ErbB family receptor inhibitors as therapeutic agents in breast cancer: current status and future clinical perspective.
Breast cancer is the most common cancer diagnosed in women and the second most common cause of female cancer-related deaths, with more than one million new cases diagnosed per year throughout the world. With the recent advances in the knowledge of cellular processes and signaling pathways involved in the pathogenesis of breast cancer, the current focus of researchers and clinicians is to develop novel treatment strategies that can be included in the armamentarium against breast cancer. With the failure of endocrine-targeted therapy and the development of resistance to existing chemotherapy, the most explored pathway as next generation target for breast cancer therapy has been the epidermal growth factor receptor (EGFR) (ErbB-1)/herceptin-2 (HER-2) (ErbB-2) pathway. This review focuses on the rationale for targeting members of ErbB receptor family and numerous agents that are in use for inhibiting the pathway. The mechanism of action, preclinical and clinical trial data of the agents that are in use for targeting the EGFR/HER-2 pathway and the current status, thereof, have been discussed in detail. In addition, the future clinical trial promises these agents hold either as monotherapy or as combination therapy with conventional agents or with other antisignaling agents have been pondered, so as to provide better and more efficacious treatment strategies for breast cancer patients.


Enhanced Stability of Li-RHC Embedded in an Adaptive TPX™ Polymer Scaffold.
In this work, the possibility of creating a polymer-based adaptive scaffold for improving the hydrogen storage properties of the system 2LiH+MgB2+7.5(3TiCl3·AlCl3) was studied. Because of its chemical stability toward the hydrogen storage material, poly(4-methyl-1-pentene) or in-short TPXTM was chosen as the candidate for the scaffolding structure. The composite system was obtained after ball milling of 2LiH+MgB2+7.5(3TiCl3·AlCl3) and a solution of TPXTM in cyclohexane. The investigations carried out over the span of ten hydrogenation/de-hydrogenation cycles indicate that the material containing TPXTM possesses a higher degree of hydrogen storage stability.


Reconstitution of the costunolide biosynthetic pathway in yeast and Nicotiana benthamiana.
The sesquiterpene costunolide has a broad range of biological activities and is the parent compound for many other biologically active sesquiterpenes such as parthenolide. Two enzymes of the pathway leading to costunolide have been previously characterized: germacrene A synthase (GAS) and germacrene A oxidase (GAO), which together catalyse the biosynthesis of germacra-1(10),4,11(13)-trien-12-oic acid. However, the gene responsible for the last step toward costunolide has not been characterized until now. Here we show that chicory costunolide synthase (CiCOS), CYP71BL3, can catalyse the oxidation of germacra-1(10),4,11(13)-trien-12-oic acid to yield costunolide. Co-expression of feverfew GAS (TpGAS), chicory GAO (CiGAO), and chicory COS (CiCOS) in yeast resulted in the biosynthesis of costunolide. The catalytic activity of TpGAS, CiGAO and CiCOS was also verified in planta by transient expression in Nicotiana benthamiana. Mitochondrial targeting of TpGAS resulted in a significant increase in the production of germacrene A compared with the native cytosolic targeting. When the N. benthamiana leaves were co-infiltrated with TpGAS and CiGAO, germacrene A almost completely disappeared as a result of the presence of CiGAO. Transient expression of TpGAS, CiGAO and CiCOS in N. benthamiana leaves resulted in costunolide production of up to 60 ng.g(-1) FW. In addition, two new compounds were formed that were identified as costunolide-glutathione and costunolide-cysteine conjugates.


Electrochemical immunosensor using p-aminophenol redox cycling by hydrazine combined with a low background current.
Signal amplification and noise reduction are crucial for obtaining low detection limits in biosensors. Here, we present an electrochemical immunosensor in which the signal amplification is achieved using p-aminophenol (AP) redox cycling by hydrazine, and the noise level is reduced by implementing a low background current. The redox cycling is obtained in a simple one-electrode, one-enzyme format. In a sandwich-type heterogeneous immunosensor for mouse IgG, an alkaline phosphatase label converts p-aminophenyl phosphate into AP for 10 min. This generated AP is electrooxidized at an indium tin oxide (ITO) electrode modified with a partially ferrocenyl-tethered dendrimer (Fc-D). The oxidized product, p-quinone imine (QI), is reduced back to AP by hydrazine, and then AP is electrooxidized again to QI, resulting in redox cycling. Moreover, hydrazine protects AP from oxidation by air, enabling long incubation times. The small amount of ferrocene in a 0.5% Fc-D-modified ITO electrode, where 0.5% represents the ratio of ferrocene groups to dendrimer amines, results in a low background current, and this electrode exhibits high electron-mediating activity for AP oxidation. Moreover, there is insignificant hydrazine electrooxidation on this electrode, which also results in a low background current. The detection limit of the immunosensor using a 0.5% Fc-D-modified electrode is 2 orders of magnitude lower than that of a 20% Fc-D-modified electrode (10 pg/mL vs 1 ng/mL). Furthermore, the presence of hydrazine reduces the detection limit by an additional 2 orders of magnitude (100 fg/mL vs 10 pg/mL). These results indicate that the occurrence of redox cycling combined with a low background current yields an electrochemical immunosensor with a very low detection limit (100 fg/mL). Mouse IgG could be detected at concentrations ranging from 100 fg/mL to 100 microg/mL (i.e., 9 orders of magnitude) in a single assay.


Use of electronic reminder devices to improve adherence to antiretroviral therapy: a systematic review.
Adherence to prescribed antiretroviral therapy (ART) is one of the strongest predictors of progression to AIDS and death among people living with HIV/AIDS. Incorrect or inconsistent adherence to ART compromises the effectiveness of medications in achieving viral suppression. The objective of this review is to systematically and critically appraise existing evidence on the use of electronic reminder devices (ERDs) to improve adherence to ART among people living with HIV/AIDS. Twelve electronic databases not limited by language or nationality were systematically searched using a combination of relevant search criteria through early August 2007. Primary outcomes of interest were level of adherence and virologic or immunologic response. Ten intervention studies, 5 qualitative studies, and 6 unpublished studies presented in conference abstracts were included. Methodological limitations across the 15 published studies precluded meta-analysis. Evidence that patient adherence to ART was significantly improved with the use of an ERD was reported in 4 of the 8 included studies that examined ERD use as a stand-alone adherence strategy. Patient satisfaction with devices was noted across studies, and conflicting evidence of improved virological and immunological outcomes was reported in the two studies that included such measures. The authors conclude that there is a lack of definitive data resulting in insufficient evidence about the effectiveness of ERDs as strategies for improving patient adherence to antiretroviral medications. Further and more rigorous research is warranted.


Evaluating Efficiencies of Dual AAV Approaches for Retinal Targeting.
Retinal gene therapy has come a long way in the last few decades and the development and improvement of new gene delivery technologies has been exponential. The recent promising results from the first clinical trials for inherited retinal degeneration due to mutations in RPE65 have provided a major breakthrough in the field and have helped cement the use of recombinant adeno-associated viruses (AAV) as the major tool for retinal gene supplementation. One of the key problems of AAV however, is its limited capacity for packaging genomic information to a maximum of around 4.8 kb. Previous studies have demonstrated that homologous recombination and/or inverted terminal repeat (ITR) mediated concatemerization of two overlapping AAV vectors can partially overcome the size limitation and help deliver larger transgenes. The aim of this study was to investigate and compare the use of different AAV dual-vector approaches in the mouse retina using a systematic approach comparing efficiencies in vitro and in vivo using a unique oversized reporter construct. We show that the hybrid approach relying on vector genome concatemerization by highly recombinogenic sequences and ITRs sequence overlap offers the best levels of reconstitution both in vitro and in vivo compared to trans-splicing and overlap strategies. Our data also demonstrate that dose and vector serotype do not affect reconstitution efficiency but a discrepancy between mRNA and protein expression data suggests a bottleneck affecting translation.


Metaphyseal bone lesions in young dogs with systemic canine distemper virus infection.
Bone lesions, restricted to the metaphyses of long bones, were observed in young dogs with systemic distemper following experimental and spontaneous infection. Canine distemper virus (CDV) antigen was found immunocytochemically in hematopoietic marrow cells, osteoclasts, osteoblasts and rarely in osteocytes. In experimentally infected dogs, viral antigen was demonstrated in the metaphysis between 5 and 36 days after infection. Associated lesions, characterized by necrosis of osteoclasts, persistence of primary spongiosa and atrophy and necrosis of osteoblasts and marrow cells, were mild and most prominent between 8 and 32 days postinfection. Metaphyseal osteosclerosis (MO) of the long bones, varying from mild to severe, was observed macroscopically in 8 (19%) out of 42 dogs with spontaneous distemper. Affected animals were between 3 and 6 months of age and belonged mainly to the large breeds. In these animals, MO was characterized histologically by persistence of primary spongiosa, loss of bone marrow cells and necrosis of osteoclasts and bone marrow cells varying from mild to severe. Summarized, CDV-associated bone lesions were only transient and there were no indications of viral persistence in bones of dogs experimentally infected with CDV. Although no clinical signs related to the bones were observed, the present study reveals that infection of metaphyseal bone cells is common in young dogs with systemic distemper and occurrence of viral antigen in these cells results in defects in bone modelling.


[Management of patients with castration-resistant metastatic prostate cancer].
Prostate cancer belongs to the most common malignant tumors in males. Almost in all patients in advanced stage, disease progression occurs despite of castration therapy. Initial treatment of metastatic disease is androgen deprivation therapy. In the case of castration-resistant disease development in asymptomatic patients, it is a combination of abiraterone acetate plus prednisone and in symptomatic patients docetaxel with prednisone are considered gold standards at the present time. The aim of therapy must be assurance of adequate quality of life, pain reduction and survival improvement. The paper presents an overview of current castration-resistant metastatic prostate cancer treatment.


Bacterial lipopolysaccharide acts as an adjuvant to induce autoimmune arthritis in mice.
We investigated the ability of lipopolysaccharide (LPS) as an adjuvant to induce autoimmune arthritis. LPS from Escherichia coli was intraperitoneally injected into DBA/1J mice together with the joint cartilage component type II collagen (CII) on day 0. Thereafter, the injection of CII and LPS was continued every 2 weeks up to day 56. The results showed that mice injected with CII plus LPS had signs of arthritis on day 55 and the joint inflammation reached a peak on day 75. Injection of CII or LPS alone induced no arthritis. Histologically, marked oedema of synovium and intense infiltration of inflammatory cells, including neutrophils, were observed 3 days after the onset of joint inflammation. Twenty-one days later, there were marked proliferation of synovial tissues with many mononuclear cells and destruction of cartilage. Anti-CII immunoglobulin G (IgG) and IgG2a antibodies were markedly produced in mice injected with CII plus LPS. Pronounced secretion of cytokines, including interleukins-12 and -1beta, interferon-gamma and tumour necrosis factor-alpha, was also observed in these animals. Arthritis was passively transferred into naive syngeneic mice with sera but not with lymphoid cells from mice given CII with LPS. Other types of LPS from Salmonella enteritidis, Salmonella typhimurium and Klebsiella pneumoniae as well as lipid A from E. coli, induced inflammation in joints when administered with CII. Polymixin B sulphate mixed with LPS or lipid A blocked the induction of joint inflammation. These results indicate that LPS appears to play an important role as an adjuvant in the induction of arthritis in which autoimmunity to CII is involved.


Femoral positioning of Tesio catheters for hemodialysis.
Vascular access may be of crucial importance in long-term dialyzed patients when traditional blood access fails. Long-term central vascular access devices are usually inserted in the internal jugular or subclavian veins but thrombosis may be the major factor limiting their long-term use. To solve this problem the Tesio caheter is one of the most commonly recommended tools for long-term use in RD patients, and is normally placed in the neck veins. In this study the femoral vein is indicated as an alternative site for positioning the Tesio catheter. The 'high' exit (abdominal) reported here presents some advantages for the patient who can then walk without difficulties while maintaining a high blood flow that is similar to those achieved with catheters implanted in other sites.


Decision making in dual-task environments: analysis of hemispheric competition effects.
Performance degradations in multitasking situations have been reported frequently as a predictable effect of competition that arises from different processing demands whose hemispheric locations are too proximal. This model might be useful in explaining performance deficits in complex workplaces. To test this assertion, a laboratory study was designed to create an analogue of the processing demands required by a tactical decision-making task performed by 24 right-handed men. Vocalization, dichotic listening and decision-making performance were assessed under single- and dual-task conditions. The results were consistent with the predictions from hemispheric competition in the case of dichotic listening but not with vocalization. The results are discussed in terms of their implications for both research and systems design.


Non-Debye enhancements in the Mie scattering of light from a single water droplet.
The glare spots usually seen on a single water droplet which has been illuminated by a plane wave are produced by geometrical rays which correspond to the different terms of the Debye series expansion of the Mie scattered field. Recently other glare spot enhancements have been predicted which correspond to scattering resonances coupling to the orbiting rays associated with high-order geometrical rainbows. We observed the non-Debye enhancement of the eleventh-order rainbow glare spot at an observation angle of 90 degrees on a 3.5-mm water droplet illuminated by polarized He-Ne laser light.


Soft-copy versus hard-copy interpretation of voiding cystourethrography in neonates, infants, and children.
Our aim is to determine whether agreement occurs between soft-copy (at a review workstation) and hard-copy (on laser-printed film) interpretations of fluoroscopic voiding cystourethrograms in neonates, infants, and children. Voiding cystourethrography was performed on 74 children (range, 2 weeks to 11 years old; mean, 3 years 6 months) for the evaluation of vesicoureteral reflux. The right and left ureters were scored separately by two observers on a scale of 0-5 using the international grading standard. Differences were tested for statistical significance with a marginal homogeneity test, and the strength of agreement was assessed using the kappa statistic. Of the 148 ureters evaluated, 39 showed vesicoureteral reflux and 109 showed no vesicoureteral reflux on both soft copy and hard copy. For 128 of 148 evaluations, interpretations of soft copy and hard copy produced agreement as to the grade of vesicoureteral reflux. For 11 of the 20 ureters with divergent interpretations, hard copy was scored one grade lower than soft copy; for the remaining nine ureters, hard copy was scored one grade higher than soft copy. No score differed by more than one grade. We found no statistically significant difference between soft-copy and hard-copy scores (p = .65), and agreement using the kappa statistic was substantial (.68). Soft-copy interpretation of voiding cystourethrograms is similar to hard-copy interpretation for vesicoureteral reflux.


Omalizumab (anti-IgE) therapy increases blood glucose levels in severe persistent allergic asthma patients with diabetes mellitus: 18 month follow-up.
Therapeutic anti-IgE antibodies (Xolair, omalizumab) able to reduce free IgE levels and to block the binding of IgE to Fcepsilon RI without cross-linking IgE and triggering degranulation of IgE-sensitised cells have been developed. We had two male patients of severe persistent allergic asthma with type-2 diabetes mellitus at the ages of 57 and 52 and who had suffered a side-effect of increased blood glucose level that caused a need for an extra insulin injection to control the hyperglycemia. Their asthma was not under control, frequent emergency department admissions lead us to use omalizumab treatment. Assessment of clinical changes and adverse effects were evaluated at each bimonthly patient visit including vital signs, full physical examination, details of any allergy incidents, total and specific IgE levels, serum ECP (eosinophilic cationic peptid) levels, pulmonary function test, exhaled nitric oxide concentrations, and asthma control test. Both patients were on week 42 - 45 of omalizumab treatment with a the dosage of 375 and 300 mg when they had the adverse reaction we reported here; they also had no other complaints. Blood levels of ECP and high sensitive CRP (hs-CRP) were decreased after starting the treatment of anti-IgE. To our knowledge, this is the first time an association between omalizumab use and hyperglycemia has been documented. Every vial of Xolair (150 mg) contains 145.5 mg sucrose and it might increase the blood levels of glucose in diabetics. As a conclusion the prescribing information might have been revised based on post marketing surveillance data and reported such cases indicating that different side effects may occur beyond 2 hours of the injection.


Citric acid inhibits development of cataracts, proteinuria and ketosis in streptozotocin (type 1) diabetic rats.
Although many fruits such as lemon and orange contain citric acid, little is known about beneficial effects of citric acid on health. Here we measured the effect of citric acid on the pathogenesis of diabetic complications in streptozotocin-induced diabetic rats. Although oral administration of citric acid to diabetic rats did not affect blood glucose concentration, it delayed the development of cataracts, inhibited accumulation of advanced glycation end-products (AGEs) such as N(epsilon)-(carboxyethyl)lysine (CEL) and N(epsilon)-(carboxymethyl)lysine (CML) in lens proteins, and protected against albuminuria and ketosis. We also show that incubation of protein with acetol, a metabolite formed from acetone by acetone monooxygenase, generate CEL, suggesting that inhibition of ketosis by citric acid may lead to the decrease in CEL in lens proteins. These results demonstrate that the oral administration of citric acid ameliorates ketosis and protects against the development of diabetic complications in an animal model of type 1 diabetes.


The neuronal basis and ontogeny of empathy and mind reading: review of literature and implications for future research.
Social neuro-science has recently started to investigate the neuronal mechanisms underlying our ability to understand the mental and emotional states of others. In this review, imaging research conducted on theory of mind (ToM or mentalizing) and empathy is selectively reviewed. It is proposed that even though these abilities are often used as synonyms in the literature these capacities represent different abilities that rely on different neuronal circuitry. ToM refers to our ability to understand mental states such as intentions, goals and beliefs, and relies on structures of the temporal lobe and the pre-frontal cortex. In contrast, empathy refers to our ability to share the feelings (emotions and sensations) of others and relies on sensorimotor cortices as well as limbic and para-limbic structures. It is further argued that the concept of empathy as used in lay terms refers to a multi-level construct extending from simple forms of emotion contagion to complex forms of cognitive perspective taking. Future research should investigate the relative contribution of empathizing and mentalizing abilities in the understanding of other people's states. Finally, it is suggested that the abilities to understand other people's thoughts and to share their affects display different ontogenetic trajectories reflecting the different developmental paths of their underlying neural structures. In particular, empathy develops much earlier than mentalizing abilities, because the former relys on limbic structures which develop early in ontogeny, whereas the latter rely on lateral temporal lobe and pre-frontal structures which are among the last to fully mature.


The Association between Dietary Protein Intake and the Risk of Pancreatic Cancer: Evidence from 14 Publications.
Many studies have been published to assess the association about dietary protein intake on the risk of pancreatic cancer, but with inconsistent result. This meta-analysis aimed to evaluate whether protein intake could affect the risk of pancreatic cancer. A systematic literature search was performed in PubMed, EMBASE and Web of Science up to October 1, 2019. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated using a random-effect model. A total of 14 studies (12 case-control studies and two cohort studies) were included. Overall, total protein intake had no significant association on the risk of pancreatic cancer (RR = 1.02, 95%CI= 0.85-1.22, I2=45.7%). Subgroup analyses showed such relationships were almost not influenced by study design and geographic location. Interestingly, when we performed the subgroup analysis by protein type, the opposite association was found in animal protein intake (RR = 1.37, 95%CI= 0.93-2.01) and vegetable protein intake (RR = 0.78, 95%CI= 0.54-1.14), although these two groups were not statistically significant. In conclusion, this meta-analysis indicated that dietary total protein intake may be not associated with the risk of pancreatic cancer. However, protein type may be affecting the result which was found from our research. Therefore, studies with detailed information, especially protein type, are warranted to further confirm these findings.


Unique roles of phosphorus in endochondral bone formation and osteocyte maturation.
The mechanisms by which inorganic phosphate (P(i)) homeostasis controls bone biology are poorly understood. Here we used Dmp1 null mice, a hypophosphatemic rickets/osteomalacia model, combined with a metatarsal organ culture and an application of neutralizing fibroblast growth factor 23 (FGF-23) antibodies to gain insight into the roles of P(i) in bone biology. We showed (1) that abnormal bone remodeling in Dmp1 null mice is due to reduced osteoclast number, which is secondary to a reduced ratio of RANKL/OPG expressed by osteoclast supporting cells and (2) that osteoblast extracellular matrix mineralization, growth plate maturation, secondary ossification center formation, and osteoblast differentiation are phosphate-dependent. Finally, a working hypothesis is proposed to explain how phosphate and DMP1 control osteocyte maturation.


Follicular lymphoma: expanding therapeutic options.
The most common indolent lymphoma, follicular lymphoma comprises 35% of adult non-Hodgkin's lymphoma (NHL) in the United States and 22% worldwide. Features associated with adverse outcome include age, male gender, disease stage, and performance status, with the International Prognostic Index being the most widely used risk classification system. Long-term disease-free survival is possible in select patient subgroups after treatment, but very late relapses suggest that quiescent lymphoma cells might be harbored for long periods of time. Radiation therapy is the mainstay of treatment for limited-stage follicular lymphoma, but there is some experience with chemotherapy and combined chemoradiation. When to initiate treatment in patients with advanced disease is controversial, but options include various combined chemotherapy regimens, monoclonal antibodies, radiolabeled antibodies, and bone marrow or stem cell transplantation. Future directions in the treatment of follicular lymphoma include vaccines, antisense therapy, and proteasome inhibitors.


[Vestibular efferent neurons of the guinea pig forming projections into the saccule].
The distribution of vestibular efferent neurons projecting to the saccule and efferent neurons transmitting axons to the acoustic nerve (cochlear efferent neurons) has been studied in guinea pig by comparison using the method of retrograde axonal transport of horseradish peroxidase. The saccular efferent neurons are revealed bilaterally in the subendymal granular fundus of the fourth ventricle of the brain and more laterally of the facial nerve genu, ipsilaterally in the small-celled reticular nucleus as well as in nuclei of the supraolivary complex: nucleus of lateral oliva and lateral nucleus of the trapezoid body. The cochlear efferent neurons are localized ipsilaterally in the reticular caudal nucleus of the bridge in the anteroventral cochlear nucleus and in nuclei of lateral and medial olivae. In the medial nucleus of the trapezoid body such neurons are found contralaterally. Thus, the regions of the vestibular saccular efferent neurons are partially overlapped with such of the cochlear efferent units. Possible participation of the vestibular efferent neurons of the saccule in the mechanism of the acoustic perception is discussed.


Expression of the A-raf proto-oncogene in the normal adult and embryonic mouse.
We have determined the expression pattern of the A-raf proto-oncogene in the embryonic and adult mouse. Western blot analysis of protein lysates from tissues of adult mice show that p69A-raf is ubiquitously expressed, but that levels of expression vary among different tissues. To determine the cell-specific expression pattern of A-raf, we generated transgenic mice expressing the beta-galactosidase reporter gene from the A-raf promoter. We show that A-raf expression is highly specific within a given tissue, and we identify cell types expressing this gene in the adult testis, epididymis, vas deferens, seminal vesicle, ovary, oviduct, bladder, kidney, intestine, heart, spleen, thymus, and cerebellum. In the embryo, ubiquitous expression of the reporter gene is observed, but the highest levels of expression are specifically detected in the embryonic heart at stages 9.5-11.5 days post-coitum.


Using indoor air quality monitoring in 6 counties to change policy in North Carolina.
Indoor air quality monitoring has become a valuable tool for states wanting to assess levels of particulate matter before and after smoke-free policies are implemented. However, many states face barriers in passing comprehensive smoke-free legislation, making such study comparisons unlikely. We used indoor air monitoring data to educate decision makers about the value of comprehensive smoke-free laws in a state with strong historical ties to tobacco. We trained teams in 6 counties in North Carolina to monitor air quality in hospitality venues with 1 of 3 possible smoking policy designations: 1) smoke-free, 2) separate smoking and nonsmoking sections (mixed), or 3) smoking allowed in all areas. Teams monitored 152 venues for respirable suspended particles that were less than 2.5 microm in diameter and collected information on venue characteristics. The data were combined and analyzed by venue policy and by county. Our findings were presented to key decision makers, and we then collected information on media publicity about these analyses. Overall, smoke-free venues had the lowest particulate matter levels (15 microg/m3), well below established Environmental Protection Agency standards. Venues with mixed policies and venues that permitted smoking in all areas had particulate matter levels that are considered unhealthy by Environmental Protection Agency standards. The media coverage of our findings included newspaper, radio, and television reports. Findings were also discussed with local health directors, state legislators, and public health advocates. Study data have been used to quantify particulate matter levels, raise awareness about the dangers of secondhand smoke, build support for evidence-based policies, and promote smoke-free policies among policy makers. The next task is to turn this effort into meaningful policy change that will protect everyone from the harms of secondhand smoke.


Diagnosis and management of lentigo maligna: a review.
Lentigo maligna is a melanocytic neoplasm occurring on sun-exposed skin, usually on the head and neck, of middle-aged and elderly patients. It is thought to represent the in situ phase of lentigo maligna melanoma. The ill-defined nature and potentially large size of lesions can pose significant diagnostic and treatment challenges. The goal of therapy is to cure the lesions in order to prevent development of invasive disease, and surgical excision is the treatment of choice to achieve clear histological margins. Nonsurgical treatment modalities have been reported; however, evidence is lacking to support their use. Age, general health, and comorbidities need to be taken into account when deciding the right treatment modality for each individual patient.


Intraocular lens optic edge design for the prevention of posterior capsule opacification after cataract surgery.
Posterior capsule opacification (PCO) is a clouding of the posterior part of the lens capsule, a skin-like transparent structure, which surrounds the crystalline lens in the human eye. PCO is the most common postoperative complication following modern cataract surgery with implantation of a posterior chamber intraocular lens (IOL). The main symptoms of PCO are a decrease in visual acuity, 'cloudy', blurred vision and reduced contrast sensitivity. PCO is treated with a neodymium:YAG (Nd:YAG) laser to create a small opening in the opaque capsule and regain a clear central visual axis. This capsulotomy might cause further ocular complications, such as raised intraocular pressure or swelling of the central retina (macular oedema). This procedure is also a significant financial burden for health care systems worldwide. In recent decades, there have been advances in the selection of IOL materials and optimisation of IOL designs to help prevent PCO formation after cataract surgery. These include changes to the side structures holding the lens in the centre of the lens capsule bag, called IOL haptics, and IOL optic edge designs. To compare the effects of different IOL optic edge designs on PCO after cataract surgery. We searched CENTRAL, Ovid MEDLINE, Ovid Embase, Latin American and Caribbean Health Sciences Literature Database (LILACS), the ISRCTN registry, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) up to 17 November 2020. We included randomised controlled trials (RCTs) that compared different types of IOL optic edge design. Our prespecified primary outcome was the proportion of eyes with Nd:YAG capsulotomy one year after surgery. Secondary outcomes included PCO score, best-corrected distance visual acuity (BCDVA) and quality of life score at one year. Due to availability of important long-term data, we also presented data at longer-term follow-up which is a post hoc change to our protocol. We used standard methods expected by Cochrane and the GRADE approach to assess the certainty of the evidence. We included 10 studies (1065 people, 1834 eyes) that compared sharp- and round-edged IOLs. Eight of these studies were within-person studies whereby one eye received a sharp-edged IOL and the fellow eye a round-edged IOL. The IOL materials were acrylic (2 studies), silicone (4 studies), polymethyl methacrylate (PMMA, 3 studies) and different materials (1 study). The studies were conducted in Austria, Germany, India, Japan, Sweden and the UK. Five studies were at high risk of bias in at least one domain. We judged two studies to be at low risk of bias in all domains. There were few cases of Nd:YAG capsulotomy at one year (primary outcome): 1/371 in sharp-edged and 4/371 in round-edged groups. The effect estimate was in favour of sharp-edged IOLs but the confidence intervals were very wide and compatible with higher or lower chance of Nd:YAG capsulotomy in sharp-edged compared with round-edged lenses (Peto odds ratio (OR) 0.30, 95% CI 0.05 to 1.74; I2 = 0%; 6 studies, 742 eyes). This corresponds to seven fewer cases of Nd:YAG capsulotomy per 1000 sharp-edged IOLs inserted compared with round-edged IOLs (95% CI 9 fewer to 7 more). We judged this as low-certainty evidence, downgrading for imprecision and risk of bias. A similar reduced risk of Nd:YAG capsulotomy in sharp-edge compared with round-edge IOLs was seen at two, three and five years but as the number of Nd:YAG capsulotomy events increased with longer follow-up this effect was more precisely measured at longer follow-up: two years, risk ratio (RR) 0.35 (0.16 to 0.80); 703 eyes (6 studies); 89 fewer cases per 1000; three years, RR 0.21 (0.11 to 0.41); 538 eyes (6 studies); 170 fewer cases per 1000; five years, RR 0.21 (0.10 to 0.45); 306 eyes (4 studies); 331 fewer cases per 1000. Data at 9 years and 12 years were only available from one study. All studies reported a PCO score. Four studies reported the AQUA (Automated Quantification of After-Cataract) score, four studies reported the EPCO (Evaluation of PCO) score and two studies reported another method of quantifying PCO. It was not possible to pool these data due to the way they were reported, but all studies consistently reported a statistically significant lower average PCO score (of the order of 0.5 to 3 units) with sharp-edged IOLs compared with round-edged IOLs. We judged this to be moderate-certainty evidence downgrading for risk of bias. The logMAR visual acuity score was lower (better) in eyes that received a sharp-edged IOL but the difference was small and likely to be clinically unimportant at one year (mean difference (MD) -0.06 logMAR, 95% CI -0.12 to 0; 2 studies, 153 eyes; low-certainty evidence). Similar effects were seen at longer follow-up periods but non-statistically significant data were less fully reported: two years MD -0.01 logMAR (-0.05 to 0.02); 2 studies, 311 eyes; three years MD -0.09 logMAR (-0.22 to 0.03); 2 studies, 117 eyes; data at five years only available from one study. None of the studies reported quality of life. Very low-certainty evidence on adverse events did not suggest any important differences between the groups. This review provides evidence that sharp-edged IOLs are likely to be associated with less PCO formation than round-edged IOLs, with less Nd:YAG capsulotomy. The effects on visual acuity were less certain. The impact of these lenses on quality of life has not been assessed and there are only very low-certainty comparative data on adverse events.


Renal vein leiomyosarcoma.
The third reported case of renal vein leiomyosarcoma is presented. Diagnosis was not made until exploratory celiotomy revealed a tumor originating from the left renal vein. The tumor was resected with margins of normal vein, and the patient was alive without recurrence 12 months after operation. Review of 65 cases of leiomyosarcoma originating in other retroperitoneal structures revealed a two-year survival rate of 20%. Therefore, we recommend consideration of postoperative adjunctive chemotherapy for renal vein leiomyosarcomas.


Differences between medical students and doctors in memory for clinical cases.
Many studies dealing with differences between students' and doctors' memory for clinical cases have yielded puzzling results. In this paper it is claimed that these are due to the use of inadequate techniques for isolating chunks inherent in the stimuli and the data. The purpose of this paper is to investigate whether the techniques of propositional analysis yield a clearer picture. Using this technique, the analysis of two sets of data is presented. The results show a clear difference between doctors and students when relevant clinical information is isolated from irrelevant information. This supports the notion that the process involved in the memory for clinical cases is far more complex and involves the ability to make inferences from a highly developed knowledge base.


Clinicodiagnostic features of tuberculous meningitis and the role of CSF PCR in early diagnosis: a study from north-west India.
The objective of this study was to study the clinical features and laboratory profile including acid fast bacillus microscopy, cerebrospinal fluid (CSF) culture and M. tuberculosis polymerase chain reaction (PCR) for an early diagnosis of tuberculous meningitis. Fifty consecutive patients, fulfilling the clinical criteria of tuberculous meningitis, were included in the study. All patients were subjected to detailed clinical and laboratory evaluation and radiological tests. CSF acid fast bacillus microscopy, culture and PCR were carried out in all and results were analysed. Majority of the patients presented with fever, headache, vomiting and signs of meningeal Irritation. Ziehl-Neelsen staining for acid-fast bacillus was positive in 4% cases, culture in 18% cases and CSF PCR for Mycobacterium tuberculosis was positive in 68%. Miliary pattern on chest x-ray was seen in 16% and CNS tuberculomas were seen in 14% cases. The CSF PCR estimation in clinically suspected cases of tuberculous meningitis may be an extremely valuable test for early diagnosis and institution of specific therapy.


[Electrophoretic properties of arylamidases from various cattle organs].
Agar electrophoresis was employed to study the homogeneity of arylamidase enzymes in the soluble fractions of liver, kidney, heart, spleen, brain, pancreas, and muscle homogenates and in serum. Enzymatic activity was determined in relation to the L-leucyl- and L-lysyl-p-nitroanilide chromogenic substrates. In all cases, electrophoresis made it possible to find at least two active zones with different electrophoretic mobility and with different activity in relation to the two substrates used.


The functional consequences of glaucoma for eye-hand coordination.
To examine whether patients with glaucoma exhibit differences in visually guided reaching-and-grasping (prehension) behavior compared with normally sighted control subjects. Sixteen patients with glaucoma and 16 control subjects with no ocular disease participated. Participants were required to reach out and precision grasp one of two cylindrical objects placed on a table top in front of them in laboratory conditions in three viewing conditions (binocular, right eye alone, left eye alone). Lightweight reflective markers were placed on the subject's preferred hand for recording its movement in three-dimensional space. Three motion capture units recorded the motion of these markers as the subjects reached out and precision grasped household objects. Various indices of prehension planning, execution, and control were quantified. Visual fields (VF) were measured using standard automated perimetry generating monocular mean deviation (MD) scores. Binocular VF sensitivity was estimated by using the integrated visual field (IVF). Stereoacuity was measured with the Frisby stereoacuity test. Significant differences in prehension movement between patients and control subjects in each viewing condition were investigated, and associations between prehension kinematics and VF sensitivity were examined. The patients and control subjects were of a similar age (median [range]: patient group, 72.2 years [62.5-86.9]; control group, 69.0 years [64.3-78.3]). The patient group had asymmetrical disease and relatively minor binocular overlapping defects (better eye MD, -5.7 dB [-16.7 to +0.45 dB]; worse eye MD, -11.8 dB [-29.3 to -1.5 dB]; IVF score, 3 [0-36]). They exhibited slightly poorer stereoacuity levels than did the control subjects (patient group, 55 sec arc [40-110]; control group, 40 sec arc [20-80; Mann-Whitney U test, P < 0.05]). They also showed statistically significant delays in average movement onset (MO: approximately 100 ms delay, Mann-Whitney U test P < 0.0001) and overall movement time (OMD: approximately 140 ms delay; Mann-Whitney U test P < 0.05), suggesting impairments in initial movement planning and control. Deficits were exhibited in the reaching component, with data suggesting that glaucomatous patients made more tentative movements when reaching for the object. These deficits correlated with both increasing severity of VF defect and impaired stereoacuity. There were no differences in grasping characteristics between patients and control subjects in this sample. This study provides evidence that patients with glaucoma exhibit deficits in eye-hand coordination compared with the age-matched normally sighted control. Further study is needed to assess the specific effect of field loss location on prehension kinematics.


Physical characterization of the procollagen module of human thrombospondin 1 expressed in insect cells.
Thrombospondin 1 (TSP1) is a homotrimeric glycoprotein composed of 150-kDa subunits connected by disulfide bridges. The procollagen module of thrombospondin 1 has been implicated in antiangiogenic activity. Procollagen modules are found in a number of extracellular proteins and are identifiable by 10 cysteines with characteristic spacing. We expressed and studied the procollagen module (C) of human TSP1, both by itself and in the context of the adjoining oligomerization sequence (o) and N-terminal module (N). The coding sequences were introduced into baculoviruses along with an N-terminal signal sequence and C-terminal polyhistidine tag. Proteins were purified from conditioned medium of infected insect cells by nickel-chelate chromatography. NoC is a disulfide bonded trimer and cleaves readily at a site of preferential proteolysis to yield monomeric N and trimeric oC. These are known properties of full-length TSP1. Mass spectroscopy indicated that C is N-glycosylated, and all 10 cysteine residues of C are in disulfides. By equilibrium ultracentrifugation, C is a monomer in physiological salt solution. Circular dichroism, intrinsic fluorescence, and differential scanning calorimetry experiments suggest that the stability of C is determined by the disulfides. The two tryptophans of C are in a polar, exposed environment as assessed by iodide fluorescence quenching and solvent perturbation. The oC far UV circular dichroism spectrum could be modeled as the sum of C and a coiled-coil oligomerization domain. The results indicate that the recombinant C folds autonomously into its native structure, and trimerization of the modules in TSP1 does not perturb their structures.


Management status of end-of-life vehicles and characteristics of automobile shredder residues in Korea.
An end-of-life vehicle (ELV) is dismantled to recover and recycle any re-usable parts, then shipped to the shredding facility for further recovery of iron with any remaining Automobile Shredder Residue (ASR) to be considered as wastes and to be disposed of by either thermal treatment or landfill. Overall ELVs management status in Korea, including recycling resulting from the dismantling processes, was surveyed using some questionnaires given to dismantlers and other available information to provide some feasible means for future treatment. The averaged recycle rate in the dismantling stage showed a value of 44% and the rest of an ELV was then compressed and transported to shredding companies to recover mainly the iron content which averaged 38.7% of the mass of a new vehicle. The non-ferrous metals such as copper, antimony, zinc and aluminum accounted for only 1.5%. The Shredder dusts (SDs) were found to be composed of light and heavy fluffs and soil/dust and amounted to 15.8% based on the mass of a new vehicle. Dumping of fluff and inorganic residues into a landfill site, however, will be restricted when new regulations are implemented to reduce the disposal amount to less than 5% of a new car as done in European countries and Japan. The detailed characteristics of SDs were investigated to provide an idea of how to treat them in order to meet a future expected enforcement.


Sequencing of whole plastid genomes and nuclear ribosomal DNA of Diospyros species (Ebenaceae) endemic to New Caledonia: many species, little divergence.
Some plant groups, especially on islands, have been shaped by strong ancestral bottlenecks and rapid, recent radiation of phenotypic characters. Single molecular markers are often not informative enough for phylogenetic reconstruction in such plant groups. Whole plastid genomes and nuclear ribosomal DNA (nrDNA) are viewed by many researchers as sources of information for phylogenetic reconstruction of groups in which expected levels of divergence in standard markers are low. Here we evaluate the usefulness of these data types to resolve phylogenetic relationships among closely related Diospyros species. Twenty-two closely related Diospyros species from New Caledonia were investigated using whole plastid genomes and nrDNA data from low-coverage next-generation sequencing (NGS). Phylogenetic trees were inferred using maximum parsimony, maximum likelihood and Bayesian inference on separate plastid and nrDNA and combined matrices. The plastid and nrDNA sequences were, singly and together, unable to provide well supported phylogenetic relationships among the closely related New Caledonian Diospyros species. In the nrDNA, a 6-fold greater percentage of parsimony-informative characters compared with plastid DNA was found, but the total number of informative sites was greater for the much larger plastid DNA genomes. Combining the plastid and nuclear data improved resolution. Plastid results showed a trend towards geographical clustering of accessions rather than following taxonomic species. In plant groups in which multiple plastid markers are not sufficiently informative, an investigation at the level of the entire plastid genome may also not be sufficient for detailed phylogenetic reconstruction. Sequencing of complete plastid genomes and nrDNA repeats seems to clarify some relationships among the New Caledonian Diospyros species, but the higher percentage of parsimony-informative characters in nrDNA compared with plastid DNA did not help to resolve the phylogenetic tree because the total number of variable sites was much lower than in the entire plastid genome. The geographical clustering of the individuals against a background of overall low sequence divergence could indicate transfer of plastid genomes due to hybridization and introgression following secondary contact.


Socio-biological status of Nigerian males with primary and secondary infertility.
Husbands in 100 consecutive couples complaining of lack of pregnancy after one year of normal intercourse were engaged in this study. Information from a structured questionnaire administered to these 100 men showed that 46% had primary infertility (had never impregnated any woman) and 54% secondary infertility (had in the past impregnated at least one woman irrespective of the outcome of the pregnancy). The mean ages (years) and standard error of mean for the primary and secondary infertile groups were 33.46 +/- 1.45 and 39.28 +/- 1.41 respectively. The difference was statistically significant (p < 0.05). Semen culture for growth of bacteria was positive in 59.3% of subjects with secondary infertility as opposed to 40.7% for primary infertility. The difference was, again, statistically significant (p < 0.05). These findings indicate that a higher proportion of husbands in infertile couples in a group of this environment had secondary infertility, were older and were more likely to harbour infections in their semen than those with primary infertility. Hence there should be a greater awareness of the significant involvement of bacterial infection of the genital tract of infertile Nigerian subjects than and before this factor should be taken into account in the prevention and treatment strategies for infertility in this and presumably other tropical countries.


Digestibility of phosphorus in protein-rich ingredients for pig diets.
Two experiments were run to determine the digestibility of phosphorus in different vegetable and animal proteins for the pig diet. Each experiment comprised two 4 x 4 Latin squares run concurrently. Pigs initially weighing 30 kg were kept in metabolism crates and fed twice daily at about 2.5-fold metabolisable energy requirement for maintenance. A semi-purified basal diet low in phosphorus and without intrinsic phytase activity was fed either alone or after blending into mixtures with one of the ingredients to be tested. Mixtures were calculated to contain not more than 2 g digestible P/kg DM and between 5.0 and 6.0 g Ca/kg DM. Faeces and urine were quantitatively collected for 8 days after 7 days of adaptation. Phosphorus digestibility for ingredients under test was calculated assuming the digestibility of phosphorus from the basal diets to be constant in all diets. P digestibilities in solvent extracted soybean meal from dehulled seed, rapeseed and solvent extracted rapeseed meal were 37, 42 and 24%, respectively. Supplementation of a microbial phytase (750 U/kg diet) improved digestibility coefficients significantly to 76, 66 and 73%, respectively. Digestibility of phosphorus in 3 different batches of fish meal ranged from 85 to 90%, without significant differences between batches. In 3 different types of carcass meal, digestibility coefficients were 80, 82 and 83% without significant differences between types, and digestibility of phosphorus from bone meal was 80%.


DEBATE: The inevitable decline of mindfulness.
The use of mindfulness meditation as a well-being and clinical tool is being deeply challenged on various fronts. The recent failure of showing its salutary effects on schoolchildren, in a large-scale study, which stands as the most expensive study in the history of meditation science (£6.4 million), is accompanied by growing evidence of potential adverse effects associated with mindfulness practice. It is suggested that the heightened enthusiasm surrounding the benefits of mindfulness led academics to use facile metaphors to promote it (such as comparing the mind to a muscle) and distorted its presentation - both in disseminating overhyped findings and in neglecting the report of adverse effects.


Risk factors for hydrocephalus requiring external ventricular drainage in patients with intraventricular hemorrhage.
External ventricular drainage (EVD) after intraventricular hemorrhage (IVH) without symptomatic hydrocephalus is controversial. The object of this study was to examine indicators or the timeframe for hydrocephalus in patients not immediately treated with EVD after IVH. Records from 2007 to 2014 were searched for "intraventricular hemorrhage" or "IVH." Inclusion criteria were IVH after intracerebral hemorrhage (ICH), trauma, tumor, or vascular anomalies. Exclusion criteria were IVH with more than minimal subarachnoid hemorrhage, catastrophic ICH, layering IVH only, or hydrocephalus treated immediately with EVD. IVH was measured with the modified Graeb Score (mGS). An mGS of 5 indicates a full ventricle with dilation. Statistics included chi-square, Student's t-test, and Mann-Whitney tests; receiver operating characteristics; and uni- and multivariate logistic regression. One hundred five patients met the criteria; of these, 30 (28.6%) required EVD. Panventricular IVH was the most common pattern (n = 49, 46.7%), with 25 of these patients (51%) requiring EVD. The median mGS was 18 ± 5.4 (range 12-29) and 9 ± 4.5 (range 2-21) in the EVD and No-EVD groups, respectively (p < 0.001). Factors associated with EVD were radiological hydrocephalus at presentation, midline shift > 5 mm, Glasgow Coma Scale (GCS) score < 8, mGS > 13, third ventricle mGS = 5, and fourth ventricle mGS = 5. On multivariate analysis, GCS score < 8 [4.02 (range 1.13-14.84), p = 0.032], mGS > 13 [3.83 (range 1.02-14.89), p = 0.046], and fourth ventricle mGS = 5 [5.01 (range 1.26-22.78), p = 0.022] remained significant. Most patients treated with EVD (n = 25, 83.3%) required it soon after presentation [6.4 ± 3.3 (range 1.5-14) hrs]. The remaining 5 patients (16.7%) had a delayed EVD requirement [70.7 ± 22.7 (range 50-104.5) hrs]. In this study population, the risk for EVD was variable, but greater with mGS > 13, coma, and a dilated fourth ventricle. While the need for EVD occurs within the 1st day after IVH in most patients, a minority require EVD after 48 hours.


Countering the stereotype of the unpopular patient.
Labelling theory and Stockwell's seminal work on the unpopular patient can help inform nurses' interactions with patients in the modern healthcare system. Today, older patients might be deemed unpopular because of their perceived personality, attitudes or communication, and because their needs fit poorly with the service available to them. These, and other factors, such as staffing levels, length of hospital stays, and patients' expectations as consumers, help to influence what defines an unpopular patient.


Serum albumin and the risk of contrast-induced acute kidney injury after percutaneous coronary intervention.
Serum creatinine and serum albumin levels were measured prior to surgery, and serum creatinine level was also measured at 72 hours following percutaneous coronary intervention in 819 (January 1st, 2015 and December 31th, 2018). According to whether patients developed contrast-induced acute kidney injury or not, they were assigned to either a contrast-induced acute kidney injury group (72 cases, 8.8%) or a non-contrast-induced acute kidney injury group (747 cases; control). Serum albumin was significantly lower in the contrast-induced acute kidney injury group than control (39.33 ± 5.09 g/l and 42.69 ± 5.19 g/l, respectively, P < 0.001). The results of a receiver-operating curve analysis indicated a serum albumin level of 40.5 g/L was the optimal cut-off value for prediction of contrast-induced acute kidney injury and according to a multivariate logistic regression analysis, serum albumin was an independent biomarker for prediction of (95% confidence interval: 0.836-0.935, odds ratio: 0.884, P < 0.001). Serum albumin, a low-cost and easily assessable laboratory protein, was independently related to a greater risk of contrast-induced acute kidney injury among patients that received percutaneous coronary intervention. It is proposed that under these circumstances SA is a potential biomarker for contrast-induced acute kidney injury.


XYY syndrome and other Y chromosome polysomies. Mental status and psychosocial functioning.
In this report we review the data on 75 male patients with extra Y chromosome diagnosed in Leuven in the period 1968-1993 among 98,725 patients (males and females) referred for constitutional chromosomal analysis. Special attention was given to their mental performance and psychosocial functioning. 1. Fifty male with 47,XYY karyotype were diagnosed. This is very close to the incidence of XYY in newborn studies and indicates that the frequency of MR/MCA is not increased in XYY male in general. 2. In the 60 patients with "pure" Y chromosome polysomy, the most frequent indication for karyotyping was the presence of MR and/or characterological problems in the index patients. Mental retardation was mostly borderline to mild, and severe mental retardation was rare. Characterological problems, difficulties in psychosocial integration and psychiatric problems were found in 86% of the mentally retarded versus 24% of the mentally normal men. 3. The 48,XXYY syndrome is characterized by markedly frequent and severe behavioural and psychiatric problems.


Preparation and in vitro release behaviour of 5-fluorouracil-loaded microspheres based on poly (L-lactide) and its carbonate copolymers.
A modified oil-in-oil (o/o) emulsion solvent evaporation technique was adopted to prepare 5-fluorouracil (5-Fu)-loaded poly (L-lactide) (PLLA) or its carbonate copolymer microspheres. The disperse phase was a drug:polymer solution using a solvent mixture of N,N-dimethylformamide (DMF) and acetonitrile and the continuous phase was liquid paraffin containing 1-10% (w/v) Span 80(R). The effects of preparative parameters, such as the composition of the inner oil phase, drug:polymer ratio, polymer concentration and agitation rate, on 5-Fu entrapment efficiency and microsphere characteristics were investigated. By introducing 25% (v/v) DMF into the inner oil phase, microspheres with high drug entrapment efficiency and an ameliorated burst effect were achieved. Using this modified method, microspheres with various particle sizes could be produced with a high 5-Fu entrapment efficiency (about 80%). In vitro drug release tests showed a burst release of 5-Fu from PLLA microspheres, followed by a sustained release over 50 days. In the case of poly (L-lactide-co-1,3-trimethylene carbonate) (PLTMC) and poly (L-lactide-co-2,2-dimethyl-1,3-trimethylene carbonate) (PLDTMC), the drug release could be continued for over 60 days.


Application of denaturing gradient gel electrophoresis for detection of bacterial and yeast communities along a salinity gradient in the estuary of the Cachoeira River in Brazil.
An estuary is a transition zone between freshwater and marine ecosystems, resulting in dilution of seawater. Estuaries are also considered environments of intense biological activity related to the processes of nutrient cycling. The aim of this study was to evaluate the microbial community composition along a salinity gradient in the estuary of the Cachoeira River, located in southern Bahia, Brazil. The analysis of bacterial and yeast communities was performed by determining the denaturing gradient gel electrophoresis band richness. Formation of zones with similar profiles of bands was observed, and the increasing richness at the intermediate zone demonstrated a clear spatial distinction of communities depending on salinity. In addition, the dissolved oxygen content, temperature, pH, salinity, and dissolved inorganic nutrient contents (NH3(+), NO2(-), NO3(-), PO4(-)) were determined. Nutrients were distributed in similar patterns, with decreasing concentrations as the salinity increases.


High doses of immunoglobulin G attenuate immune aggregate-mediated complement activation by enhancing physiologic cleavage of C3b in C3bn-IgG complexes.
Intravenously applied human IgG has beneficial effects in treating inflammatory diseases, presumably because it has a complement attenuating role. This role of IgG was studied in vitro by following C3 activation and inactivation in sera that were supplemented with exogenous human IgG and incubated with immune aggregates. IgG added at 2 to 10 mg/mL stimulated the physiologic inactivation of C3b-containing complexes twofold to threefold in 20% sera. This, in turn, lowered the overall C3 activation by 28%, as new C3 convertases primarily assembled on C3b-containing complexes. Exogenous IgG (5 mg/mL) also stimulated inactivation of purified C3b2-IgG complexes, whereby their half-life dropped from 3-4 to 1.5 minutes in 20% serum. IgG appeared to act like a modulator of factor H and I because it did not stimulate inactivation of C3b-containing complexes in factor I-deficient serum. Thus, the known partial protection of C3bn-IgG complexes from inactivation by factor H and I was downregulated by high concentrations of IgG. The ability of high doses of IgG to stimulate complement inactivation is a novel regulatory role of IgG. This may be one of the molecular principles for its therapeutic efficacy in treating complement-mediated inflammations.


Chemical characterization, cytotoxic, antioxidant, antimicrobial, and enzyme inhibitory effects of different extracts from one sage (Salvia ceratophylla L.) from Turkey: open a new window on industrial purposes.
In the present study, the methanolic, hydro-methanolic, dichloromethane, hexane and aqueous extracts of Salvia ceratophylla L. (Family: Lamiaceae), a lemon-scented herb, were tested for total phenolic (TPC) and flavonoid content (TFC) and antioxidant activities were evaluated using a battery of assays (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), ferric reducing antioxidant power (FRAP), cupric reducing antioxidant capacity, total antioxidant capacity (TAC) (phosphomolybdenum) and metal chelating). Enzyme inhibitory effects were investigated using acetyl- (AChE), butyryl-cholinesterase (BChE), tyrosinase, α-amylase and α-glucosidase as target enzymes. Regarding the cytotoxic abilities, HepG2, B164A5 and S17 cell lines were used. The phytochemical profile was conducted using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Our data showed that the methanolic aerial extracts possessed the highest phenolic (72.50 ± 0.63 mg gallic acid equivalent per g) and flavonoid (43.77 ± 1.09 mg rutin equivalent per g) contents. The hydro-methanolic aerial extract showed significant DPPH radical scavenging activity (193.40 ± 0.27 mg TE per g) and the highest reducing potential against CUPRAC (377.93 ± 2.38 mg TE per g). The best tyrosinase activity was observed with dichloromethane root extract (125.45 ± 1.41 mg kojic acid equivalent per g). Among the tested extracts, hexane root extract exerted the highest antimicrobial potential with a minimum inhibitory concentration value of 0.048 mg mL-1. Methanolic root extract showed the lowest cytotoxicity (28%) against HepG2 cells. Phytochemical analysis revealed the presence of important polyphenolic compounds including luteolin, gallic acid, rosmarinic acid, to name a few. This research can be used as one methodological starting point for further investigations on this lemon-scented herb.


Characterization of Amyloid-β Deposits in Bovine Brains.
Amyloid-β (Aβ) deposits are seen in aged individuals of many mammalian species that possess the same aminoacid sequence as humans. This study describes Aβ deposition in 102 clinically characterized cattle brains from animals aged 0 to 20 years. Extracellular and intracellular Aβ deposition was detected with 4G8 antibody in the cortex, hippocampus, and cerebellum. X-34 staining failed to stain Aβ deposits, indicating the non β-pleated nature of these deposits. Western blot analysis and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry revealed in Tris, Triton, and formic acid fractions the presence of different Aβ peptides, characterized mainly by C-terminally truncated forms. Exploration of the genetic variability of APOE, PSEN1, and PSEN2 genes involved in Alzheimer's disease pathogenesis revealed several previously unreported polymorphisms. This study demonstrates certain similarities between Aβ deposition patterns exhibited in cattle brains and those in the human brain in early stages of aging. Furthermore, the identification of the same Aβ peptides reported in humans, but unable to form aggregates, supports the hypothesis that cattle may be protected against amyloid plaque formation.


Determinants for Efficient Editing with Cas9-Mediated Recombineering in Escherichia coli.
In E. coli, editing efficiency with Cas9-mediated recombineering varies across targets due to differences in the level of Cas9:gRNA-mediated DNA double-strand break (DSB)-induced cell death. We found that editing efficiency with the same gRNA and repair template can also change with target position, cas9 promoter strength, and growth conditions. Incomplete editing, off-target activity, nontargeted mutations, and failure to cleave target DNA even if Cas9 is bound also compromise editing efficiency. These effects on editing efficiency were gRNA-specific. We propose that differences in the efficiency of Cas9:gRNA-mediated DNA DSBs, as well as possible differences in binding of Cas9:gRNA complexes to their target sites, account for the observed variations in editing efficiency between gRNAs. We show that editing behavior using the same gRNA can be modified by mutating the gRNA spacer, which changes the DNA DSB activity. Finally, we discuss how variable editing with different gRNAs could limit high-throughput applications and provide strategies to overcome these limitations.


Learning delayed influences of biological systems.
Boolean networks are widely used model to represent gene interactions and global dynamical behavior of gene regulatory networks. To understand the memory effect involved in some interactions between biological components, it is necessary to include delayed influences in the model. In this paper, we present a logical method to learn such models from sequences of gene expression data. This method analyzes each sequence one by one to iteratively construct a Boolean network that captures the dynamics of these observations. To illustrate the merits of this approach, we apply it to learning real data from bioinformatic literature. Using data from the yeast cell cycle, we give experimental results and show the scalability of the method. We show empirically that using this method we can handle millions of observations and successfully capture delayed influences of Boolean networks.


Neonatal, Infant, and Child Mortality in India: Progress and Future Directions.
In India, considerable progress has been made in reducing child mortality rates. Despite this achievement, wide disparities persist across and socio-economic strata, and persistent challenges, such as malnutrition, poor sanitation, and lack of clean water. This paper provides a comprehensive review of the state of child health in India, examining key risk factors and causes of child mortality, assessing the coverage of child health interventions, and highlighting critical public health programs and policies. The authors also discuss future directions and recommendations for bolstering ongoing efforts to improve child health. These include state- and region-specific interventions, prioritizing social determinants of health, strengthening data systems, leveraging existing programs like the National Health Mission (NHM) and Ayushman Bharat Pradhan Mantri Jan Arogya Yojana (PM-JAY), and the proposed Public Health Management Cadre (PHMC). The authors argue that reducing child mortality requires not only scaled-up interventions but a comprehensive approach that addresses all dimensions of health, from social determinants to system strengthening.


Evaluation of aluminum ultralight rigid wheelchairs versus other ultralight wheelchairs using ANSI/RESNA standards.
Previous studies found that select titanium ultralight rigid wheelchairs (TURWs) had fewer equivalent cycles and less value than select aluminum ultralight folding wheelchairs (AUFWs). The causes of premature failure of TURWs were not clear because the TURWs had different frame material and design than the AUFWs. We tested 12 aluminum ultralight rigid wheelchairs (AURWs) with similar frame designs and dimensions as the TURWs using the American National Standards Institute/Rehabilitation Engineering and Assistive Technology Society of North America and International Organization for Standardization wheelchair standards and hypothesized that the AURWs would be more durable than the TURWs. Across wheelchair models, no significant differences were found in the test results between the AURWs and TURWs, except in their overall length. Tire pressure, tube-wall thickness, and tube manufacturing were proposed to be the factors affecting wheelchair durability through comparison of the failure modes, frames, and components. The frame material did not directly affect the performance of AURWs and TURWs, but proper wheelchair manufacture and design based on mechanical properties are important.


Extraosseous Tc-99m MDP uptake: a pathophysiologic approach.
Scintigraphy with technetium-99m methylene diphosphonate (MDP) delineates a wide spectrum of nonosseous disorders. Neoplastic, hormonal, inflammatory, ischemic, traumatic, excretory, and artifactual entities demonstrate abnormal soft-tissue uptake of Tc-99m MDP. Mechanisms leading to increased extraosseous Tc-99m MDP uptake include extracellular fluid expansion, enhanced regional vascularity and permeability, and elevated tissue calcium concentration. The composition of the calcium deposition and the presence of other metallic ions (eg, iron and magnesium) are important. Soft-tissue Tc-99m MDP uptake is seen in benign (tumoral calcinosis, myositis ossificans) and malignant (sarcomas, adenocarcinomas, metastases) neoplastic entities. Hormonal disturbances in calcium metabolism, especially in hyperparathyroidism, can lead to metastatic calcification, visualized with Tc-99m MDP scintigraphy. Tissue damage from inflammation, infection, or physical trauma results in localized hyperemia, edema, or calcium (and hemosiderin) deposition based on their pathophysiologic characteristics. Urinary tract obstruction, anomalies, or dysfunction are demonstrated by Tc-99m MDP imaging. Common artifacts are related to faulty radiopharmaceutical preparation, Tc-99m MDP administration, and imaging technique. Recognition of these modes of extraskeletal Tc-99m MDP uptake can enhance the diagnostic value of bone scintigraphy.


NOD2 triggers an interleukin-32-dependent human dendritic cell program in leprosy.
It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I-restricted CD8(+) T cells. Expression of NOD2 and IL-32 and the frequency of CD1b(+) DCs at the site of leprosy infection correlated with the clinical presentation; they were greater in patients with limited as compared to progressive disease. The addition of recombinant IL-32 restored NOD2-induced DC differentiation in patients with the progressive form of leprosy. In conclusion, the NOD2 ligand-induced, IL-32-dependent DC differentiation pathway contributes a key and specific mechanism for host defense against microbial infection in humans.


Dentition status and frailty in community-dwelling older adults: A 5-year prospective cohort study.
To examine the longitudinal association between dentition status and incidence of frailty in older adults. The present prospective cohort study included community-dwelling Japanese adults aged 75 years at baseline (n = 322). Dental examinations, biochemical blood examinations, physical performance and anthropometric measurements, and structured questionnaires were carried out at baseline. The presence of ≥20 teeth with nine or more occluding pairs of teeth was defined as functional dentition. Annual follow-up examinations, including physical performance, anthropometric measurements and structured questionnaires, were carried out over a 5-year period to determine the incidence of frailty, defined as three or more of the following five components derived from the Cardiovascular Health Study: weight loss, weakness, slowness, poor energy and low physical activity level. Adjusted hazard ratios of frailty incidence according to dentition status were calculated from Cox proportional hazards regression analyses. At baseline, 118 participants (36.6%) were defined as having functional dentition. During the follow up, 48 participants (14.9%) developed frailty. The adjusted hazard ratio for frailty in participants with functional dentition was 0.50 (95% confidence interval 0.25-0.98) compared with participants without functional dentition, after adjusting for sex, income, education, smoking status, body mass index, serum biomarkers and comorbidities. Functional dentition was significantly associated with a lower risk of frailty defined by the Cardiovascular Health Study frailty index in older Japanese adults. These results suggest that maintaining healthy and functional dentition into later life is important for frailty prevention. Geriatr Gerontol Int 2018; 18: 256-262.


Farnesol, a mevalonate pathway intermediate, stimulates MCF-7 breast cancer cell growth through farnesoid-X-receptor-mediated estrogen receptor activation.
Farnesoid X receptor (FXR) is a metabolic nuclear receptor expressed in the liver and traditionally considered as a bile acid sensor. Yet, FXR has been recently demonstrated in other tissues and cells, such as the kidneys, the adrenals, and arterial smooth muscle cells. Immunohistochemical data reported in this study point to the expression of FXR in human breast cancer. In addition, FXR expression was also found by Western blotting and immunofluorescence microscopy in breast-cancer-derived cell lines MCF-7 (estrogen receptor [ER]-positive) and MDA-MB-231 (ER-negative). The FXR activator farnesol, a mevalonate pathway intermediate, exerts a mitogenic effect on MCF-7 cells. The growth stimulation is completely suppressed by antiestrogens. In contrast, MDA-MB-231 cells appear farnesol-insensitive, suggesting an involvement of ER in farnesol mitogenicity. In accordance with this interpretation, farnesol induces in MCF-7 cells a decrease of ER level, consistent with a phenomenon of receptor downregulation. Farnesol also increases progesterone receptor (PgR) expression in MCF-7 cells and stimulates ER-mediated gene transactivation in MVLN cells (MCF-7 cells stably transfected with an ER reporter gene). Of note, both effects of farnesol on ER expression and activity are completely suppressed by antiestrogens. In addition, farnesol-induced PgR is markedly reduced by FXR gene silencing (siRNA), demonstrating the involvement of FXR in the estrogenic effects of farnesol. Finally, coimmunoprecipitation experiments (FXR immunoprecipitation followed by Western blot analysis of ER in the immunoprecipitate) produced definite evidence that FXR interacts with ER. Altogether, these observations reveal the hitherto unreported presence of FXR in breast cancer and show that the latter receptor functionally interacts with ER. The occurrence of such a crosstalk calls for some caution regarding the pharmacological use of FXR agonists.


Functional significance for a heterogenous ribonucleoprotein A18 signature RNA motif in the 3'-untranslated region of ataxia telangiectasia mutated and Rad3-related (ATR) transcript.
The predominantly nuclear heterogenous ribonucleoprotein A18 (hnRNP A18) translocates to the cytosol in response to cellular stress and increases translation by specifically binding to the 3'-untranslated region (UTR) of several mRNA transcripts and the eukaryotic initiation factor 4G. Here, we identified a 51-nucleotide motif that is present 11.49 times more often in the 3'-UTR of hnRNP A18 mRNA targets than in the UniGene data base. This motif was identified by computational analysis of primary sequences and secondary structures of hnRNP A18 mRNA targets against the unaligned sequences. Band shift analyses indicate that the motif is sufficient to confer binding to hnRNP A18. A search of the entire UniGene data base indicates that the hnRNP A18 motif is also present in the 3'-UTR of the ataxia telangiectasia mutated and Rad3-related (ATR) mRNA. Validation of the predicted hnRNP A18 motif is provided by amplification of endogenous ATR transcript on polysomal fractions immunoprecipitated with hnRNP A18. Moreover, overexpression of hnRNP A18 results in increased ATR protein levels and increased phosphorylation of Chk1, a preferred ATR substrate, in response to UV radiation. In addition, our data indicate that inhibition of casein kinase II or GSK3beta significantly reduced hnRNP A18 cytosolic translocation in response to UV radiation. To our knowledge, this constitutes the first demonstration of a post-transcriptional regulatory mechanism for ATR activity. hnRNP A18 could thus become a new target to trigger ATR activity as back-up stress response mechanisms to functionally compensate for absent or defective responders.


Normal Respiratory Flora as a Cause of Community-Acquired Pneumonia.
Intensive studies have failed to identify an etiologic agent in >50% cases of community-acquired pneumonia (CAP). Bacterial pneumonia follows aspiration of recognized bacterial pathogens (RBPs) such as Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus after they have colonize the nasopharynx. We hypothesized that aspiration of normal respiratory flora (NRF) might also cause CAP. We studied 120 patients hospitalized for CAP who provided a high-quality sputum specimen at, or soon after admission, using Gram stain, quantitative sputum culture, bacterial speciation by matrix-assisted laser desorption ionization time-of-flight, and viral polymerase chain reaction. Thresholds for diagnosis of bacterial infection were ≥105 colony-forming units (cfu)/mL sputum for RBPs and ≥106 cfu for NRF. Recognized bacterial pathogens were found in 68 of 120 (56.7%) patients; 14 (20.1%) of these had a coinfecting respiratory virus. Normal respiratory flora were found in 31 (25.8%) patients; 10 (32.2%) had a coinfecting respiratory virus. Infection by ≥2 RBPs occurred in 10 cases and by NRF together with RBPs in 13 cases. Among NRF, organisms identified as Streptococcus mitis, which share many genetic features of S pneumoniae, predominated. A respiratory virus alone was found in 16 of 120 (13.3%) patients. Overall, an etiologic diagnosis was established in 95.8% of cases. Normal respiratory flora, with or without viral coinfection, appear to have caused one quarter of cases of CAP and may have played a contributory role in an additional 10.8% of cases caused by RBPs. An etiology for CAP was identified in >95% of patients who provided a high-quality sputum at, or soon after, the time of admission.


Selenium and vitamin E for prostate cancer--justifications for the SELECT study.
There are several studies that relate oxidative damage as possible mechanism for many cancers. Many studies have also shown that anti-oxidants like selenium and vitamin E decrease the risk for prostate cancer. The main objective of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) study was to look for the benefits of selenium and vitamin E supplementation on prostate cancer. The study had a large sample size, stringent experimental conditions, very long duration, standardized laboratories for biochemical analyses and other factors that contribute to high external validity. The SELECT study failed to show any significant risk reduction for prostate cancers ascribable to selenium and vitamin E supplementations. Because of these conflicting results, many researchers argue about the methods used, supplementations administered (selenium and vitamin E) and indicators used for assessing levels of supplementations. We reviewed many epidemiological studies, clinical trials, and pre-clinical studies. With corroborative evidences we justify that SELECT study has a sound methodology and rationale. In lieu of the contrary results of the select study, researchers should focus on the probable mechanisms for these contrary findings and continue their search for newer and effective agents for prevention of prostate cancer.


Sensory elements within the circular muscle are essential for mechanotransduction of ongoing peristaltic reflex activity in guinea-pig distal colon.
We have recently identified a population of mechanosensory myenteric S-interneurons in the distal colon of guinea-pigs. However, the role of the longitudinal (LM) and circular muscle (CM) in transducing these mechanosensory signals into enteric reflexes is unclear. In this study, we have investigated whether the LM or CM layer is necessary for activation of ascending excitatory and descending inhibitory neuronal pathways by static stretch of the paralysed isolated guinea-pig distal colon. Simultaneous intracellular recordings were made from pairs of CM cells at either end of isolated sheet preparations of distal colon that were devoid of mucosa and submucous plexus; and were maintained under circumferential stretch. In the presence of nifedipine (1 microm), an ongoing discharge of excitatory junction potentials (EJPs) and inhibitory junction potentials (IJPs) were recorded simultaneously at the oral and anal ends of the preparation. When the LM was sharp dissected off the myenteric plexus, the synchronized discharge of ascending EJPs and descending IJPs in the CM layer was unaffected. In contrast, when the majority of CM was sharp dissected off the myenteric plexus, ongoing neural activity was absent, or substantially decreased in both the LM and CM. In these preparations, immunohistochemical staining, together with transmural electrical stimuli confirmed that the myenteric plexus was always present and intact in these preparations. When full-thickness strips of CM were removed from progressively longer lengths of myenteric plexus, a graded reduction in the correlation of coordinated oral EJPs and anal IJPs occurred. However, removing approximately 40% of the thickness of CM layer from the entire preparation did not significantly disrupt, nor reduce the degree of correlation between oral EJPs and anal IJPs, suggesting that critical sensory elements did not lie adjacent to the submucosal plexus. It is concluded that mechanosensory transmission that underlies repetitive firing of ascending excitatory and descending inhibitory neuronal pathways is critically dependent upon sensory elements within the CM layer. These elements are likely to activate stretch-sensitive interneurons in the myenteric plexus. No evidence was found to suggest that the connectivity between the LM and the myenteric plexus was required for mechanotransduction.


Central imidazoline receptors as a target for centrally acting antihypertensive drugs.
Imidazoline (I1)-receptors in the central nervous system play a role in the central regulation of blood pressure and heart rate. Stimulation of these receptors in the rostral ventrolateral medulla induces peripheral sympathoinhibition, and hence a reduction of elevated blood pressure. The imidazoline derivatives moxonidine and rilmenidine are moderately selective I1 receptor stimulants which have been introduced as centrally acting antihypertensives. Since they have little affinity for alpha 2-adrenoceptors, they may be expected to cause less sedation and dry mouth than the alpha 2-adrenoceptor agonists clonidine and methyldopa. The concept of I1 receptors and their agonists therefore offers the possibility to develop centrally acting antihypertensives with a more favourable profile of adverse reactions than the classical alpha 2-adrenoceptor stimulants such as clonidine and methyldopa.


Micronutrient Deficiency in Inherited Metabolic Disorders Requiring Diet Regimen: A Brief Critical Review.
Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion of certain macronutrients, putting one at risk of a reduced intake of micronutrients. In this review, we aim to provide available evidence on the most common micronutrient deficits related to specific dietary approaches and on the management of their deficiency, in the meanwhile discussing the main critical points of each nutritional supplementation. The emerging concepts are that a great heterogeneity in clinical practice exists, as well as no univocal evidence on the most common micronutrient abnormalities. In phenylketonuria, for example, micronutrients are recommended to be supplemented through protein substitutes; however, not all formulas are equally supplemented and some of them are not added with micronutrients. Data on pyridoxine and riboflavin status in these patients are particularly scarce. In long-chain fatty acid oxidation disorders, no specific recommendations on micronutrient supplementation are available. Regarding carbohydrate metabolism disorders, the difficult-to-ascertain sugar content in supplementation formulas is still a matter of concern. A ketogenic diet may predispose one to both oligoelement deficits and their overload, and therefore deserves specific formulations. In conclusion, our overview points out the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of high-quality studies, particularly for some under-investigated deficits.


Cooperative updating in the Hopfield model.
We propose a new method for updating units in the Hopfield model. With this method two or more units change at the same time, so as to become the lowest energy state among all possible states. Since this updating algorithm is based on the detailed balance equation, convergence to the Boltzmann distribution is guaranteed. If our algorithm is applied to finding the minimum energy in constraint satisfaction and combinatorial optimization problems, then there is a faster convergence than those with the usual algorithm in the neural network. This is shown by experiments with the travelling salesman problem, the four-color problem, the N-queen problem, and the graph bi-partitioning problem. In constraint satisfaction problems, for which earlier neural networks are effective in some cases, our updating scheme works fine. Even though we still encounter the problem of ending up in local minima, our updating scheme has a great advantage compared with the usual updating scheme used in combinatorial optimization problems. Also, we discuss parallel computing using our updating algorithm.


Imaging of atherosclerosis in apoliprotein e knockout mice: targeting of a folate-conjugated radiopharmaceutical to activated macrophages.
Early detection of heart disease is essential for the implementation of intervention strategies that reduce the risk of cardiovascular events. Radioimaging methods that have been explored for this purpose include (18)F-FDG, which measures sites of elevated metabolic activity; (99m)Tc-annexin A5, which reveals regions of enhanced apoptosis and thrombosis; and (99m)Tc-labeled anti-lectinlike oxidized low-density lipoprotein receptor 1 antibody, which detects the lectinlike oxidized low-density lipoprotein receptor 1 that is overexpressed on a variety of vasculature-associated cells. In this study, we examine the use of a folate-targeted chelate of (99m)Tc, termed (99m)Tc-EC20, for imaging of folate receptor (FR)-expressing macrophages that accumulate in atherosclerotic plaques, internalize cholesterol-rich lipoprotein particles, and evolve into foam cells that form components of vulnerable atherosclerotic lesions. (99m)Tc-EC20 was injected into apoliprotein E knockout (apoE-/-) mice fed a normal or Western (high-fat) diet for 25 wk and imaged by gamma-scintigraphy. Treated mice were also dissected, and radioactivities in excised aortas were quantified by gamma-counting and imaged by autoradiography. The role of FR-expressing macrophages in uptake of (99m)Tc-EC20 was also examined by comparing images of apoE-/- mice before and after treatment with clodronate liposomes to deplete tissue macrophages, comparing the sites of (99m)Tc-EC20 enrichment with sites of macrophage accumulation in thin sections of atherosclerotic tissues, and examining the expression of FRs on atherosclerotic plaque-derived macrophages by flow cytometry. ApoE-/- mice on Western chow exhibited significantly greater accumulation of (99m)Tc-EC20 in atherosclerotic lesions than their counterparts on normal chow. The aortas of apoE-/- mice on a Western diet demonstrated greater numbers of FR-positive macrophages by flow cytometry than did those of apoE-/- mice on a normal diet. Clodronate liposome treatment significantly reduced the accumulation of (99m)Tc-EC20 in atherosclerotic tissues, suggesting that macrophages or monocytes are responsible for uptake of the folate-linked radioimaging agent. Histologic and autoradiographic analysis of tissue sections demonstrated that macrophage accumulation correlated with regions of (99m)Tc-EC20 uptake. (99m)Tc-EC20 can be used for the imaging of atherosclerosis by selectively targeting FR-positive activated macrophages.


Early use of ICD-10-CM code "U07.1, COVID-19" to identify 2019 novel coronavirus cases in Military Health System administrative data
This report describes early exploratory analysis of ICD-10-CM code U07.1 (2019-nCoV acute respiratory disease [COVID-19]) to assess the use of administrative data for case ascertainment, syndromic surveillance, and future epidemiological studies. Out of the 2,950 possible COVID-19 cases identified between 1 April 2020 and 4 May 2020, 600 (20.3%) were detected in the Defense Medical Surveillance System (DMSS) and not in the Disease Reporting System internet (DRSi) or in Health Level 7 laboratory data from the Composite Health Care System. Among the 150 out of 600 cases identified exclusively in the DMSS and selected for Armed Forces Health Longitudinal Technology Application (AHLTA) review, 16 (10.7%) had a certified positive lab result in AHLTA, 17 (11.3%) met Council of State and Territorial Epidemiologists (CSTE) criteria for a probable case, 46 (30.7%) were not cases based on CSTE criteria, and 71 (47.3%) had evidence of a positive lab result from an outside source. Lack of full capture of lab results may continue to be a challenge as the variety of available tests expands. Administrative data may provide an important stopgap measure for detecting lab positive cases, pending incorporation of new COVID-19 tests and standardization of test and result nomenclature.


[The antioxidant system in patients with influenza and influenza pneumonia].
The paper deals with the topical theme--the state of antioxidant protective components in influenza infection. The values of catalase in red blood cells and those of ceruloplasmin in plasma were studied as an indicator of antiperoxide defense. The patients were grouped according to the severity of their condition and associated complications. The studies revealed a regular reduction in plasma ceruloplasmic levels at the height of influenza. In the waning period of clinical symptoms and in early convalescence, the parameter under study did not differ from that of healthy individuals. At the same time, the trend in influenza showed a significant increase in red blood cell catalase levels with the maximum values at the height of the disease and their normalization in early and late convalescence.


Psychiatric issues in pediatric organ transplantation.
Solid organ transplantation has become the first line of treatment for a growing number of life-threatening pediatric illnesses. With improved survival, research into the long-term outcome of transplant recipients has become important to clinicians. Adherence to medical instructions remains a challenge, particularly in the adolescent population. New immunosuppressant approaches promise to expand organ transplantation in additional directions. Extension of transplantation into replacement of organs such as faces and hands raises complex ethical issues.


Motivators and Barriers to Exercise in Parkinson's Disease.
Despite evidence for the benefits of exercise in Parkinson's disease (PD), many patients remain sedentary for undefined reasons. To compare exercise habits, perceptions about exercise, and barriers to exercise in 'low' (<3 h/week) and 'high' (≥3 h/week) exercisers with PD. A 48-item survey was administered to PD patients at an outpatient academic center. Chi-squared tests were used to compare the percentage differences between low- and high-exercisers with two-sided tests and a significant level of 0.05. 243 surveys were collected over three months; 28 were excluded due to incomplete data, leaving 215 to be analyzed. 49.3% reported 'low'-exercise and 50.7% reported 'high'-exercise. High-exercisers participated in higher intensity exercise regimens (83.4% versus 32.1%, p≤0.001). High-exercisers were more likely to start exercising after being diagnosed (54.2% versus 27.8%, p < 0.001), whereas low-exercisers were more likely to reduce their amount of exercise (40.2% versus 15.9%, p < 0.001). Low-exercisers required more motivating factors. Both groups benefited from having a significant other or a personal trainer motivate them, and both were more likely to exercise if their neurologist encouraged them. Low-exercisers reported twice as many barriers as high-exercisers (p = 0.001). Barriers that were significantly more common in low-exercisers were: lacking someone to motivate them (33.3% versus 10.5%, p < 0.001), fatigue (20.8% versus 15.2%, p = 0.005), and depression (16.7% versus 7.6%, p = 0.045). There are significant differences between people with PD who exercise regularly and those who do not in terms of motivators and barriers. These findings should be considered when tailoring recommendations for PD patients to encourage exercise, and in designing future interventions.


Seafood nitrogen factors.
The determination of nitrogen as a quantitative marker for seafood fat-free protein, allowing the calculation of seafood content of seafood products, is well established, and is the official chemical enforcement method. It is also is widely used by food producers to check the specification and added water of their seafood raw materials. A "nitrogen factor" is the average nitrogen content of seafood tissues, on a fat free basis unless the fat content is low as in white fish. Most seafood is prepared by using wet processes as part of good hygienic practice (GHP). Therefore, in establishing nitrogen factors for seafood, keeping water uptake to a minimum and using good manufacturing practice (GMP) has to be taken into account.


Tuning Cell Differentiation into a 3D Scaffold Presenting a Pore Shape Gradient for Osteochondral Regeneration.
Osteochondral regeneration remains nowadays a major problem since the outcome of current techniques is not satisfactory in terms of functional tissue formation and development. A possible solution is the combination of human mesenchymal stem cells (hMSCs) with additive manufacturing technologies to fabricate scaffolds with instructive properties. In this study, the differentiation of hMSCs within a scaffold presenting a gradient in pore shape is presented. The variation in pore shape is determined by varying the angle formed by the fibers of two consequent layers. The fiber deposition patterns are 0-90, which generate squared pores, 0-45, 0-30, and 0-15, that generate rhomboidal pores with an increasing major axis as the deposition angle decreases. Within the gradient construct, squared pores support a better chondrogenic differentiation whereas cells residing in the rhomboidal pores display a better osteogenic differentiation. When cultured under osteochondral conditions the trend in both osteogenic and chondrogenic markers is maintained. Engineering the pore shape, thus creating axial gradients in structural properties, seems to be an instructive strategy to fabricate functional 3D scaffolds that are able to influence hMSCs differentiation for osteochondral tissue regeneration.


Results of chemoirradiation after curative resection of locally advanced gastric cancer.
To evaluate the results of post-operative chemoirradiation for gastric carcinoma. The records of 58 patients who underwent resection for gastric carcinoma were retrospectively reviewed. Forty-six patients had complete resection without any residual disease but with high-risk factors of relapse. Twelve patients had microscopic residual disease. Doses of irradiation ranged from 45 to 54 Gy with a median dose of 49 Gy in 1.8 Gy fractions. Fifty-three of the patients received 5-fluorouracil-based concomitant chemoradiotherapy, and all of them received chemotherapy after the completion of radiotherapy. The median survival of the entire group of patients was 21 months. The 30th month disease-free and overall survival after surgery was 32 and 45%, respectively. The median survival time and 30th month survival rate was 23 months and 54% in patients with no residual disease, and 15 months and 18% for those with residual disease, respectively (p = 0.049). A statistically significant correlation was detected between residual disease and survival and between high-grade tumour and survival (p < 0.05 for each). Patients with both nodal involvement and direct tumour extension beyond the gastric wall have a high risk of locoregional failure, and adjuvant chemoradiotherapy reduces local failure and improves survival.