating the illusion. Experiment 1 found that, in a length perception task, the perceived length of a vertical bar was about 10% longer than that of a horizontal bar with the same physical size. Similar amount of HVI was found in a length comparison task, in which the length of a horizontal bar was compared to that of a vertical bar and the two bars were presented separately in space or in time. In contrast, when the length comparison task was conducted with the two bars being arranged in a connected L-shape, the illusion was halved in strength. Experiment 2 and 3 studied what might be the cause of this L-shape induced HVI-underestimation. Two factors were investigated: the connectedness of the two lines, and the 45° absolute orientation or the 45° inner angle information embedded in the upright isosceles L-shape. The results showed that the HVI strength was not much affected when the 45° absolute orientation and the 45° angle information was made useless for the length comparison task. In contrast, the illusion was significantly reduced in strength whenever the two lines were separated as compared to when they were connected. These results suggested that the connectedness of the two lines must underlie the underestimation of the horizontal vertical illusion in the L-shaped configurations.


Cartilage repair: generations of autologous chondrocyte transplantation.
Articular cartilage in adults has a limited capacity for self-repair after a substantial injury. Surgical therapeutic efforts to treat cartilage defects have focused on delivering new cells capable of chondrogenesis into the lesions. Autologous chondrocyte transplantation (ACT) is an advanced cell-based orthobiologic technology used for the treatment of chondral defects of the knee that has been in clinical use since 1987 and has been performed on 12,000 patients internationally. With ACT, good to excellent clinical results are seen in isolated post-traumatic lesions of the knee joint in the younger patient, with the formation of hyaline or hyaline-like repair tissue. In the classic ACT technique, chondrocytes are isolated from small slices of cartilage harvested arthroscopically from a minor weight-bearing area of the injured knee. The extracellular matrix is removed by enzymatic digestion, and the cells are then expanded in monolayer culture. Once a sufficient number of cells has been obtained, the chondrocytes are implanted into the cartilage defect, using a periosteal patch over the defect as a method of cell containment. The major complications are periosteal hypertrophy, delamination of the transplant, arthrofibrosis and transplant failure. Further improvements in tissue engineering have contributed to the next generation of ACT techniques, where cells are combined with resorbable biomaterials, as in matrix-associated autologous chondrocyte transplantation (MACT). These biomaterials secure the cells in the defect area and enhance their proliferation and differentiation.


A single-centre long-term outcome analysis of artificial urinary sphincter placement in children.
To retrospectively evaluate the outcome of artificial urinary sphincter (AUS) placement in 79 children, with a mean follow-up of 12.5 years. A total of 89 children had an AUS placed between 1977 and 1994; complete data were obtained for 79 (63 boys and 16 girls). The indication for AUS placement was urinary incontinence caused by sphincteric deficiency with a stable bladder. Before and after surgery, all patients underwent ultrasonography, voiding cysto-urethrography and urodynamics. Logistic regression was used to assess the factors influencing the outcome. The mean (range) age at surgery was 11.7 (3-18) years. The cause of incontinence was a neuropathic bladder in 74 patients and bladder exstrophy in five. At a mean (range) follow-up of 12.5 (5-22) years, 63 of 79 patients (80%) had an intact AUS. The AUS was removed in 16 patients (20%) because of erosion at a mean (range) of 5.6 (1-11) years after insertion; there were 0.035 revisions per patient-year. Of 63 patients with an AUS in place, 57 (90%) are completely dry and 36 (57%) are using clean intermittent catheterization. Thirteen patients (20%) developed bladder instability during the follow-up, which was managed by anticholinergics in eight, spinal cord de-tethering in three and enterocystoplasty in two. Hydronephrosis occurred in 12 of 126 renal units (10%) that improved after enterocystoplasty or anticholinergics. The overall 10-year survival of the AUS was 79% (78% for early models and 80% for the AMS800); the survival was not affected by age, sex, model, previous bladder neck surgery, augmentation cystoplasty or intermittent catheterization. Bladder exstrophy was associated with lower AUS survival, as four of the five patients affected had the AUS removed secondary to erosion (P = 0.014). In children the AUS has a 79% 10-year survival and gives a 90% continence rate. Bladder instability after AUS placement can be managed with anticholinergics or enterocystoplasty. The AUS is not a justifiable treatment option for patients with bladder exstrophy.


Cause-specific mortality by county, race, and ethnicity in the USA, 2000-19: a systematic analysis of health disparities.
Large disparities in mortality exist across racial-ethnic groups and by location in the USA, but the extent to which racial-ethnic disparities vary by location, or how these patterns vary by cause of death, is not well understood. We aimed to estimate age-standardised mortality by racial-ethnic group, county, and cause of death and describe the intersection between racial-ethnic and place-based disparities in mortality in the USA, comparing patterns across health conditions. We applied small-area estimation models to death certificate data from the US National Vital Statistics system and population data from the US National Center for Health Statistics to estimate mortality by age, sex, county, and racial-ethnic group annually from 2000 to 2019 for 19 broad causes of death. Race and ethnicity were categorised as non-Latino and non-Hispanic American Indian or Alaska Native (AIAN), non-Latino and non-Hispanic Asian or Pacific Islander (Asian), non-Latino and non-Hispanic Black (Black), Latino or Hispanic (Latino), and non-Latino and non-Hispanic White (White). We adjusted these mortality rates to correct for misreporting of race and ethnicity on death certificates and generated age-standardised results using direct standardisation to the 2010 US census population. From 2000 to 2019, across 3110 US counties, racial-ethnic disparities in age-standardised mortality were noted for all causes of death considered. Mortality was substantially higher in the AIAN population (all-cause mortality 1028·2 [95% uncertainty interval 922·2-1142·3] per 100 000 population in 2019) and Black population (953·5 [947·5-958·8] per 100 000) than in the White population (802·5 [800·3-804·7] per 100 000), but substantially lower in the Asian population (442·3 [429·3-455·0] per 100 000) and Latino population (595·6 [583·7-606·8] per 100 000), and this pattern was found for most causes of death. However, there were exceptions to this pattern, and the exact order among racial-ethnic groups, magnitude of the disparity in both absolute and relative terms, and change over time in this magnitude varied considerably by cause of death. Similarly, substantial geographical variation in mortality was observed for all causes of death, both overall and within each racial-ethnic group. Racial-ethnic disparities observed at the national level reflect widespread disparities at the county level, although the magnitude of these disparities varied widely among counties. Certain patterns of disparity were nearly universal among counties; for example, in 2019, mortality was higher among the AIAN population than the White population in at least 95% of counties for skin and subcutaneous diseases (455 [97·8%] of 465 counties with unmasked estimates) and HIV/AIDS and sexually transmitted infections (458 [98·5%] counties), and mortality was higher among the Black population than the White population in nearly all counties for skin and subcutaneous diseases (1436 [96·6%] of 1486 counties), diabetes and kidney diseases (1473 [99·1%]), maternal and neonatal disorders (1486 [100·0%] counties), and HIV/AIDS and sexually transmitted infections (1486 [100·0%] counties). Disparities in mortality among racial-ethnic groups are ubiquitous, occurring across locations in the USA and for a wide range of health conditions. There is an urgent need to address the shared structural factors driving these widespread disparities. National Institute on Minority Health and Health Disparities; National Heart, Lung, and Blood Institute; National Cancer Institute; National Institute on Aging; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Office of Disease Prevention; and Office of Behavioral and Social Sciences Research, US National Institutes of Health.


In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol.
A novel ketone ester, bis hexanoyl (R)-1,3-butanediol (BH-BD), has been developed as a means to elevate blood ketones, for use as an energy substrate and a signaling metabolite. The metabolism of BH-BD and its effects on blood beta-hydroxybutyrate (BHB) levels was evaluated in various in vitro matrices and through analysis of plasma collected from Sprague Dawley rats and C57/BL6 mice in two oral gavage studies. A well-characterized ketone ester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (HB-BHB), was used as an active control throughout. In vitro assay results demonstrated that BH-BD likely remains intact in the stomach and is hydrolyzed in the small intestine into hexanoate and (R)-1,3-butanediol. If absorbed intact, BH-BD is subject to hydrolysis by non-CYP enzymes in liver and esterases in plasma. If BH-BD reaches the lower intestine it is metabolized by gut flora. Plasma BHB delivery increased in a dose-dependent manner in rats and mice following oral administration of BH-BD. All doses of BH-BD were well tolerated. At doses over 3 g/kg, BHB delivery was similar between BH-BD and HB-BHB. The results of these studies support the hydrolysis of BH-BD into hexanoate and (R)-1,3-butanediol which are metabolized into BHB, delivering a well-tolerated, sustained and dose-dependent increase in plasma BHB in rodents.


Late presenting complicated coronary stent infection of left anterior descending artery with antero-posterior communication.
Coronary stent infections (CSI) are rare but a potentially life-threatening disease, the incidence of which has been on a rise over the last two decades. We report the case of a patient who presented with episodes of fever and discharging sternal wound. The patient was diagnosed as CSI arising from the left anterior descending artery stent which was communicating anteriorly to the skin and posteriorly as lobar-fistula. He was treated by stent removal and plication of the fistula. Blood culture, culture of the pus and infected stent, and coronary angiography are the preferred diagnostic modalities, followed by positron emission tomography (PET) scan and cardiac magnetic resonance imaging (MRI) for delineating the extent of pathology. Surgery seems to be the treatment of choice, providing a definitive diagnosis of CSI and removing the source of infection, repairing aneurysms, and providing bypass vascular grafts if feasible. Thorough evaluation and a multidisciplinary approach with the institution of appropriate medical and surgical therapy lead to timely detection and good outcome.


Traumatic Brain Injury and Behavior: A Practical Approach.
Traumatic brain injury (TBI) is a complex neurologic and neuropathologic process that may affect the patient's behavior permanently. Clinically, TBI is associated with a wide gamut of neurologic and psychiatric disorders, such as amnesia, cognitive decline, seizures, attention and concentration deficits, depression, manic behavior, psychosis, hostile and violent behavior, and personality alterations. Therapy and rehabilitative efforts should be designed based on the type of injury and the patient's specific needs. Gaining familiarity with the behavioral disorders outlined in this article and understanding how to identify and treat them plays a significant role in the management of patients with TBI.


The effect of polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair) on oral microbial colonization and pain control compared with other rinsing solutions in patients with oral mucositis after allogeneic stem cells transplantation.
Gelclair is an oral lubricating gel used in the management of oral mucositis (OM). We evaluated its efficacy, tolerance and impact on oral cavity microbial colonization in patients with OM after allogeneic hematopoietic stem cells transplantation. Gelclair was administered in a group of 22 patients with active OM. A control group of 15 patients used other rinsing solutions (chlorhexidine, benzydamine, salvia). Tests with oral cavity swabs for microbiology analysis were performed once a week. The characteristics of OM in both groups were comparable, and rinsing solutions had satisfactory tolerability. There was no difference in the median improvement of oral intake and OM-related pain relief, which was assessed mostly as "slight effect". In the Gelclair group, the effect duration was longer (median 3 [0-5] vs. 1 [0-3] hours, p = 0.001). There was significant increase of Enterococcus faecalis and Candida sp. colonization of the oral cavity over the course of the hospitalization and significantly reduced incidence of such colonization in patients with OM in the Gelclair group: 1/22 (5%) vs. 6/15 (40%), p = 0.01. In vitro tests showed inhibited growth of Enterococcus faecalis and Candida sp. colonies within the area of the Gelclair application. Gelclair may be individually helpful in the management of OM and pain in patients after allogeneic stem cells transplantation. Its use did not lead to worsened oral bacterial and yeast colonization and probably even helped to protect mucosa from Enterococcus and Candida sp. Further studies based on larger cohorts are needed.


[Treatment of swine cell line with antibiotics: effect on growth kinetics and susceptibility to foot-and-mouth disease virus and to mycoplasma-like organisms].
Cell cultures treated with tylosin tartrate and kanamycin sulphate antibiotics were studied in relation to the cell growth rate, the susceptibility to the foot-and-mouth disease virus and to the microorganism eradication. These treatments did not affect the cell growth rate and the cell behavior to the viral infection. On the other hand, the decontamination of the intracytoplasmatic formas of mycoplasma-like organism was not observed.


Three-dimensional visualization of heart-wide myocardial architecture and vascular network simultaneously at single-cell resolution.
Obtaining various structures of the entire mature heart at single-cell resolution is highly desired in cardiac studies; however, effective methodologies are still lacking. Here, we propose a pipeline for labeling and imaging myocardial and vascular structures. In this pipeline, the myocardium is counterstained using fluorescent dyes and the cardiovasculature is labeled using transgenic markers. High-definition dual-color fluorescence micro-optical sectioning tomography is used to perform heart-wide tissue imaging, enabling the acquisition of whole-heart data at a voxel resolution of 0.32 × 0.32 × 1 μm3. Obtained structural data demonstrated the superiority of the pipeline. In particular, the three-dimensional morphology and spatial arrangement of reconstructed cardiomyocytes were revealed, and high-resolution vascular data helped determine differences in the features of endothelial cells and complex coiled capillaries. Our pipeline can be used in cardiac studies for examining the structures of the entire heart at the single-cell level.


Comparison of Different Scoring Systems Based on Both Donor and Recipient Characteristics for Predicting Outcome after Living Donor Liver Transplantation.
In order to provide a good match between donor and recipient in liver transplantation, four scoring systems [the product of donor age and Model for End-stage Liver Disease score (D-MELD), the score to predict survival outcomes following liver transplantation (SOFT), the balance of risk score (BAR), and the transplant risk index (TRI)] based on both donor and recipient parameters were designed. This study was conducted to evaluate the performance of the four scores in living donor liver transplantation (LDLT) and compare them with the MELD score. The clinical data of 249 adult patients undergoing LDLT in our center were retrospectively evaluated. The area under the receiver operating characteristic curves (AUCs) of each score were calculated and compared at 1-, 3-, 6-month and 1-year after LDLT. The BAR at 1-, 3-, 6-month and 1-year after LDLT and the D-MELD and TRI at 1-, 3- and 6-month after LDLT showed acceptable performances in the prediction of survival (AUC>0.6), while the SOFT showed poor discrimination at 6-month after LDLT (AUC = 0.569). In addition, the D-MELD and BAR displayed positive correlations with the length of ICU stay (D-MELD, p = 0.025; BAR, p = 0.022). The SOFT was correlated with the time of mechanical ventilation (p = 0.022). The D-MELD, BAR and TRI provided acceptable performance in predicting survival after LDLT. However, even though these scoring systems were based on both donor and recipient parameters, only the BAR provided better performance than the MELD in predicting 1-year survival after LDLT.


Molecular mechanisms of heavy metal hyperaccumulation and phytoremediation.
A relatively small group of hyperaccumulator plants is capable of sequestering heavy metals in their shoot tissues at high concentrations. In recent years, major scientific progress has been made in understanding the physiological mechanisms of metal uptake and transport in these plants. However, relatively little is known about the molecular bases of hyperaccumulation. In this paper, current progresses on understanding cellular/molecular mechanisms of metal tolerance/hyperaccumulation by plants are reviewed. The major processes involved in hyperaccumulation of trace metals from the soil to the shoots by hyperaccumulators include: (a) bioactivation of metals in the rhizosphere through root-microbe interaction; (b) enhanced uptake by metal transporters in the plasma membranes; (c) detoxification of metals by distributing to the apoplasts like binding to cell walls and chelation of metals in the cytoplasm with various ligands, such as phytochelatins, metallothioneins, metal-binding proteins; (d) sequestration of metals into the vacuole by tonoplast-located transporters. The growing application of molecular-genetic technologies led to the well understanding of mechanisms of heavy metal tolerance/accumulation in plants, and subsequently many transgenic plants with increased resistance and uptake of heavy metals were developed for the purpose of phytoremediation. Once the rate-limiting steps for uptake, translocation, and detoxification of metals in hyperaccumulating plants are identified, more informed construction of transgenic plants would result in improved applicability of the phytoremediation technology.


Multilayers based on cationic nanocomplexes for co-delivery of doxorubicin and DNA.
Co-delivery of drugs and genes has synergistic advantages in many fields such as cancer treatments. In this study, we present a multilayers for co-delivery of doxorubicin (DOX) and DNA. Ferrocene-modified polyethyleneimine (PEI-Fc) is synthesized, and it can form micelles in solution with ferrocene core and PEI shell. DOX and DNA are thus incorporated into the core and shell of the micelles, respectively, to form the PEI-Fc-DOX-DNA nanocomplexes. Such cationic nanocomplexes are used to construct multilayers through layer-by-layer assembly with negatively charged dextran sulfate (DS). We show that the multilayers can release DOX, and the release can be significantly enhanced in a hydrogen peroxide condition. Moreover, the multilayers have the ability to transfect cells through a substrate-mediated mode. The (PEI-Fc-DOX-DNA/DS) multilayers can be potentially applied to the biomedical devices for cancer treatment, regenerative medicine, etc.


James Fitzjames Fraser West, FRCS (1833-83): his involvement in Birmingham's local medical societies and the role they played in his life.
Professional institutions played an important role in the life of Birmingham surgeon James FF West and his colleagues. West held office in the Birmingham Medical Institute, the Midland Medical Society, the Birmingham Medical Benevolent Society and the local branch of the British Medical Association. He was an energetic and active participant who helped promote the principles and maintain the usefulness of the societies with which he was involved. Societies came into existence mostly thanks to the generosity and endeavours of those they served, and exclusivity was both jealously guarded and challenged. Spreading expertise through debate and fostering social intercourse was the raison d'être of most of Birmingham's societies but, when less fortunate colleagues needed support, the Birmingham Medical Benevolent Society was not the only society to provide it.


The influence of obesity on androstenedione to testosterone ratio in women with polycystic ovary syndrome (PCOS) and hyperandrogenemia.
The aim of the present study was to evaluate the impact of obesity and insulin resistance on testosterone formation from androstenedione and its contribution to biochemical hyperandrogenemia in all different phenotypic subgroups of PCOS patients. The case-control study included 1087 PCOS women and 206 regularly menstruating, ovulatory controls. The main clinical measurements included anthropometric and basal hormonal characteristics and evaluation of hyperandrogenic and insulin resistance-related features. The results were the following: In PCOS women with biochemical hyperandrogenemia, obesity significantly lowers serum A levels and increases T to A ratio. These findings were not present in PCOS women with clinical hypeandrogenemia and in normal ovulatory controls.


Cardiovascular risk factors in semi-urban communities in southwest Nigeria: Patterns and prevalence.
Over 80% of cardiovascular deaths take place in low- and middle-income countries; most of these deaths are due to modifiable risk factors. The study aimed at estimating the prevalence and pattern of major cardiovascular risk factors in both men and women older than 18 years. This is a cross-sectional study of cardiovascular risk factors among semi-urban dwellers in Ekiti State, south-western, Nigeria. 750 participants were drawn from 10 communities. The instrument used was the standard WHO STEPS (II) questionnaire, while blood samples were obtained for analysis. There were 750 participants with 529 (70.53%) females. The mean age of participants was 61.7±18.50 years and participants' ⩾65 years comprised 38.3%. There were 0.8%, 24.9% and 12.4%, who at the time of this study smoked cigarettes, consumed alcohol, and ate a high salt diet, respectively. The prevalence of hypertension, diabetes, generalized and abdominal obesity was 47.2%, 6.8%, 8.5% and 32.0%, respectively, with only 48.9% receiving hypertension treatment. Elevated total cholesterol, LDL-cholesterol, and low HDL was seen in 4.4%, 16.7% and 56.3% respectively. High prevalence of cardiovascular risk factors call for an urgent need for more public health attention and reinforcement of primary preventive strategies to curb its menace.


The awareness of hindfoot malalignment on non-weight-bearing ankle MRI.
Hindfoot malalignment is a relatively common clinical finding and several studies have suggested that hindfoot valgus can be identified on non-weight-bearing ankle MRI. The aim of this study was to determine the awareness of hindfoot malalignment on ankle MRI amongst consultant musculoskeletal radiologists. All MRI studies referred by Foot and Ankle Unit Consultants reported by one of 14 consultant musculoskeletal radiologists between March 2016 and August 2019 were retrieved from the Hospital Radiology Information System. These were reviewed independently by a radiology fellow and a consultant radiologist. Tibiocalcaneal angle (TCA) was measured, and extra-articular talocalcaneal (EA-TCI) and calcaneofibular impingement (EA-CFI) were recorded. Radiology reports were then analysed for mention of hindfoot malalignment and the presence of EA-TCI and EA-CFI. The study group comprised 129 patients, 46 males and 83 females with a mean age of 46.8 years (range 8-84 years). Based on review, hindfoot valgus was present in 78-80 cases (60.5-62%), EA-TCI in 30-36 cases (23.2-27.9%) and EA-CFI in 18-21 cases (14-16.3%). By comparison, MRI reports mentioned hindfoot valgus in 18 cases (2 incorrectly), EA-TCI in 8 cases (1 incorrectly) and EA-CFI in 10 cases (1 incorrectly). Hindfoot valgus, EA-TCI and EA-CFI were present relatively commonly on review of ankle MRI studies in patients referred from a specialist Foot and Ankle Unit but were commonly under-reported highlighting a relative lack of awareness of hindfoot malalignment on ankle MRI amongst musculoskeletal radiologists, which could impact negatively on patient management.


Control of protein trafficking by reversible masking of transport signals.
Systems that allow the control of protein traffic between subcellular compartments have been valuable in elucidating trafficking mechanisms. Most current approaches rely on ligand or light-controlled dimerization, which results in either retardation or enhancement of the transport of a reporter. We developed an alternative approach for trafficking regulation that we term "controlled unmasking of targeting elements" (CUTE). Regulated trafficking is achieved by reversible masking of the signal that directs the reporter to its target organelle, relying on the streptavidin-biotin system. The targeting signal is generated within or immediately after a 38-amino acid streptavidin-binding peptide (SBP) that is appended to the reporter. The binding of coexpressed streptavidin to SBP causes signal masking, whereas addition of biotin causes complex dissociation and triggers protein transport to the target organelle. We demonstrate the application of this approach to the control of nuclear and peroxisomal protein import and the generation of biotin-dependent trafficking through the endocytic and COPI systems. By simultaneous masking of COPI and endocytic signals, we were able to generate a synthetic pathway for efficient transport of a reporter from the plasma membrane to the endoplasmic reticulum.


Pretreatment pain predicts perineural invasion in patients with head and neck squamous cell carcinoma.
Perineural invasion (PNI) in head and neck cancer (HNC) is a distinct pathological feature used to indicate aggressive tumor behavior and drive treatment strategies. Our study examined the prevalence and predictors of PNI in HNC patients stratified by tumor site. A retrospective analysis of head and neck squamous cell carcinoma (HNSCC) patients who underwent surgical resection at the University of Pittsburgh Medical Center between 2015 and 2018 was performed. Pretreatment pain was assessed at least 1 week before surgery using the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N). Demographics, clinical characteristics, and concomitant medications were obtained from medical records. Patients with cancers at the oropharynx and non-oropharynx (i.e., cancer at oral cavity, mandible, larynx) sites were separately analyzed. Tumor blocks were obtained from 10 patients for histological evaluation of intertumoral nerve presence. A total of 292 patients (202 males, median age = 60.94 ± 11.06) were assessed. Pain and PNI were significantly associated with higher T stage (p < 0.001) and tumor site (p < 0.001); patients with non-oropharynx tumors reported more pain and had a higher incidence of PNI compared to oropharynx tumors. However, multivariable analysis identified pain as a significant variable uniquely associated with PNI for both tumor sites. Evaluation of nerve presence in tumor tissue showed 5-fold higher nerve density in T2 oral cavity tumors compared to oropharyngeal tumors. Our study finds that PNI is associated with pretreatment pain and tumor stage. These data support the need for additional research into the impact of tumor location when investigating targeted therapies of tumor regression.


Cholecystectomy in Danish children--a nationwide study.
An increase in the frequency of cholecystectomy in children has been described during the last decades. Part of the reason is that more cholecystectomies in children are performed for dyskinesia of the gallbladder and not only for gallstone disease. We conducted the first nationwide study to describe outcome of cholecystectomies performed in children in Denmark by using data from the national Danish Cholecystectomy Database (DCD). In the DCD, two data sources were combined: administrative data from the National Patient Registry (NPR) and clinical data entered into the secure Web site by the surgeon immediately after the operation. In the present analysis, we have included children ≤ 15 years from the five year period January 1, 2006, to December 31, 2010. In the study period 35,444 patients were operated with a cholecystectomy. Of these, 196 (0.5%) were ≤ 15 years. The median age was 14 years, and 82% were girls. Predisposing medical factors for gallstones (despite obesity) were found in only 5%. More than 50% were overweight, and one third were obese. Ninety-seven percent of the operations were completed laparoscopically, and the conversion rate was 0. 5%. Nearly half of the operations (45%) were performed as same day surgery, and 80% of the children stayed in hospital 0-1 day without readmission. 91% were discharged within 3 days and not readmitted. Morbidity was low, and no bile duct lesions occurred. The 30 day mortality was zero. Our nationwide outcome results indicate good quality with 91% of the patients discharged within 3 days without readmission, no bile duct injuries, and no mortality. All patients except two were operated for symptomatic gallstone disease in accordance to the Danish national guidelines. We have not experienced a demand or a need to expand the indications for cholecystectomy beyond gallstone disease.