The Use of Plant Sterols and Stanols as Lipid-Lowering Agents in Cardiovascular Disease.
The prevalence of premature atherosclerosis and cardiovascular disease (CVD) is constantly increasing worldwide. It has been proved that LDL-cholesterol (LDL-C) plays causal role in the development of coronary atherosclerosis. The fact that atherosclerosis is a chronic and progressive disease which onsets during the first three decades of life bores questions what to do to maintain LDL-C at low levels throughout life and thus to delay and/or prevent the progress this disease. Currently, most of public health expenses are spared on treatment, but not on prophylaxis. This is a review article summarizing novel reports concerning the efficacy of sterols/stanols as lipidlowering agents, assessing their influence on cardiovascular risk and safety. It has been suggested that sterols and stanols are effective in the lowering of low-density cholesterol levels and diminishing cardiovascular risk. However, the results of other studies suggest that phytosterols may not exert positive effects during atherogenesis. Firstly, patients with phytosterolaemia (genetic disease in which high plant sterol plasma concentrations are observed) develop malignant premature atherosclerosis. Moreover, several epidemiological studies demonstrated the association between upper normal plasma concentrations of plant sterols and increased risk of cardiovascular events. Finally, the supplementation with plant stanols and plant sterols may be not beneficial due to their incorporation in various tissues and potentially resulting in adverse effects. Despite the worldwide promotion of sterols as health improving supplements, it seems that in some people responding with relatively high phytosterol serum levels after its consumption such additives may turn out to be as good as it has been believed.


Developmental toxicity studies with 6 forms of titanium dioxide test materials (3 pigment-different grade & 3 nanoscale) demonstrate an absence of effects in orally-exposed rats.
Six different commercial forms and sizes of titanium dioxide particles were tested in separate developmental toxicity assays. The three pigment-grade (pg) or 3 ultrafine (uf)/nanoscale (anatase and/or rutile) titanium dioxide (TiO2) particle-types were evaluated for potential maternal and developmental toxicity in pregnant rats by two different laboratories. All studies were conducted according to OECD Guideline 414 (Prenatal Developmental Toxicity Study). In addition, all test materials were robustly characterized. The BET surface areas of the pg and uf samples ranged from 7 to 17 m(2)/g and 50-82 m(2)/g respectively (see Table 1). The test substances were formulated in sterile water. In all of the studies, the formulations were administered by oral gavage to time-mated rats daily beginning around the time of implantation and continuing until the day prior to expected parturition. In 3 of the studies (uf-1, uf-3, & pg-1), the formulations were administered to Crl:CD(SD) rats beginning on gestation day (GD) 6 through GD 20. In 3 additional studies (uf-2, and pg-2, pg-3 TiO2 particles), the formulations were administered to Wistar rats beginning on GD 5 through 19. The dose levels used in all studies were 0, 100, 300, or 1000 mg/kg/day; control group animals were administered the vehicle. During the in-life portions of the studies, body weights, food consumption, and clinical observations before and after dosing were collected on a daily basis. All dams were euthanized just prior to expected parturition (GD 21 for Crl:CD(SD) rats and GD 20 for Wistar rats). The gross necropsies included an examination and description of uterine contents including counts of corpora lutea, implantation sites, resorptions, and live and dead fetuses. All live fetuses were sexed, weighed, and examined externally and euthanized. Following euthanasia, fresh visceral and head examinations were performed on selected fetuses. The fetal carcasses were then processed and examined for skeletal alterations. There was no evidence of maternal or developmental toxicity at any dose level tested in any of the six studies. Based on these results, the no-observed-adverse-effect level (NOAEL) for titanium dioxide was 1000 mg/kg/day, the highest administered dose, in both the Sprague-Dawley (Crl:CD(SD) and Wistar rat strains.


Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations.
Hematopoietic stem cell transplantation (HSCT) is effective therapy for patients with chronic myelogenous leukemia (CML) but is now mostly indicated for patients who develop resistance to tyrosine kinase inhibitors (TKIs), which can be associated with point mutations in BCR-ABL1. We reviewed the outcomes of imatinib-resistant CML patients (chronic phase, n = 34; accelerated phase [AP], n = 9; and blast phase [BP], n = 4) who underwent HSCT and had BCR-ABL1 sequencing. Mutations were found in 19 patients (40%); 15 of 19 had advanced CML (AP + BP + second chronic phase). Patients with mutations were more likely to transform to AP/BP at time of imatinib failure (69% vs 35%, P = .03). Forty-two patients (89%) responded to HSCT: 32 (68%) had at least a major molecular response. The 2-year event-free survival was 36% and 58% (P = .05) for the mutant and nonmutant groups, respectively; and the 2-year overall survival was 44% and 76% (P = .02), respectively. HSCT is an important salvage option for TKI-resistant patients with or without BCR-ABL1 mutations. Patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT. HSCT should be considered early for patients deemed to have a low probability of responding to second-generation TKI.


Making ATP.
We present a mesoscopic model for ATP synthesis by F(1)F(o) ATPase. The model combines the existing experimental knowledge of the F(1) enzyme into a consistent mathematical model that illuminates how the stages in synthesis are related to the protein structure. For example, the model illuminates how specific interactions between the gamma, epsilon, and alpha(3)beta(3) subunits couple the F(o) motor to events at the catalytic sites. The model also elucidates the origin of ADP inhibition of F(1) in its hydrolysis mode. The methodology we develop for constructing the structure-based model should prove useful in modeling other protein motors.


Serological dynamics and risk factors of Besnoitia besnoiti infection in breeding bulls from an endemically infected purebred beef herd.
Bovine besnoitiosis has been deemed a re-emerging disease in Western Europe and considered endemic in Spain, Portugal, France and in some areas of Northern Italy. This report refers to an infection outbreak in a purebred beef herd from Northern Italy involving a large number of bulls. In October 2013, 544 animals were serologically tested with an in-house ELISA followed by a confirmatory Western blot to evaluate Besnoitia besnoiti seroprevalence. A year later, 461 animals were then serologically re-tested together with imported animals (n = 268). Overall, 812 animals were involved in the study. Histology and immunohistochemistry were performed on skin biopsies of suspected animals and several tissue samples from a slaughtered bull. In the first sampling, 100 animals were seropositive (18.4%); in the second sampling, prevalence increased up to 36.5%, with incidence calculated at 39.6%. The risk factor analysis revealed that the infection was associated with age (OR = 1.007) and sex, with males presenting a greater risk (OR = 2.006). In fact, prevalence values in bulls increased from 29.6 to 56.7%, with an incidence of infection of 53.3%. Moreover, mating with a seropositive bull enhanced infection risk for a seronegative cow (OR = 1.678). Clinical signs typical of bovine besnoitiosis were found in seven seropositive animals, with confirmation of B. besnoiti through histology and immunohistochemistry. The study outcomes confirm that bovine besnoitiosis is a disease with serious economic impact on beef cattle breeding, particularly on bulls in service. Good management practises such as clinical monitoring and serological testing of imported animals should be implemented to control its occurrence.


Different behaviour of normal and neoplastic cells cultured in vitro in the presence of catalase and superoxide dismutase.
Chicken embryo fibroblasts and hepatocytes were studied in the presence of catalase and superoxide dismutase in order to establish whether these enzymes had the capacity to favour cell multiplication as previously shown for in vitro tumour ascites cells (ATP C+). The results indicate that, unlike ATP C+ cells, both fibroblasts and hepatocytes are inhibited in their multiplication by superoxide dismutase. Similar effects are exerted on hepatocytes by catalase, whereas the multiplication of fibroblasts is favoured by high doses of this enzyme. Enzyme determinations revealed high levels of catalase and superoxide dismutase in hepatocytes, whereas both enzymes were poor in fibroblasts and ATP C+.


Insulin-mediated glucose disposal in black south Africans with essential hypertension.
We used the hyperinsulinaemic euglycaemic clamp method to assess insulin-mediated glucose disposal in ten black South African patients with newly-diagnosed essential hypertension, compared to ten normotensive controls. The patients were all nonobese with normal glucose tolerance. Comparisons were made before and 12 weeks after treatment with a long-acting ACE inhibitor. The mean glucose disposal (M) and disposal expressed as glucose sensitivity index (M/I) were significantly reduced in the hypertensives vs. controls (M: 6.8 +/- 0.9 vs. 9.7 +/- 0.8 mg/kg/min; MI: 7.1 +/- 1.0 vs. 12.5 +/- 1.7 mg/kg/min/mU/l x 100) (p = 0.03 and 0.01, respectively). Following therapy, M/I increased in the patients to values not significantly different to those of the controls. Insulin resistance is an independent feature of essential hypertension in black South African patients, and is partially corrected by treatment with a long-acting ACE inhibitor.


The community mental health nurse: a new professional role.
This review of recent literature explores the similarities and differences between the work of community psychiatric nurses and their mental handicap counterparts. The comparisons which have been made between these groups of nurses are related to the authors' own research studies. These included an observational study of one community mental handicap nursing team and a national survey of all such teams in England and Wales. The importance of trad union membership, the place of the Community Psychiatric Nursing Association and the implications of joint training courses are discussed. The emergence of a new professional role, that of the "community mental health nurse" is discussed and the implications which this might have for the future organization of community psychiatric nursing services is outlined.


Agent-Based Modelling Reveals the Role of the Tumor Microenvironment on the Short-Term Success of Combination Temozolomide/Immune Checkpoint Blockade to Treat Glioblastoma.
Glioblastoma is the most common and deadly primary brain tumor in adults. All glioblastoma patients receiving standard-of-care surgery-radiotherapy-chemotherapy (i.e., temozolomide (TMZ)) recur, with an average survival time of only 15 months. New approaches to the treatment of glioblastoma, including immune checkpoint blockade and oncolytic viruses, offer the possibility of improving glioblastoma outcomes and have as such been under intense study. Unfortunately, these treatment modalities have thus far failed to achieve approval. Recently, in an attempt to bolster efficacy and improve patient outcomes, regimens combining chemotherapy and immune checkpoint inhibitors have been tested in trials. Unfortunately, these efforts have not resulted in significant increases to patient survival. To better understand the various factors impacting treatment outcomes of combined TMZ and immune checkpoint blockade, we developed a systems-level, computational model that describes the interplay between glioblastoma, immune, and stromal cells with this combination treatment. Initializing our model to spatial resection patient samples labeled using imaging mass cytometry, our model's predictions show how the localization of glioblastoma cells, influence therapeutic success. We further validated these predictions in samples of brain metastases from patients given they generally respond better to checkpoint blockade compared with primary glioblastoma. Ultimately, our model provides novel insights into the mechanisms of therapeutic success of immune checkpoint inhibitors in brain tumors and delineates strategies to translate combination immunotherapy regimens more effectively into the clinic. SIGNIFICANCE STATEMENT: Extending survival times for glioblastoma patients remains a critical challenge. Although immunotherapies in combination with chemotherapy hold promise, clinical trials have not shown much success. Here, systems models calibrated to and validated against patient samples can improve preclinical and clinical studies by shedding light on the factors distinguishing responses/failures. By initializing our model with imaging mass cytometry visualization of patient samples, we elucidate how factors such as localization of glioblastoma cells and CD8+ T cell infiltration impact treatment outcomes.


Short exposure to glyphosate induces locomotor, craniofacial, and bone disorders in zebrafish (Danio rerio) embryos.
Glyphosate [N-(phosphonomethyl)glycine] is the active ingredient in widely used broad-spectrum herbicides. Even though the toxicity mechanism of this herbicide in vertebrates is poorly understood, evidence suggests that glyphosate is an endocrine disruptor capable of producing morphological anomalies as well as cardiotoxic and neurotoxic effects. We used the zebrafish model to assess the effects of early life glyphosate exposure on the development of cartilage and bone tissues and organismal responses. We found functional alterations, including a reduction in the cardiac rate, significant changes in the spontaneous tail movement pattern, and defects in craniofacial development. These effects were concomitant with alterations in the level of the estrogen receptor alpha osteopontin and bone sialoprotein. We also found that embryos exposed to glyphosate presented spine deformities as adults. These developmental alterations are likely induced by changes in protein levels related to bone and cartilage formation.


The phospho-opsin phosphatase from bovine rod outer segments. An insight into the mechanism of stimulation of type-2A protein phosphatase activity by protamine.
The vertebrate visual transduction system involves a cycle of phosphorylation and dephosphorylation of a transmembranous photoreceptor (rhodopsin). Upon illumination, the activated photoreceptor (metarhodopsin-II) is phosphorylated by a specific kinase on up to seven serine and threonine residues. A dephosphorylation process must then be undertaken to return the photoreceptor to its ground state. Initial work, along with studies using the rabbit skeletal muscle catalytic subunit of protein phosphatase 2A, indicated that the phosphatase responsible was a member of the type-2 family. The work has been further extended and using 1000 bovine retinae, the catalytic subunit and a holoenzyme form of phospho-opsin phosphatase were purified 2100-fold and 550-fold respectively. The stimulation of the activities of both these fractions with protamine sulphate and the inhibition by okadaic acid are consistent with the fact that these phosphatases belong to the type-2A family. Western blotting using a variety of specific antibodies established that the catalytic subunit (36 kDa, C subunit) was indeed of type 2A, while the holoenzyme was a heterotrimer comprising the preceding catalytic subunit complexed to two other polypeptides of 55 kDa (B subunit) and 65 kDa (A subunit), both of which were of alpha subtype; phospho-opsin phosphatase may thus be described as a trimeric enzyme containing the ABC subunits of type-2A protein phosphatase, i.e. PP2A1. The dephosphorylation of phospho-opsin by both fractions was found to be stimulated (4-8-fold) by the presence of protamine sulphate (250 micrograms/ml; 50 microM). However, when phospho-peptides corresponding to the C-terminal region of opsin were used, these were maximally dephosphorylated without requiring the presence of protamine; at equivalent concentrations of substrates the phospho-peptides were dephosphorylated (in the absence of protamine) at rates which were approximately equal to those obtained with phospho-opsin (in the presence of protamine). It was shown that type-1 phosphatases had little activity against these phospho-peptides. Furthermore, if phospho-opsin was treated with protamine, the activity of the phosphatase assumed an elevated level and was not significantly stimulated by the addition of exogenous protamine. This effect could be reversed by washing the protamine-treated substrate with 1 M NaCl, whence the protamine-dependent stimulation returned to normal levels. To this end, studies revealed that protamine was binding to the particulate substrate in a ratio of protamine/opsin of 0.7:1. The cumulative finding may be rationalised by suggesting that the effect of protamine is a substrate-directed phenomenon and a hypothetical mechanism for this effect is considered.


Mechanism of the citrate transporters in carbohydrate and citrate cometabolism in Lactococcus and Leuconostoc species.
Citrate metabolism in the lactic acid bacterium Leuconostoc mesenteroides generates an electrochemical proton gradient across the membrane by a secondary mechanism (C. Marty-Teysset, C. Posthuma, J. S. Lolkema, P. Schmitt, C. Divies, and W. N. Konings, J. Bacteriol. 178:2178-2185, 1996). Reports on the energetics of citrate metabolism in the related organism Lactococcus lactis are contradictory, and this study was performed to clarify this issue. Cloning of the membrane potential-generating citrate transporter (CitP) of Leuconostoc mesenteroides revealed an amino acid sequence that is almost identical to the known sequence of the CitP of Lactococcus lactis. The cloned gene was expressed in a Lactococcus lactis Cit- strain, and the gene product was functionally characterized in membrane vesicles. Uptake of citrate was counteracted by the membrane potential, and the transporter efficiently catalyzed heterologous citrate-lactate exchange. These properties are essential for generation of a membrane potential under physiological conditions and show that the Leuconostoc CitP retains its properties when it is embedded in the cytoplasmic membrane of Lactococcus lactis. Furthermore, using the same criteria and experimental approach, we demonstrated that the endogenous CitP of Lactococcus lactis has the same properties, showing that the few differences in the amino acid sequences of the CitPs of members of the two genera do not result in different catalytic mechanisms. The results strongly suggest that the energetics of citrate degradation in Lactococcus lactis and Leuconostoc mesenteroides are the same; i.e., citrate metabolism in Lactococcus lactis is a proton motive force-generating process.


The frequency of thrombotic events among adults given antifibrinolytic drugs for spontaneous bleeding: systematic review and meta-analysis of observational studies and randomized trials.
The antifibrinolytic drug tranexamic acid (TXA) improves survival after trauma. Antifibrinolytic drugs may also improve outcome after spontaneous bleeding, so we conducted a systematic review of the frequency of thrombotic events associated with their use after spontaneous bleeding, to help design future randomized controlled trials. We sought trials or observational studies of ≥20 adults involving any antifibrinolytic drug (TXA, epsilonaminocaproic acid (EACA) or aprotinin) for spontaneous (non-traumatic, non-surgical/iatrogenic), non-heamophiliac bleeding. We searched the Cochrane Central Register of Controlled Trials, OVID Medline from 1966, EMBASE from 1980, and the bibliographies of relevant articles in October 2009. We meta-analysed proportions of patients with thrombotic events, using a random effects model. We found 57 studies involving 5,049 patients, 3,616 (72%) of whom had spontaneous subarachnoid haemorrhage. 3,414 (68%) patients received TXA-based treatment and 1,635 (32%) received EACA. The frequencies of limb ischaemia and myocardial infarction were <1% for TXA and EACA. The frequency of deep vein thrombosis or pulmonary embolism was 1.9% (95% confidence interval (CI) 1.1 to 2.9) for TXA and 3.0% (95% CI 1.8 to 4.6) for EACA. The occurrence of cerebral infarction was restricted to studies of subarachnoid haemorrhage when compared to other indications, both for TXA (9.7% [95% CI 5.5 to 14.8] versus 0% [95% CI 0 to 0.5]) and for EACA (7.7% [95% CI 1.8 to 17.4] versus 0% [95% CI 0 to 2.1]). Thrombotic events have occurred infrequently with antifibrinolytic drugs after spontaneous bleeding apart from subarachnoid haemorrhage, so further exploration of their safety and efficacy after spontaneous bleeding is justified in randomized trials.


Unexpected placenta accreta spectrum after the use of assisted reproductive technology in women with adenomyomectomy.
Placenta accreta spectrum (PAS) is a rare complication that can lead to life-threatening postpartum hemorrhage. PAS can sometimes occur unexpectedly, without placenta previa;such cases can lead to higher maternal mortality and morbidity than expected cases. Here, the authors report a case of unexpected PAS caused by assisted reproductive technology (ART) in a woman with adenomyosis. The patient was a 37-year-old Japanese primipara woman who presented to our hospital at 11 weeks gestation, later returning to her parents' house to give birth. The woman had adenomyosis and underwent adenomyomectomy, which was followed by an ART pregnancy. The patient was admitted to our hospital because of a life-threatening preterm birth, with a short cervix and no evidence of placenta previa. Despite strict perinatal management, preterm rupture of the membrane (PROM) occurred. During laparotomy, the small intestine, rectum, and both right and left ovaries were clumped together and severely adhered to the surface of the uterus. After delivery, manual partial removal of the placenta was performed, resulting in heavy bleeding from the implantation site, which was diagnosed as an unexpected PAS. Following several uterine compression efforts, we successfully preserved the uterus.


The type II signal peptidase of Legionella pneumophila.
Legionella pneumophila is a facultative intracellular Gram-negative bacterium that has become an important cause of community-acquired and nosocomial pneumonia. Recent studies concerning the unravelling of bacterial virulence have suggested the involvement of protein secretion systems in bacterial pathogenicity. In this respect, the type II signal peptidase (LspA), which is specifically required for the maturation of lipoproteins, is of particular interest. This paper reports the cloning and functional characterization of the L. pneumophila lspA gene encoding the type II signal peptidase (SPase II). Activity of the L. pneumophila LspA was demonstrated using a globomycin sensitivity assay in Escherichia coli. In L. pneumophila, the lspA gene is flanked by the isoleucyl-tRNA synthetase (ileS) gene and the gene encoding a 2-hydroxy-3-deoxy-phosphogluconate aldolase. Although there is no apparent physiological connection, transcriptional analysis demonstrated that, as in some other Gram-negative bacteria, lspA is cotranscribed with ileS in L. pneumophila. Finally, in silico analysis revealed that several proteins known to be crucial for virulence and intracellular growth of L. pneumophila are predicted to be lipoproteins. These include, in particular, proteins involved in protein secretion and motility. Results obtained strongly suggest an important role for LspA in the pathogenicity of L. pneumophila, making it a promising new target for therapeutic intervention.


The relationship of adult attachment constructs to object relational patterns of representing self and others.
This study examined the relation between attachment constructs assessed by self-report and object relations constructs assessed from narratives. Young adult participants (N = 65; median age 28) completed the Reciprocal Attachment Questionnaire (West, Sheldon, &Reiffer, 1987), provided a set of interpersonal narratives rated using the Social Cognition and Object Relations Scale (SCORS; Westen, Barends, Leigh, Mendel, &Silbert, 1994), and completed other relationship-related measures. Results suggest some conceptual convergence between internal working models and representations of self, others, and relationships; for example, individuals who perceive significant others as offering a secure base for emotional connection tend to have complex, well-differentiated representations of self and others. In addition, multiple dimensions of object relationships were found to be significantly associated with participants' relationship status (current involvement in a significant relationship) and their parents' marital status.


Total Direct Medical Expenses and Characteristics of Privately Insured Adolescents Who Incur High Costs.
Accountable care payment models aim to reduce total direct medical expenses for high-cost patients through improved quality of care and preventive health services. Little is known about health care expenditures of privately insured adolescents, especially those who incur high costs. To assess health care expenditures for high-cost adolescents and to describe the patient characteristics associated with high medical costs. A retrospective cohort analysis was conducted of data from January 1 to December 31, 2012, of 13,103 privately insured adolescents aged 13 to 21 years (mean [SD] age, 16.3 [2.4] years; 6764 [51.6%] males) at 82 independent pediatric primary care practices in Massachusetts. Analysis was conducted from April 1, 2014, to April 1, 2015. We compared demographic (age, sex, median income by zip code) and clinical (obesity, behavioral health problem, complex chronic condition) characteristics between high-cost (top 1%) and non-high-cost adolescents. We assigned high-cost adolescents to clinical categories using software from the Agency for Healthcare Research and Quality to describe clinically relevant patterns of spending. Total direct medical expenses were $41.2 million for the entire cohort and a median $1167 per patient. A total of 132 (1.0%) patients with the highest costs accounted for 23.6% of expenses of the cohort, with a median $52,577 per patient. Mental health disorders were the most common diagnosis in high-cost patients; 78 (59.1%) of these patients had at least 1 behavioral health diagnosis. Pharmacy costs accounted for 28.4% of total direct medical expenses of high-cost patients; primary care accounted for 1.0%. Characteristics associated with being a high-cost patient included having 1 complex chronic condition (relative risk [RR], 6.5; 95% CI, 4.7-9.0), having 2 or more complex chronic conditions (RR, 23.5; 95% CI, 14.2-39.1), having any behavioral health diagnosis (RR, 3.6; 95% CI, 2.6-5.1), and obesity (RR, 2.0; 95% CI, 1.3-3.0). Total direct medical expenses for privately insured high-cost adolescents are associated with medical complexity, mental health conditions, and obesity. Cost reduction strategies in similar populations should be tailored to these cost drivers.


Models, movements, and minds: bridging the gap between decision making and action.
Decision making is a fundamental cognitive function, which not only determines our day-to-day choices but also shapes the trajectories of our movements, our lives, and our societies. While immense progress has been made in recent years on our understanding of the mechanisms underlying decision making, research on this topic is still largely split into two halves. Good-based models largely state that decisions are made between representations of abstract value associated with available options; while action-based models largely state that decisions are made at the level of action representations. These models are further divided between those that state that a decision is made before an action is specified, and those that regard decision making as an evolving process that continues until movement completion. Here, we review computational models, behavioral findings, and results from neural recordings associated with these frameworks. In synthesizing this literature, we submit that decision making is best understood as a continuous, graded, and distributed process that traverses a landscape of behaviorally relevant options, from their presentation until movement completion. Identifying and understanding the intimate links between decision making and action processing has important implications for the study of complex, goal-directed behaviors such as social communication, and for elucidating the underlying mechanisms by which decisions are formed.


Studies on B- and T-cell receptors for lysozyme.
BALB/c mice have been immunized by intravenous administration of native or reduced and alkylated lysozyme. Primary immune response to these antigens was studied at the humoral level (by the Farr assay) and at the cellular level (by the rosette and the plaque assays using lysozyme coupled to sheep or pigeon erythrocytes). Antibodies and theta-negative RFC were specific for the antigen used for immunization. Specific inhibition of theta-negative RFC after incubation with the soluble immunizing antigen confirmed this specificity. Conversely, most theta-positive RFC had double specificity both to native and denatured lysozyme and showed lower avidity for the immunizing antigen, as shown by inhibition studies with soluble antigen. These data suggest that T cells have a broader specificity for lysozyme than B cells and also that, in this particular system, cytophilic antibodies are probably not responsible for the formation of theta-positive rosettes.


Adult human gingival epithelial cells as a source for whole-tooth bioengineering.
Teeth develop from interactions between embryonic oral epithelium and neural-crest-derived mesenchyme. These cells can be separated into single-cell populations and recombined to form normal teeth, providing a basis for bioengineering new teeth if suitable, non-embryonic cell sources can be identified. We show here that cells can be isolated from adult human gingival tissue that can be expanded in vitro and, when combined with mouse embryonic tooth mesenchyme cells, form teeth. Teeth with developing roots can be produced from this cell combination following transplantation into renal capsules. These bioengineered teeth contain dentin and enamel with ameloblast-like cells and rests of Malassez of human origin.


A simple surgical technique for correction of macrotia with poorly defined helical fold.
Macrotia is a relatively rare auricular deformity and few techniques for treatment have been described, most of which include skin and cartilage excisions. Effacement of the helical fold may accompany this deformity and should be reconstructed for aesthetic integrity. The authors present their ear reduction technique that achieves ear reduction and helical fold reconstruction through a posterior approach. The method is a simple procedure performed by incising and overlapping the cartilage and should be indicated for selected mild macrotia cases.


The quantitative protein composition of calf thymus chromatin.
The proteins of calf thymus chromatin were analysed quantitatively using a combination of polyacrylamide and cellogel electrophoreses. Quantification was achieved by determining the staining values of each purified histone with amido-black. The results indicate that, on average, 700 molecules histone F1, 850 of F2al, 1440 of F2a2, 1 890 of F2b, 2380 of F3 and 500-1000 non-histone molecules are bound per 10(5) base pairs of DNA. This suggests a moderately dense protein covering of the DNA.


Photodynamic Therapy for Glioblastoma: Illuminating the Path toward Clinical Applicability.
Glioblastoma (GBM) is the most common adult brain cancer. Despite extensive treatment protocols comprised of maximal surgical resection and adjuvant chemo-radiation, all glioblastomas recur and are eventually fatal. Emerging as a novel investigation for GBM treatment, photodynamic therapy (PDT) is a light-based modality that offers spatially and temporally specific delivery of anti-cancer therapy with limited systemic toxicity, making it an attractive option to target GBM cells remaining beyond the margins of surgical resection. Prior PDT approaches in GBM have been predominantly based on 5-aminolevulinic acid (5-ALA), a systemically administered drug that is metabolized only in cancer cells, prompting the release of reactive oxygen species (ROS), inducing tumor cell death via apoptosis. Hence, this review sets out to provide an overview of current PDT strategies, specifically addressing both the potential and shortcomings of 5-ALA as the most implemented photosensitizer. Subsequently, the challenges that impede the clinical translation of PDT are thoroughly analyzed, considering relevant gaps in the current PDT literature, such as variable uptake of 5-ALA by tumor cells, insufficient tissue penetrance of visible light, and poor oxygen recovery in 5-ALA-based PDT. Finally, novel investigations with the potential to improve the clinical applicability of PDT are highlighted, including longitudinal PDT delivery, photoimmunotherapy, nanoparticle-linked photosensitizers, and near-infrared radiation. The review concludes with commentary on clinical trials currently furthering the field of PDT for GBM. Ultimately, through addressing barriers to clinical translation of PDT and proposing solutions, this review provides a path for optimizing PDT as a paradigm-shifting treatment for GBM.


Efficacy of cognitive behavioural therapy delivered over the Internet for depressive symptoms: A systematic review and meta-analysis.
Introduction Cognitive behavioural therapy has been shown to improve depressive symptoms in adults with mild to moderate depression. To overcome many of the barriers associated with delivering this treatment, attempts have been made to deliver cognitive behavioural therapy via the Internet. The objective of this meta-analysis is to assess whether Internet-based cognitive behavioural therapy delivered to adults with depressive symptoms leads to a reduction in these symptoms as compared to those who receive no therapy. Methods In September 2015, the Cochrane, PubMed and PsycInfo databases were searched; studies were also found through bibliography searches. Studies were included if they were randomized controlled trials published in English between 2005-2015 conducted with adults >18 years of age experiencing mild to moderate depression where study subjects received Internet-based cognitive behavioural therapy, and the control group was placed on a wait-list. The search yielded 257 articles; 14 of these were included in the meta-analysis. Results Internet delivered cognitive behavioural therapy had a medium effect on reducing depressive symptoms at the end of the study period (standardized mean difference: 0.74, confidence interval: 0.62-0.86, p < 0.001). Internet-delivered cognitive behavioural therapy also has a large sustained effect in maintaining reduction of depressive symptoms in follow-up measures done 3-6 months after the conclusion of the therapy (standardized mean difference: 0.83, confidence interval: 0.69-0.99, p < 0.001). There was no publication bias and low heterogeneity. Discussion Cognitive behavioural therapy delivered over the Internet leads to immediate and sustained reduction in depressive symptoms; thus, it may be a good treatment modality for individuals unable or unwilling to access traditional face-to-face therapy.


Development and testing of a filter system for isolation of Giardia lamblia cysts from water.
An inexpensive, practical, and reliable method for isolation of Giardia lamblia cysts from potable and environmental water has been developed from commercially available components. This system was successfully used to isolate cysts from well water associated with a family outbreak of giardiasis.


The prevalence of person-perceived participation restriction in community-dwelling older adults.
To estimate the prevalence, nature and distribution of person-perceived participation restriction, in community-dwelling older adults. Population based cross-sectional postal survey of 11,055 adults aged 50 years and over in North Staffordshire, United Kingdom. Person-perceived participation restriction was measured using the Keele Assessment of Participation which covers 11 different aspects of life mapped to the World Health Organization's International Classification of Functioning. Four-week period prevalence was calculated for restriction in any, multiple and for each aspect separately. Prevalence estimates were calculated for the total sample, and for each age and gender stratum. A total of 7,878 subjects responded (adjusted response--71.3%). The 4-week period prevalence of any participation restriction was 51.8%; 3.3% had substantial restriction. Participation restriction increased with age (p<0.001) and, for moderate and substantial restriction, was more frequent in women. The prevalence of restricted participation in individual aspects of life ranged from 3.8% (work) to 25.9% (mobility outside the home). Some restriction of participation 'as and when we want it' is common in the general population and increases with age, although severe restriction only affects a minority. The distribution of person-perceived participation restriction is similar to that of impairments and activity limitation in community-dwelling older adults.


Increased ROS Level in Spinal Cord of Wobbler Mice due to Nmnat2 Downregulation.
Amyotrophic lateral sclerosis is a devastating motor neuron disease and to this day not curable. While 5-10% of patients inherit the disease (familiar ALS), up to 95% of patients are diagnosed with the sporadic form (sALS). ALS is characterized by the degeneration of upper motor neurons in the cerebral cortex and of lower motor neurons in the brainstem and spinal cord. The wobbler mouse resembles almost all phenotypical hallmarks of human sALS patients and is therefore an excellent motor neuron disease model. The motor neuron disease of the wobbler mouse develops over a time course of around 40 days and can be divided into three phases: p0, presymptomatic; p20, early clinical; and p40, stable clinical phase. Recent findings suggest an essential implication of the NAD+-producing enzyme Nmnat2 in neurodegeneration as well as maintenance of healthy axons. Here, we were able to show a significant downregulation of both gene and protein expression of Nmnat2 in the spinal cord of the wobbler mice at the stable clinical phase. The product of the enzyme NAD+ is also significantly reduced, and the values of the reactive oxygen species are significantly increased in the spinal cord of the wobbler mouse at p40. Thus, the deregulated expression of Nmnat2 appears to have a great influence on the cellular stress in the spinal cord of wobbler mice.


Significant negative impact of adjuvant chemotherapy on health-related quality of life (HR-QoL) in women with breast cancer treated by conserving surgery and postoperative 3-D radiotherapy. A prospective measurement.
To prospectively assess health-related quality of life (HR-QoL) in women after conserving surgery for breast cancer during/after postoperative 3-D radiotherapy. 109 consecutively treated patients were analyzed. HR-QoL was assessed at initiation (t1), end (t2), and 6 weeks after radiotherapy (t3) using the EORTC modules QLQ-C30/BR23. Patients were divided into three therapy groups. Group I comprised 41 patients (radiotherapy and adjuvant chemotherapy), group II 45 patients (radiotherapy and adjuvant hormonal therapy), and group III 23 patients (radiotherapy alone). Reliability was tested. Scale means were calculated. Univariate (ANOVA) and multivariate (MANCOVA) analyses were performed. Reliability testing revealed mean Cronbach's alpha> 0.70 at all measurement points. ANOVA/MANCOVA statistics revealed significantly better HR-QoL for patients in group II versus I. Patients receiving radiotherapy alone (group III) showed the best results in HR-QoL. However, scale mean differences between groups II and III were not significant. HR-QoL measurement using EORTC instruments during/after radiotherapy is reliable. Adjuvant chemotherapy significantly lowered HR-QoL versus hormones or radiotherapy alone. Chemotherapy patients did not recover longitudinally (from t1 to t3).


The self-nonself concept as a basis for immune complex to replace "autoimmune diseases".
The remarkable history of the 1951 pp 66 year old woman with gastric adenocarcinoma is reviewed. After subtotal gastrectomy she survived for 22 years without any metastases. Presumably the artificially induced high titer IgG, anti-P1 proved to be cytotoxic in two stages: (1) binding of anti-P1 to the terminal fifth sugar, galactose, and (2) the action of cellular immunity in the form of killer T derived lymphocytes containing receptors for IgG molecules. An identical mechanism may be operative in inducing abortions in the pp pregnant woman with a P1 fetus. P1 illegitimate glycolipid (GL) red cell antigen and Forssman (Fs) tissue in adenocarcinoma suggest the self-nonself concept because these are genetically foreign to the host. This concept applies also to numerous "autoimmune" diseases such as RA, lupus, glomerulonephritis, Coombs positive hemolytic anemia and other diseases with immune complexes (ICs) of 20--22 Svedberg units deposited as lesions with tissue damage. In the presence of the GL antigens (ABO, P, Fs), the normal serum contains antibodies for the missing antigen(s). The predicted anti-Fs was present in about 80% of normal employees of ages 18--70. In cancer sera the incidence was 35--40%. On testing normal sera by age in terms of decades anti-Fs was present in 93% in the youngest, and only 55% in the oldest group. This may be associated with the gradual loss of protein synthesis with aging and/or the accumulation of soluble ICs which bind the C1q portion of the C added to the test mixture of heat-inactivated serum (1 : 8) g.p. C (1 : 30) and srbc. In "autoimmune" diseases there is an active immune response to viral or bacterial infections or infestations or drugs which attach to rbc and/or tissue cell membranes. This results in the deposition in selected organs of ICs of 20--22 S units with lesions and tissue damage. For therapy plasma (from young donors) exchange has been recommended to compensate for the loss of IgG antibodies and C.


Metal-Organic Framework Stabilizes a Low-Coordinate Iridium Complex for Catalytic Methane Borylation.
Catalytic borylation has recently been suggested as a potential strategy to convert abundant methane to fine chemicals. However, synthetic utility of methane borylation necessitates significant improvement of catalytic activities over original phenanthroline- and diphosphine-Ir complexes. Herein, we report the use of metal-organic frameworks (MOFs) to stabilize low-coordinate Ir complexes for highly active methane borylation to afford the monoborylated product. The mono(phosphine)-Ir based MOF, Zr-P1-Ir, significantly outperformed other Ir catalysts in methane borylation to afford CH3Bpin with a turnover number of 127 at 110 °C. Density functional theory calculations indicated a significant reduction of activation barrier for the rate limiting oxidative addition of methane to the four-coordinate (P1)IrIII(Bpin)3 catalyst to form the six-coordinate (P1)IrV(Bpin)3(CH3)(H) intermediate, thus avoiding the formation of sterically encumbered seven-coordinate IrV intermediates as found in other Ir catalysts based on chelating phenanthroline, bipyridine, and diphosphine ligands. MOF thus stabilizes the homogeneously inaccessible, low-coordinate (P1)Ir(boryl)3 catalyst to provide a unique strategy to significantly lower the activation barrier for methane borylation. This MOF-based catalyst design holds promise in addressing challenging catalytic reactions involving highly inert substrates.


An Evaluation of Ischaemic Preconditioning as a Method of Reducing Ischaemia Reperfusion Injury in Liver Surgery and Transplantation.
Liver Ischaemia Reperfusion (IR) injury is a major cause of post-operative liver dysfunction, morbidity and mortality following liver resection surgery and transplantation. There are no proven therapies for IR injury in clinical practice and new approaches are required. Ischaemic Preconditioning (IPC) can be applied in both a direct and remote fashion and has been shown to ameliorate IR injury in small animal models. Its translation into clinical practice has been difficult, primarily by a lack of knowledge regarding the dominant protective mechanisms that it employs. A review of all current studies would suggest that IPC/RIPC relies on creating a small tissue injury resulting in the release of adenosine and l-arginine which act through the Adenosine receptors and the haem-oxygenase and endothelial nitric oxide synthase systems to reduce hepatocyte necrosis and improve the hepatic microcirculation post reperfusion. The next key step is to determine how long the stimulus requires to precondition humans to allow sufficient injury to occur to release the potential mediators. This would open the door to a new therapeutic chapter in this field.


[Factors Related to the Use of Inhaled and Intravenous Heroin, Granada, Spain].
Heroin use has stabilized in recent years in Spain, and the use of injected heroin having decreased. Nevertheless,major differences exist among different Autonomous Communities and among injected heroin users profile. This study is aimed at ascertaining the forms of heroin use (how administered) in an intentional sample of users in a situation of social exclusion andsome variables related to said forms of use. The sample was comprised of 285 participants (82.8% males; average age 36.06). This study was conducted in the city of Granada in July-October 2002. Structured surveys conducted by onthe-street interviewers and individuals having knowledge of the environment («peers») using the «snowball» technique. A total of 48.4% of the participants alternate inhaled and intravenous heroin use; 25.6% using only inhaled and 25.6% only intravenous. Following a regression analysis, it was found that the females, the youngest users and those having started use at an older age were at less risk of intravenous heroin use. A total of 21.5% of the participants who started using heron in inhaled form, also currently use both the injected and inhaled forms, the remaining 79.5% continue to use the inhaled form. Among individuals in a situation of social exclusion the intravenous form exceeds the estimated percentages in the Autonomous Community of Andalusia.


Long-lasting hormonal alterations to extreme stress in humans: normative or maladaptive?
The biological consequences of stress have been studied for over half a decade, however, little is known about persistent biological alterations after extreme stress in humans. Posttraumatic stress disorder (PTSD) is a syndrome that occurs in some individuals after exposure to extreme stress. In this review, we summarize some of our studies of hypothalamic-pituitary-adrenal axis alterations in PTSD and compare and contrast these findings with knowledge concerning biological changes following stress.


Integration of interpreters in mental health interventions with children and adolescents: The need for a framework.
Few empirical studies have detailed the specificities of working with interpreters in mental healthcare for children. The integration of interpreters in clinical teams in child mental healthcare was explored in two clinics, in Montreal and Paris. Four focus groups were conducted with interpreters and clinicians. Participants described the development of the working alliance between interpreters and clinicians, the delineation of interpreters' roles, and the effects of translation on the people in the interaction. Integrating interpreters in a clinical team is a slow process in which clinicians and interpreters need to reflect upon a common framework. An effective framework favours trust, mutual understanding, and valorization of the contribution of each to the therapeutic task. The interpreter's presence and activities seem to have some therapeutic value.


[Radiation from mobile phone and the health].
With the development of the mobile communication industry, there are considerable public concerns about the relationship between mobile phone radiations and human health. With regard to electromagnetic field emitted by mobile phone maybe influence tumor,learning and memory, subjective symptoms and blood-brain barrier, a large number of studies have been performed abroad. This paper reviews the research development abroad on these problems, and analysizes the mechanism, through which the mobile phone effects on human health.


Examining lethality risk for rodent studies of primary blast lung injury.
While protective measures have been taken to mitigate injury to the thorax during a blast exposure, primary blast lung injury (PBLI) is still evident in mounted/in vehicle cases during military conflicts. Moreover, civilians, who are unprotected from blast exposure, can be severely harmed by terrorist attacks that use improvised explosive devices (IEDs). Since the lungs are the most susceptible organ due to their air-filled nature, PBLI is one of the most serious injuries seen in civilian blast cases. Determining lethality threshold for rodent studies is crucial to guide experimental designs centered on therapies for survival after PBLI or mechanistic understanding of the injury itself. Using an Advanced Blast Simulator, unprotected rats were exposed to a whole body blast to induce PBLI. The one-hour survival rate was assessed to determine operating conditions for a 50% lethality rate. Macroscopic and histological analysis of lung was conducted using hematoxylin and eosin staining. Results demonstrated lethality risk trends based on static blast overpressure (BOP) for rodent models, which may help standardized animal studies and contribute to scaling to the human level. The need for a standardized method of producing PBLI is pressing and establishing standard curves, such as a lethality risk curve for lung blasts, is crucial for this condensing of BOP methods.


Prognostic factors in Acanthamoeba keratitis.
To assess the prognostic factors influencing visual prognosis and length of treatment after acanthamoeba keratitis (AK). Forty-two AK eyes of 41 patients treated between 1999 and 2006 were included. A diagnosis of AK was made on the basis of culture results with a corresponding clinical presentation. We calculated the prognostic effect of the various factors on final visual acuity and the length of treatment. Multivariate regression analysis was used to adjust for the simultaneous effects of the various prognostic factors. Mean follow-up was 19.7 ± 21.0 months. Sixty-four percent of cases had > 1 identified risk factor for AK, the most common risk factor being contact lens wear (92.9% of eyes). At presentation, median best spectacle corrected visual acuity (BCVA) was 20/200 (20/30 to Hand Motion [HM]) that improved after treatment to 20/50 (20/20 to Counting Fingers [CF]). Infection acquired by swimming or related to contact lenses had significantly better final BCVA (p = 0.03 and p = 0.007, respectively). Neuritis and pseudodendrites were also associated with better final BCVA (p = 0.04 and p = 0.05, respectively). Having had an epithelial defect on presentation and having been treated with topical steroid were associated with worse final best spectacle corrected visual acuity (BSCVA) (p = 0.0006 and p = 0.04). Multivariate regression analysis found a good initial visual acuity (p = 0.002), infections related to swimming (p = 0.01), the absence of an epithelial defect (p = 0.03), having been treated with chlorhexidine (p = 0.05), and not having receive steroids (p = 0.003) to significantly forecast a good final BCVA. We identified several prognostic factors that can help clinicians evaluate the expected visual damage of the AK infection and thus tailor treatment accordingly.


High-Loading Self-Assembling Peptide Nanoparticles as a Lipid-Free Carrier for Hydrophobic General Anesthetics.
Typical hydrophobic amino acids (HAAs) are important motifs for self-assembling peptides (SAPs), but they lead to low water-solubility or compact packing of peptides, limiting their capacity for encapsulating hydrophobic drugs. As an alternative, we designed a peptide GQY based on atypical HAAs, which could encapsulate hydrophobic drugs more efficiently. Although hydrophobic general anesthetics (GAs) have been formulated as lipid emulsions, their lipid-free formulations have been pursued because of some side effects inherent to lipids. Using GAs as targets, potential application of GQY as a carrier for hydrophobic drugs was evaluated. Thioflavin-T (ThT) binding test, dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to examine the self-assembling ability of GQY. Pyrene and 8-Anilino-1-naphthalenesulfonic acid (ANS) were used to confirm formation of hydrophobic domain in GQY nanoparticles. Using pyrene as a model, GQY's capacity to encapsulate hydrophobic drugs was evaluated. GAs including propofol, etomidate and ET26 were encapsulated by GQY. Loss of righting reflex (LORR) test was conducted to assess the anesthetic efficacy of these lipid-free formulations. Paw-licking test was used to evaluate pain-on-injection of propofol-GQY (PROP-GQY) formulation. Hemolytic and cytotoxicity assay were used to evaluate biocompatibility of GQY. Stable nanoparticles containing plenty of hydrophobic cavities could be formed by GQY, which could encapsulate hydrophobic drugs at very high concentration and form stable suspensions. Propofol, etomidate and ET26 formulated by GQY showed anesthetic efficacy comparable to their currently available formulations. Unlike clinic lipid emulsion, PROP-GQY formulation did not cause pain-on-injection in rats. Neither obvious cytotoxicity nor hemolytic activity of GQY was observed. GQY could encapsulate GAs to obtain stable and effective formulations. As a lipid-free carrier, GQY exhibited considerable biocompatibility and other side benefits such as reducing pain-on-injection. More SAPs based on atypical HAAs could be designed as promising carriers for hydrophobic drugs.


Does the canine dental follicle cause resorption of permanent incisor roots? A computed tomographic study of erupting maxillary canines.
We performed computed tomography (CT) on 107 children and adolescents aged 9-15 years with 176 unerupted maxillary canines (152 erupting ectopically and 24 erupting normally) to determine whether there is an association between widened dental follicles of the maxillary canines and resorption of the adjacent incisors during eruption. Contiguous axial (transverse) CT scans were obtained through the maxilla in the region of the canines. The width and shape of the dental follicles were recorded, as were any contacts between the follicles and the crowns of the maxillary canines and neighboring incisors. Fifty-eight lateral incisors (38%) and 14 central incisors (9%) had some type of root resorption. The position of the maxillary canine in relation to the root of the lateral incisor varied greatly, as did the width and shape of the canine dental follicle. Follicle width ranged from 0.5 mm to 7.0 mm. The mean +/- SD width of dental follicles was, on average, larger for the ectopically positioned canines (2.9 +/- 0.8 mm) than for the normally erupting canines (2.5 +/- 0.8 mm) (P < or = .01). We found that during eruption, the follicle of the erupting maxillary canine frequently resorbed the periodontal contours of adjacent permanent teeth but not the hard tissues of the roots. We concluded that the dental follicle did not cause root resorption of permanent teeth. Resorption of neighboring permanent teeth during maxillary canine eruption was most probably an effect of the physical contacts between the erupting canine and the adjacent tooth, active pressure during eruption, and cellular activities in the tissues at the contact points, all of which are part of the eruptive mechanism. The findings also confirm an association between root resorption of deciduous canines and the dental follicles of erupting permanent canines.


Association of PD-1.5 C/T, but Not PD-1.3 G/A, with Malignant and Benign Brain Tumors in Iranian Patients.
Programmed death-1 (PD-1) negatively regulates the immune response. The aims of this study were to assess the association of two single nucleotide polymorphisms in the PD-1 gene, PD-1.5 (+7785 C/T-rs2227981) and PD-1.3 (+7146 G/A- rs11568821), with benign and malignant brain tumors. Patients with brain tumors (96 patients with benign and 56 with malignant brain tumors) and 150 healthy control individuals were included. PCR-RFLP was performed for genotyping. It was revealed that the genotype and allele frequencies of PD-1.5 C/T polymorphism were significantly different between all brain tumor patients and the control group. The frequencies of the CT genotype and T allele were higher in brain tumor patients. In contrast, the frequency of PD-1.3 G/A genotypes and alleles showed no significant difference between all brain tumor patients and controls. Patients were then divided into malignant and benign groups. The results revealed a significant difference in both patients groups compared with the controls only at PD-1.5 C/T position. Arlequin analysis showed the GC haplotype was the most frequent haplotype in the whole group of patients and controls, and the GT haplotype was significantly different between patient and control groups. In conclusion, we demonstrate that PD-1.5 C/T polymorphism, but not PD-1.3 G/A, is associated with brain tumors in Iranian patients.


Modifying the ICRP 66 dosimetry model based on results obtained from Mayak plutonium workers.
Results obtained in a study of the microscopic distribution of plutonium in the lungs of deceased Pu workers from the Mayak Production Association showed that the long-term retention of Pu was greater than predicted by the current ICRP 66 respiratory tract dosimetry model (HRTM). These data were therefore applied to the HRTM by modifying selected parameters, namely the transfer rate of Pu from the transformed state compartment and the fraction of Pu that transfers to the bound state compartment. Invoking the latter compartment into the modelling allowed a better representation of the long-term Pu retention as well as providing a convenient means of describing the workplace-specific characteristics of the different Pu aerosols found in the Mayak plant. In particular, the present model describes a significantly greater long-term retention of Pu nitrate aerosols in the lung compared with the Type M default.


Long-term follow-up of vitrectomy in patients with pathologic myopic foveoschisis.
To report the long-term surgical outcomes of pathologic myopic foveoschisis (MF) following vitrectomy. We performed a retrospective case series analysis of 50 consecutive patients diagnosed with MF who experienced vision loss due to progression of foveoschisis. The 50 patients (67 eyes) were treated in our hospital with vitrectomy with internal limiting membrane (ILM) peeling from December 2004 to September 2010. Best corrected visual acuity (BCVA), refractive error, optical coherence tomography (OCT), and routine examination results were analysed. The changes of BCVA, foveal anatomical features on OCT scan, and complications were the main outcome measures. The mean follow-up duration was 42±17mo (range 24 to 93mo). BCVA improved significantly postoperatively (0.76±0.65 logMAR) compared with preoperative baselines (1.31±0.78 logMAR, P<0.0001), and in 53 eyes (79%) including 3 lines gain in 44 eyes (66%) at the last follow-up visit. OCT scans showed that central retinal thickness decreased from 580.0±270.0 µm preoperatively (n=67) to 179.7±84.7 µm postoperatively (n=58, P<0.0001). Total resolution of foveoschisis occurred in 41 eyes (61%). Preoperative BCVA correlated well with postoperative BCVA, whereas other factors such as age, axial length, and refractive error were not correlated. The most common complications were cataract and full-thickness macular hole formation in 14 and 9 cases, respectively. Patients with progressive vision loss due to MF who were treated with vitrectomy with ILM peeling show favourable outcomes. In most eyes, visual acuity and foveal structure remain stable during long-term observation.


Reproduction in couples who are affected by human immunodeficiency virus: medical, ethical, and legal considerations.
There has been a transformation in the treatment of human immunodeficiency virus from the treatment of complications that define acquired immune deficiency syndrome to the maintenance of long-term health, with an expanding number of antiretroviral medications. Because human immunodeficiency virus infection now is considered to be a chronic disease, couples will be seen in greater numbers for preconception counseling. The ethical and legal implications, including the relevance of the Americans with Disability Act, are complex but support the assistance with reproduction of couples who are affected by human immunodeficiency virus in many instances. All couples who are affected by human immunodeficiency virus, whether fertile or infertile, who want to have genetically related offspring should be seen preconceptionally for counseling and testing. Intensive education involves a multidisciplinary approach to ensure that a couple is fully informed. Determination of whether to offer treatment should be based on the same criteria that are applied to couples who are affected by other chronic diseases. Medical treatment is dependent on the unique circumstances of each couple. In general, the affected partner(s) should be treated aggressively with antiretrovirals and then serum; if applicable, semen testing is required to document undetectable concentrations of human immunodeficiency virus (<50-100 copies/mL).


MoS2 Nanoflowers Grown on Plasma-Induced W-Anchored Graphene for Efficient and Stable H2 Production Through Seawater Electrolysis.
Herein, it is found that 3D transition metal dichalcogenide (TMD)-MoS2 nanoflowers-grown on 2D tungsten oxide-anchored graphene nanosheets (MoS2 @W-G) functions as a superior catalyst for the hydrogen evolution reaction (HER) under both acidic and alkaline conditions. The optimized weight ratio of MoS2 @W-G (MoS2 :W-G/1.5:1) in 0.5 M H2 SO4 achieves a low overpotential of 78 mV at 10 mA cm-2 , a small Tafel slope of 48 mV dec-1 , and a high exchange current density (0.321 mA cm⁻2 ). Furthermore, the same MoS2 @W-G composite exhibits stable HER performance when using real seawater, with Faradaic efficiencies of 96 and 94% in acidic and alkaline media, respectively. Density functional theory calculations based on the hybrid MoS2 @W-G structure model confirm that suitable hybridization of 3D MoS2 and 2D W-G nanosheets can lower the hydrogen adsorption: Gibbs free energy (∆GH* ) from 1.89 eV for MoS2 to -0.13 eV for the MoS2 @W-G composite. The excellent HER activity of the 3D/2D hybridized MoS2 @W-G composite arises from abundance of active heterostructure interfaces, optimizing the electrical configuration, thereby accelerating the adsorption and dissociation of H2 O. These findings suggest a new approach for the rational development of alternative 3D/2D TMD/graphene electrocatalysts for HER applications using seawater.


Case Report: Campylobacter fetus caused pyogenic spondylodiscitis with a presentation of cauda equina syndrome after instrumented lumbar fusion surgery.
Spondylodiscitis with/without neurologic impairment is a serious infection, predominantly occurring in high-risk patients. Campylobacter fetus caused spondylodiscitis is very rare. Evidence-based therapeutic concepts for lumbar spondylodiscitis are lacking. A 64-year-old high-risk woman underwent decompression with instrumented lumbar fusion. Six months after index surgery, she developed pyelonephritis, which deteriorated to sepsis and presentation of cauda equina syndrome. She underwent urgent revision with decompression, debridement, and instrumentation removal, and received long-term antibiotics. Culture grew Campylobacter fetus, previously not reported as a cause of spondylodiscitis after elective instrumented lumbar fusion. Emergent debridement and removal of instrumentation, with 2 months of targeted intravenous antibiotics followed by 6 weeks of oral antibiotics led to complete spondylodiscitis resolution. Prompt diagnostics and targeted antibiotic treatment are paramount when dealing with spinal infections, particularly in patients with rare causative pathogens like Campylobacter fetus. Concomitant neurological complications may require emergent surgical management in the case of cauda equina syndrome.


Implementing RSA for Wireless Sensor Nodes.
As wireless sensor networks (WSNs) become more widespread, potential attacks against them also increase and applying cryptography becomes inevitable to make secure WSN nodes. WSN nodes typically contain only a constrained microcontroller, such as MSP430, Atmega, etc., and running public key cryptography on these constrained devices is considered a challenge. Since WSN nodes are spread around in the field, the distribution of the shared private key, which is used in a symmetric key cryptographic algorithm for securing communications, is a problem. Thus, it is necessary to use public key cryptography to effectively solve the key distribution problem. The RSA cryptosystem, which requires at least a 1024-bit key, is the most widely used public key cryptographic algorithm. However, its large key size is considered a drawback for resource constrained microcontrollers. On the other hand, RSA allows for extremely fast digital signature generation which may make it desirable in applications where messages transmitted by sensor nodes need to be authenticated. Furthermore, for compatibility with an existing communication infrastructure, it may be desirable to adopt RSA in a WSN setting. With this work, we show that, in spite of its long key size, RSA is applicable for wireless sensor networks when optimized arithmetic, low-level coding and some acceleration algorithms are used. We pick three versions of the MSP430 microcontroller, which is used widely on wireless sensor network nodes, and implement 1024-bit RSA on them. Our implementation achieves 1024-bit RSA encryption and decryption operations on MSP430 in only 0 . 047 s and 1 . 14 s, respectively. In order to achieve these timings, we utilize several acceleration techniques, such as the subtractive Karatsuba-Ofman, Montgomery multiplication, operand scanning, Chinese remainder theorem and sliding window method. To the best of our knowledge, our timings for 1024-bit RSA encryption and decryption operations are the fastest reported timings in the literature for the MSP430 microcontroller.


Natural products: a strategic lead generation approach in crop protection discovery.
With the anticipated population growth in the coming decades, the changing regulatory environment, and the continued emergence of resistance to commercial pesticides, there is a constant need to discover new lead chemistries with novel modes of action. We have established a portfolio of approaches to accelerate lead generation. One of these approaches capitalizes on the rich bioactivity of natural products (NPs), highlighted by the numerous examples of NP-based crop protection compounds. Within Corteva Agriscience and the affiliated preceding companies, NPs have been a fruitful approach, for nearly three decades, to identifying and bringing to the market crop protection products inspired by or originating from NPs, . Included in these NP-based crop protection products are the spinosyns family of insecticides, and those from more recent areas of NP-based fungicidal chemistry, as highlighted in this perspective. © 2019 Society of Chemical Industry.


Study on Ignition Delay and Reaction Mechanism of RP-3/Air Combustion Adding C6F12O.
RP-3 jet fuel is the main fuel for aircraft in China, and it is also a source of fire. C6F12O (Novec 1230) has an outstanding fire extinguishing performance and minimal environmental impacts. In this study, the application of C6F12O in the inhibition of RP-3 jet fuel fire was considered, and the ignition delay time (IDT) of C6F12O/air and RP-3/air adding C6F12O was measured using a shock tube. In addition, the results showed that the IDT of C6F12O was 500-900 μs and less sensitive to temperature compared with those of common fuels in the range of 1150-1958 K, and the influence of C6F12O on the IDT of RP-3 jet fuel was influenced by many factors including temperature, the concentration of C6F12O, and the stoichiometric ratio of RP-3 jet fuel. According to the experimental results, the mechanism of C6F12O was verified and modified, and then integrated with the mechanisms of RP-3 jet fuel; the integrated mechanism can well predict the IDT of C6F12O/air and RP-3/air adding C6F12O. This work provides a good basis for the chemical kinetics analysis of the inhibition of RP-3 jet fuel combustion by C6F12O.


Variability in response assessment in solid tumors: effect of number of lesions chosen for measurement.
This study was performed to systematically evaluate the variability in tumor response assessments that occurs depending on how many tumor deposits are selected for measurement at imaging. The two largest perpendicular diameters of all tumor deposits in 36 patients were measured on computed tomography scans obtained at baseline and first posttherapy follow-up. A computerized modeling analysis of those data was performed to determine each patient's therapeutic response category assignment for every possible number of lesions in a grouping. The variance in the sum of measurements of these lesion groupings was calculated, and the frequency of response assessment categories was plotted against the number of lesions. The computerized analysis of the resultant 1,833,821 possible combinations of tumor deposits showed that when six lesions were measured bidimensionally and four lesions were measured undimensionally, the average variance decreased by 90%. The number of different response assessment categories into which a patient was assigned decreased with increasing lesion grouping size. When six or more lesions were measured bidimensionally, 9% of all possible lesion groupings still fell into a second response category, reflecting the effect of which particular lesions are chosen for measurement. Measuring larger numbers of lesions will decrease the variance. In this population, the variance decreased by at least 90% when six or more lesions were measured bidimensionally. Further confirmatory studies with larger series of patients are warranted before adopting this number as a criterion in clinical trials for assessing the activity of antineoplastic therapies.


[Information flow between medical and social sciences].
In order to reveal impacts of natural and social sciences on each other, the authors examined connections between fields of medical and social sciences using a search for references and citations of scientific publication. 1. The largest affinity between the medical and social sciences was found between neurosciences and psychology, but there was a significant affinity between clinical sciences and general social sciences, as well. 2. The example of General & Internal Medicine papers in the topics of "diabetes" suggests that in the period 2001-2010 the share of references to social sciences was significantly increased. In the meantime, social science papers in the same topics contained references to Clinical Medicine papers in a constantly high percentage. 3. In the sample under study, the age distribution of social science papers in the references did not differ significantly from that of the other sources. 4. Share of references to social science papers was found to be extremely high among Hungarian General & Internal Medicine papers in the topics of "diabetes". This finding still requires clarification, nevertheless, since e.g. it was not supported by an institutional comparison including the largest Hungarian medical research university. 5. The intensity of the reference/citation mediated information flows between the Hungarian Medical Journal, Orvosi Hetilap and social sciences appears to be in accordance with the current international trends.


Contemporary use and results of intra-aortic balloon pump counterpulsation.
Intra-aortic balloon pump (IABP) counterpulsation is the most widely used form of left ventricular mechanical support today, with more than 160,000 patients worldwide receiving this therapy annually. Currently, IABP support is indicated in patients with acute left ventricular systolic failure and cardiogenic shock whose management remains particularly complex and still today characterized by high mortality rates. While the available clinical practice guidelines support the indication to IABP placement in acute myocardial infarction (MI) with cardiogenic shock, recent clinical studies have questioned the benefits of IABP in these clinical settings. However, the rate of complications associated to IABP use is high and therefore the eventual IABP benefits must be weighed over the disadvantages. IABP still represents a very important mechanical support, however recent scientific evidences have challenged the value of its use, thus, it will be absolutely necessary to confirm these findings in a definitive RCT. This review will describe the role of IABP in the modern clinical practice.


Pancreatic and Islet Development and Function: The Role of Thyroid Hormone.
A gradually expanding body of literature suggests that Thyroid Hormone (TH) and Thyroid Hormone Receptors (TRs) play a contributing role in pancreatic and islet cell development, maturation, and function. Studies using a variety of model systems capable of exploiting species-specific developmental paradigms have revealed the contribution of TH to cellular differentiation, lineage decisions, and endocrine cell specification. Moreover, in vitro and in vivo evidence suggests that TH is involved in islet β cell proliferation and maturation; however, the signaling pathway(s) connected with this function of TH/TR are not well understood. The purpose of this review is to discuss the current literature that has defined the effects of TH and TRs on pancreatic and islet cell development and function, describe the impact of hyper- and hypothyroidism on whole body metabolism, and highlight future and potential applications of TH in novel therapeutic strategies for diabetes.


Contents of 1,4-benzoxazin-3-ones and 2-benzoxazolinone from Stenandrium dulce (Nees).
Secondary metabolites, DIBOA, HBOA, 7-OH-HBOA and BOA, were isolated and quantified from S. dulce (Nees), a native species in Chile belonging to the Acanthaceae family. The highest DIBOA and HBOA contents were determined in leaves (9.25 mmol kg(-1) fr. wt) and root (6.81 mmol kg(-1) fr. wt), respectively. Aglycones, 7-OH-HBOA and HBOA, were isolated together from root extracts of Acanthaceae species. Both, HBOA and 7-OH-HBOA should be direct precursors in the biosynthesis of DIBOA and DIMBOA, respectively.


Localized mucormycosis following intramuscular corticosteroid. Case report and review of the literature.
A case of subcutaneous localized mucormycosis infection which developed following intramuscular (IM) injection of corticosteroid in a patient with leukemia is presented. Aggressive treatment, which included wide local excision, systemic amphotericin-B, and chemotherapy for the leukemia, resulted in eradication of the infection and complete healing of the wound. A review of the literature revealed nine other patients with the localized subcutaneous form of mucormycosis (excluding patients with burns and rhinocerebral types) and six of those nine patients also survived the infection. It is possibly the mildness of the underlying predisposing factors that allows some of these patients to contain the infection at a single site. It is apparent from review of the literature that in subcutaneous localized forms of mucormycosis, the outcome has been generally good. This contrasts sharply with other clinical forms of mucormycosis infections where the underlying predisposing factors are usually severe and any kind of therapeutic approach has been almost always futile. Subcutaneous mucormycosis infection differs clinically and histopathologically from subcutaneous localized entomophthoromycosis which is seen predominantly in tropical countries. An attempt is made to clarify the terminology of these interesting fungi in language that is taxonomically up-to-date and still useful to clinicians.


The effect of aging on conductive heat exchange in the skin at two environmental temperatures.
Ageing diminishes the blood flow (BF) response of the skin to autonomic stressors. While the diminished response of skin BF to global heating has been well documented, the effect of this reduction in skin BF on the ability of the skin to dissipate heat has not. When heat is added to the skin by the application of hot packs, if heat is not adequately removed, the skin can become dangerously hot and become damaged. The present investigation examined the heat dissipating properties of the skin in older individuals. This study has importance for the therapeutic application of hot packs which might cause burns easier in older people. In the present investigation, 10 younger and 10 older subjects were examined. The average age of the younger group was 25.9+/-3.4 years and the older group was 60 +/- 5.8 years. Heat was applied through a 49 gram brass probe that was heated to 41 degrees C and by a Peltier junction in a cool and warm environment. Skin required about 20 calories of heat to raise skin temperature 1 degrees C the cool room and double this Figure in the warm room. Ageing reduced the caloric requirement to increase skin temperature under both conditions (p < 0.01). The results of the experiments showed that older individuals had impaired ability of the skin to dissipate heat in both environments. Special precautions should be taken in physical therapy when applying hot packs in older populations.


Persistent psychophysiologic insomnia: preliminary Research Diagnostic Criteria and EEG sleep data.
Some patients with persistent psychophysiologic insomnia have a history of generalized anxiety, minor depression, or drug misuse. Their sleep resembles sleep of patients with generalized anxiety (except for night 2 improvement in the insomniacs' sleep continuity) but differs from sleep of patients with major depression.


[Teaching method of the basic ability of acupuncture in training the manipulation skills in Techniques of Acupuncture and Moxibustion].
Through checking the ancient books and the articles at the modern times and combining the disciplinary characteristics of techniques of acupuncture and moxibustion, the training of manipulation skills was discussed. It is proposed that during the teaching of the techniques of acupuncture and moxibustion, the most basic ability of needling technique should be trained in the first place. This ability includes the ability of spiritual cultivation, the ability of tactile perception and the specific training for the needling techniques. The ability of spiritual cultivation refers to the consciousness concentration to the patient when providing acupuncture, which may promotes deqi and conducts qi to the affected area. The ability of tactile perception refers to the different feelings of different tissues under the hands before and after acupuncture, the perception to the different needling sensations corresponding to the chief complains of patients as well as the different body responses after acupuncture. In order to ensure the better learning results, the specific manipulations of needling techniques should be provided accordingly on the base of these basic training skills of acupuncture.


Identifying potentially preventable readmissions.
The potentially preventable readmission (PPR) method uses administrative data to identify hospital readmissions that may indicate problems with quality of care. The PPR logic determines whether the reason for readmission is clinically related to a prior admission, and therefore potentially preventable. The likelihood of a PPR was found to be dependent on severity of illness, extremes of age, and the presence of mental health diagnoses. Analyses using PPRs show that readmission rates increase with increasing severity of illness and increasing time between admission and readmission, vary by the type of prior admission, and are stable within hospitals over time.


Efficacy and Safety of Ramucirumab With Docetaxel Versus Placebo With Docetaxel as Second-Line Treatment of Advanced Non-Small-Cell Lung Cancer: A Subgroup Analysis According to Patient Age in the REVEL Trial.
Ramucirumab, a recombinant human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2), was evaluated as second-line treatment in combination with docetaxel in patients with non-small-cell lung cancer in the REVEL trial (NCT01168973). Ramucirumab significantly improved overall survival (OS) and progression-free survival (PFS). We report age subgroup analysis results primarily on the basis of a 65-year cutoff. Patients were randomized 1:1 to ramucirumab with docetaxel or placebo with docetaxel (n = 1253). Of these, 798 were younger than 65 years (ramucirumab, n = 391; control, n = 407) and 455 were 65 years or older (ramucirumab, n = 237; control, n = 218). Treatment comprised 21-day cycles of 75 mg/m2 docetaxel with 10 mg/kg ramucirumab or placebo. Prespecified age subgroup analyses were performed, including OS, PFS, and objective response rate. Quintiles age analysis was conducted to establish a relationship between efficacy and age. The Lung Cancer Symptom Scale (LCSS) measured quality of life outcomes. Safety was assessed according to adverse events (AEs). Patients younger than 65 years showed favorable OS outcomes with ramucirumab treatment (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.62-0.87; P < .001) and PFS (HR, 0.68; 95% CI, 0.59-0.79; P < .001). In patients 65 years or older, benefits of ramucirumab were not as evident; after model adjustment for prognostic factors, OS and PFS HRs were 0.96 (95% CI, 0.77-1.21; P = .04) and 0.87 (95% CI, 0.71-1.05; P = .03), respectively. Age analysis according to quintiles showed HRs favoring ramucirumab for all age groupings. LCSS scores and AEs did not considerably differ between age groups. In this subgroup analysis, true treatment effect differences on the basis of age have not been established, and treatment should not be deterred solely because of age.


Five-year results of single-incision arthroscopic anterior cruciate ligament reconstruction with patellar tendon autograft.
We performed a retrospective study on 80 patients who underwent single-incision arthroscopic anterior cruciate ligament reconstruction with patellar tendon autograft and interference fit screw fixation in 1989. Twelve patients were lost to followup, allowing a clinical assessment of 68 patients to be conducted by independent examiners at 1 and 5 years after surgery, with radiographic assessment at 5 years. Thirty-three patients had chronic anterior cruciate ligament-deficient knees. Three patients reruptured their grafts during sports at 29, 48, and 56 months. At 5 years, 64 patients (98%) had grade 0 or 1 Lachman and pivot shift tests with manual stability testing. Fifty patients (77%) were participating in level I or II activities according to the International Knee Documentation Committee scale. Twenty-nine patients (45%) experienced low levels of pain when performing at their highest activity level. Five (8%) had thigh atrophy greater than 1 cm, and three (5%) had an extension loss of more than 3 degrees. Eleven patients (17%) had tenderness over the graft site when kneeling. Fifteen of 62 patients (24%) had degenerative changes on radiographs, and this was more common in patients with chronic anterior cruciate ligament-deficient knees. Fifty-two patients (80%) had normal or nearly normal knees according to the overall International Knee Documentation Committee score.


B cell maturation in chronic lymphocytic leukemia. III. Effect of recombinant cytokines on leukemic B cell proliferation.
Proliferation and differentiation of B lymphocytes is influenced by a variety of soluble mediators. The recent cloning of various cytokines has made it possible to study the effect of molecularly defined lymphokines and other cytokines on B-cell activation. In the present study, we have analyzed the effect of several cytokines on the in vitro proliferation of highly purified leukemic B cells from patients with chronic lymphocytic leukemia (CLL). The recombinant human cytokines tested included interleukins 1, 2, 3, and 4 tumor necrosis factor-alpha (TNF-alpha) and interferon-alpha (IFN alpha), all of which are known to play a role in B-cell activation. B cells from 10 of 13 patients (all with white blood cell counts greater than 100,000/ul) did not respond to any of the cytokines tested. In contrast, B cells from 3 other patients responded well to IL-2 when preactivated for 24 h with phorbolester TPA and ionomycin. Moreover, preactivated B cells from 2 of these patients also proliferated in response to TNF-alpha, and some proliferation of unactivated B cells in response to TNF-alpha was seen in one case. Together, these results stress the clonal heterogeneity of CLL B-cell populations, and demonstrate that both IL-2 and TNF-alpha may act as a B-cell growth factor on B cells from certain CLL patients.


Pharmacokinetic/pharmacodynamic assessment of tolerance to central nervous system effects of a 3 mg sustained release tablet of rilmenidine in hypertensive patients.
Previous single-dose studies have shown clear blood pressure-lowering effects of a potential sustained release (SR) profile of rilmenidine, with concentration-dependent effects on the central nervous system. The aim of this study was to evaluate potential changes in concentration-effect-relationships for these central nervous system effects during a 4-week treatment period with an experimental SR formulation of rilmenidine 3 mg once daily in 15 mild-to-moderate hypertensive patients. The central nervous system effects of the treatment were evaluated using saccadic eye movements for sedative effects and visual analogue scales for subjective effects on alertness, mood and calmness. Measurements for pharmacokinetic and pharmacodynamic evaluations were performed on the first day of the treatment period and repeated after 1 week and 4 weeks of treatment. Drug concentrations increased during the study, whereas treatment related reductions in saccadic peak velocity (SPV) remained similar on all three study days. The slopes of the concentration-effect-curves for SPV remained unchanged throughout the study, while the intercepts tended to increase as a result of increased pre-dose values. Similar effects were observed for visual analogue scales for alertness: pre-dose values increased significantly during the study, while the size of the treatment responses (slopes) remained unaltered. The reasons for these adaptations cannot be determined but may include drug tolerance and habituations to study procedures. Blood pressure control remained stable and adequate throughout the study.


The PIWI protein acts as a predictive marker for human gastric cancer.
To investigate the expression of the human PIWI subfamily proteins in gastric cancer and their potential roles in the occurrence, development and prognosis of gastric cancer. Expression of the PIWI proteins were assessed by immunohistochemistry (IHC) in tissue microarrays (TMA), containing paired tumor tissue and adjacent non-cancer tissue from 182 patients who had undergone surgery in hospital for histologically proven gastric cancer (GC). Prognostic value and correlation with other clinicopathologic factors were evaluated in two classifications. The expression of PIWIL1-4 was significantly higher in tumor tissue than that in adjacent tissue; A significant correlation was observed between the higher expression of PIWI protein with the T stage, lymph node metastasis and clinical TNM (cTNM); Survival analysis by Kaplan-Meier survival curve and log-rank test demonstrated that elevated PIWIL1 and PIWIL2 expression in cancer tissue predicted poorer overall survival (OS) compared with group in lower expression (36.5% VS 67.6%; 37.4% VS 54.2%; respectively). Notably, multivariate analyses by Cox's proportional hazard model revealed that expression of PIWIL1 was an independent prognostic factor in gastric cancer. The PIWI subfamily protein is an absolutely key molecular factor along with the tumor occurrence and development. And the PIWI protein could act as a potential biomarker for prognosis evaluation of gastric cancer.


Detecting Hearing Loss in Infants With a Syndrome or Craniofacial Abnormalities Following the Newborn Hearing Screen.
Purpose The current Joint Committee on Infant Hearing guidelines recommend that infants with syndromes or craniofacial abnormalities (CFAs) who pass the universal newborn hearing screening (UNHS) undergo audiological assessment by 9 months of age. However, emerging research suggests that children with these risk factors are at increased risk of early hearing loss despite passing UNHS. To establish whether earlier diagnostic audiological assessment is warranted for all infants with a syndrome or CFA, regardless of screening outcome, this study compared audiological outcomes of those who passed UNHS and those who referred. Method A retrospective analysis was performed on infants with a syndrome or CFA born between July 1, 2012, and June 30, 2017 who participated in Queensland, Australia's state-wide UNHS program. Results Permanent childhood hearing loss (PCHL) yield was higher among infants who referred on newborn hearing screening (51.20%) than in those who passed. Nonetheless, 27.47% of infants who passed were subsequently diagnosed with hearing loss (4.45% PCHL, 23.02% transient conductive), but PCHL was generally milder in this cohort. After microtia/atresia, the most common PCHL etiologies were Trisomy 21, other syndromes, and cleft palate. Of the other syndromes, Pierre Robin sequence featured prominently among infants who passed the hearing screen and were subsequently diagnosed with PCHL, whereas there was a broader mix of other syndromes that caused PCHL in infants who referred on screening. Conclusion Children identified with a syndrome or CFA benefit from early diagnostic audiological assessment, regardless of their newborn hearing screening outcome.


[Development and relapse of gastroduodenal ulcer in patients taking nonsteroid anti-inflammatory drugs: effects of standard risk factors].
To investigate incidence and recurrence rate of endoscopic ulcers in patients with rheumatic diseases (RD) taking NSAID in respect to factors of NSAID gastropathy risk. Endoscopic findings in the gastrointestinal tract were analysed for 6103 patients (age 50.1 +/- 14.6 years, 83.1% females) with RD taking NSAID regularly, 1642 of them took also glucocorticoids (GC). Control RD patients (n = 504) matched by age and sex took no NSAID, GC and low dose aspirin a month and more before the trial. Gastric or duodenal ulcers were detected in 763 (12.5%) RD patients treated with NSAID, in 20 (4.0%) in the control group, p < 0.0001. Ulcers were more frequent in older patients (65 years of age and older) with ulcer history treated with nonselective NSAID in combination with low aspirin doses (15.1 and 12.0, p < 0.05; 27.3 and 9.7%, p < 0.001; 13.1 and 9.8%, p < 0.001; 19.1 and 12.2%, p < 0.001; respectively). No significant difference in ulcer occurrence was observed in patients given NSAID+GC and NSAID only (11.3 and 12.9%, respectively; p = 0.041). The recurrence rate was assessed in 407 patients with NSAID-induced ulcer 12 months later. Control consisted of 1640 patients having no ulcer, multiple erosions after 12 months of regular intake of NSAID. Ulcer recurrence rose in 163 of 407 patients (40%) while only in 107 f 1640 controls (6.5%, p < 0.0001). Old age and GC administration had no impact on the recurrence rate. Recurrences were less frequent in patients taking nonselective NSAID than those taking nonselective ones (23.4 and 46.5%, respectively; p < 0.001) and in patients treated with NSAID in combination with proton pump inhibitors (24.6 and 42.6%, respectively; p < 0.001). Prophylactic intake of H-2 blockers did not reduce recurrence rate. Old age, ulcer history and intake of nonselective NSAID increased the risk of endoscopic GI ulcer. Combined use of NSAID and GC did not increase the risk of ulcer development or recurrence. In a year or later of NSAID continuation recurerences arose in 40% patients with NSAID-induced ulcers. Recurrence risk was reduced by selective NSAID and proton pump inhibitors.


Muscle regeneration through myostatin inhibition.
Myostatin is an endogenous, negative regulator of muscle growth. Selective inhibition of myostatin may have broad clinical utility by improving regeneration in diverse and burdensome muscle disorders. An understanding of this potential is relevant because inhibitors of myostatin have recently entered clinical trials. This article reviews the structure and function of myostatin, the effect of inhibiting myostatin in models of disease, and potential therapeutic approaches to blocking myostatin pharmacologically. The possibility that a myostatin inhibitor will promote muscle regeneration in human disease, as seen in animal models, is suggested by the observation that loss of myostatin results in muscle hypertrophy in a human subject. Multiple approaches to inhibiting myostatin are suggested by the recent elucidation of its signaling pathway. An inhibitor of myostatin may be the first drug specifically designed to enhance muscle growth and regeneration.


Deep learning-based model for diagnosing Alzheimer's disease and tauopathies.
This study aimed to develop a deep learning-based model for differentiating tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease (PiD), based on tau-immunostained digital slide images. We trained the YOLOv3 object detection algorithm to detect five tau lesion types: neuronal inclusions, neuritic plaques, tufted astrocytes, astrocytic plaques and coiled bodies. We used 2522 digital slide images of CP13-immunostained slides of the motor cortex from 10 cases each of AD, PSP and CBD for training. Data augmentation was performed to increase the size of the training dataset. We next constructed random forest classifiers using the quantitative burdens of each tau lesion from motor cortex, caudate nucleus and superior frontal gyrus, ascertained from the object detection model. We split 120 cases (32 AD, 36 PSP, 31 CBD and 21 PiD) into training (90 cases) and test (30 cases) sets to train random forest classifiers. The resultant random forest classifier achieved an average test score of 0.97, indicating that 29 out of 30 cases were correctly diagnosed. A validation study using hold-out datasets of CP13- and AT8-stained slides from 50 cases (10 AD, 17 PSP, 13 CBD and 10 PiD) showed >92% (without data augmentation) and >95% (with data augmentation) diagnostic accuracy in both CP13- and AT8-stained slides. Our diagnostic model trained with CP13 also works for AT8; therefore, our diagnostic tool can be potentially used by other investigators and may assist medical decision-making in neuropathological diagnoses of tauopathies.


Distributed Aberration Correction Techniques Based on Tomographic Sound Speed Estimates.
Phase aberration is widely considered a major source of image degradation in medical pulse-echo ultrasound. Traditionally, near-field phase aberration correction techniques are unable to account for distributed aberrations due to a spatially varying speed of sound in the medium, while most distributed aberration correction techniques require the use of point-like sources and are impractical for clinical applications where diffuse scattering is dominant. Here, we present two distributed aberration correction techniques that utilize sound speed estimates from a tomographic sound speed estimator that builds on our previous work with diffuse scattering in layered media. We first characterize the performance of our sound speed estimator and distributed aberration correction techniques in simulations where the scattering in the media is known a priori. Phantom and in vivo experiments further demonstrate the capabilities of the sound speed estimator and the aberration correction techniques. In phantom experiments, point target resolution improves from 0.58 to 0.26 and 0.27 mm, and lesion contrast improves from 17.7 to 23.5 and 25.9 dB, as a result of distributed aberration correction using the eikonal and wavefield correlation techniques, respectively.