An Unusual Case of Bilateral Subperiosteal Orbital Hemorrhage.
Subperiosteal orbital hemorrhage usually occurs in the setting of facial or orbital trauma. Non-traumatic subperiosteal orbital hemorrhage (NTSOH) has rarely been reported in literature. The proposed mechanism of NTSOH is the transmission of sudden increase in cranial venous pressure to the orbital veins, which are valveless. We present a case of a 37 year old right-handed woman with a past medical history significant for type 1 diabetes, end-stage renal disease, peripheral artery disease and hypertension who developed NTSOH following an elective revision of a clotted right upper extremity arteriovenous fistula. During this procedure, she had acute eye pain, bilateral complete vision loss and emesis. CT of the orbits revealed large heterogeneously hyperdense lesions in the bilateral orbital apex extending anteriorly along the roof of the orbit, concerning for hemorrhage. Cultures obtained through nasal endoscopy were negative for a bacterial or fungal infection involving the sinuses. Ophthalmology was consulted and she underwent bilateral canthotomy and lateral cantholysis. Postoperatively, she was started on systemic and topical ocular antihypertensives, as well as prophylactic antibiotics. Visual acuity remained poor with finger counting on the right eye and lack of consistent response to light on the left eye. This case highlights periprocedural increase in systemic venous pressure secondary to a fistula repair procedure as a potential cause of NTSOH.


In vitro toxicity of fungicides with different modes of action to alfalfa anthracnose fungus, Colletotrichum destructivum.
Sensitivity of 24 isolates of Colletotrichum destructivum O'Gara, collected from alfalfa plants in Serbia, to eight selected fungicides, was investigated in this study. Molecular identification and pathogenicity test of isolates tested were also performed. Fungicide sensitivity was evaluated in vitro, using mycelial growth assay method. All isolates exhibited significant pathogenicity, causing necrosis at the alfalfa seedling root tips two days after inoculation. Using the primer pair GSF1-SR1 and by comparing the amplified fragments of the tested isolates with the marker (M), the presence of the amplicon of the expected size of about 900 bp was determined for all isolates. The isolates tested in this study showed different sensitivity towards fungicides in vitro. Mycelial growth was highly inhibited by QoI (quinone outside inhibitors) fungicide pyraclostrobin (mean EC50=0.39 µg mL-1) and by DMI (demethylation-inhibiting) fungicide tebuconazole (mean EC50=0.61 µg mL-1), followed by azoxystrobin (mean EC50=2.83 µg mL-1) and flutriafol (mean EC50=2.11 µg mL-1). Multi-site fungicide chlorothalonil and MBC (methyl benzimidazole carbamate) fungicide thiophanate-methyl evinced moderate inhibition with mean EC50=35.31 and 62.83 µg mL-1, respectively. Thirteen isolates were sensitive to SDHI (succinate dehydrogenase inhibitors) fungicide boscalid and fluxapyroxad, (mean EC50=0.49 and 0.19 µg mL-1, respectively), while the rest of isolates were highly resistant.


Effect of culture conditions on tremorgen production by some Penicillium species.
Four strains each of seven tremorgenic Penicillium species were grown under various conditions and tested for tremorgen production by intraperitoneal injection of mice and by chemical analysis. Half of the strains had previously been found to be tremorgenic on bioassay after growth on Czapek Dox yeast extract broth or potato-milk-sucrose broth for 3 weeks at 26 degrees C. In the tests reported here nearly all previously nontremorgenic strains were either tremorgenic to mice or produced tremorgens detectable by chemical analysis but did so after longer incubation periods than used in the original screening. Bioassay was not suitable for the estimation of absolute levels but was preferable to chemical analysis when the identity of the tremorgens was not known. Species and strains within species gave different responses to changes in culture medium, incubation temperature, light irradiation, and shaking. Overall, tremorgen production was maximal at 20 or 26 degrees C, increased with time, and was reduced in shaken culture.


Comparison of Gonadotropin-Releasing Hormone Agonists and Orchiectomy: Effects of Androgen-Deprivation Therapy.
Androgen-deprivation therapy (ADT) through surgical castration is equally effective as medical castration in controlling prostate cancer (PCa). However, the adverse effect profiles of both ADT groups have never been compared. To provide a comparative effectiveness analysis of the adverse effects of gonadotropin-releasing hormone agonists (GnRHa) vs bilateral orchiectomy in a homogeneous population. A population-based cohort of 3295 men with metastatic PCa between January 1995 and December 2009 66 years or older was selected from the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database. Orchiectomy or GnRHa. Any fractures, peripheral arterial disease, venous thromboembolism, cardiac-related complications, diabetes mellitus, and cognitive disorders. To minimize treatment group biases, the inverse probability of treatment was weighted using the propensity score. Multivariable competing risk regression models were performed with the adjustment of all-cause mortality. Secondary analyses examined the effect of increasing duration of GnRHa treatment. Multivariable logistic regression models examined expenditures. Overall, 3295 men with a primary diagnosis of metastatic PCa treated with GnRHa or orchiectomy were identified between years 1995 and 2009, and in adjusted analyses, patients who received a bilateral orchiectomy had significantly lower risks of experiencing any fractures (hazard ratio [HR], 0.77; 95% CI, 0.62-0.94; P = .01), peripheral arterial disease (HR, 0.65; 95% CI, 0.49-0.87; P = .004), and cardiac-related complications (HR, 0.74; 0.58-0.94; P = .01) compared with those treated with GnRHa. No statistically significant difference was noted between orchiectomy and GnRHa for diabetes and cognitive disorders. In individuals treated with GnRHa for 35 months or more, the increased risk for GnRHa compared with orchiectomy was noted for fractures (HR, 1.80), peripheral arterial disease (HR, 2.25), venous thromboembolism (HR, 1.52), cardiac-related complications (HR, 1.69), and diabetes mellitus (HR, 1.88) (P ≤ .01 for all). At 12 months after PCa diagnosis, the median total expenditures was not significantly different between GnRHa and orchiectomy. Gonadotropin-releasing hormone agonist therapy is associated with higher risks of several clinically relevant adverse effects compared with orchiectomy.


Psychiatric and behavioral manifestations of Williams syndrome.
The purpose of this review is to synthesize recent advances in the psychiatric and behavioral manifestations of Williams syndrome, a rare genetic syndrome. Recent advances have focused on more deeply characterizing the social phenotype and developing social skill interventions, improving the assessment and treatment of anxiety, and exploring eating behaviors. The social cognitive phenotype in Williams syndrome, which consists of both high social drive and social cognition deficits, is present cross-culturally and may be related to reduced eye gaze. Social skills training for adults with Williams syndrome has demonstrated promise. Adapted exposure therapy and cognitive behavioral therapy programs for children and adults respectively, have been piloted in Williams syndrome. The majority of adults with Williams syndrome are either underweight or overweight, and problematic food-related behaviors likely contribute to bodyweight status. Williams syndrome is associated with a number of core social and psychiatric difficulties which have a significant impact on functioning and quality of life. Recent work has begun to utilize a more nuanced understanding of the clinical presentations of these problems to develop interventions tailored to this unique population. However, larger trials, particularly those inclusive of a more diverse Williams syndrome population, are needed.


Caught in the act: the structure of phosphorylated beta-phosphoglucomutase from Lactococcus lactis.
Phosphoglucomutases catalyze the interconversion of D-glucose 1-phosphate and D-glucose 6-phosphate, a reaction central to energy metabolism in all cells and to the synthesis of cell wall polysaccharides in bacterial cells. Two classes of phosphoglucomutases (alpha-PGM and beta-PGM) are distinguished on the basis of their specificity for alpha- and beta-glucose-1-phosphate. beta-PGM is a member of the haloacid dehalogenase (HAD) superfamily, which includes the sarcoplasmic Ca(2+)-ATPase, phosphomannomutase, and phosphoserine phosphatase. beta-PGM is unusual among family members in that the common phosphoenzyme intermediate exists as a stable ground-state complex in this enzyme. Herein we report, for the first time, the three-dimensional structure of a beta-PGM and the first view of the true phosphoenzyme intermediate in the HAD superfamily. The crystal structure of the Mg(II) complex of phosphorylated beta-phosphoglucomutase (beta-PGM) from Lactococcus lactis has been determined to 2.3 A resolution by multiwavelength anomalous diffraction (MAD) phasing on selenomethionine, and refined to an R(cryst) = 0.24 and R(free) = 0.28. The active site of beta-PGM is located between the core and the cap domain and is freely solvent accessible. The residues within a 6 A radius of the phosphorylated Asp8 include Asp10, Thr16, Ser114, Lys145, Glu169, and Asp170. The cofactor Mg(2+) is liganded with octahedral coordination geometry by the carboxylate side chains of Asp8, Glu169, Asp170, and the backbone carbonyl oxygen of Asp10 along with one oxygen from the Asp8-phosphoryl group and one water ligand. The phosphate group of the phosphoaspartyl residue, Asp8, interacts with the side chains of Ser114 and Lys145. The absence of a base residue near the aspartyl phosphate group accounts for the persistence of the phosphorylated enzyme under physiological conditions. Substrate docking shows that glucose-6-P can bind to the active site of phosphorylated beta-PGM in such a way as to position the C(1)OH near the phosphoryl group of the phosphorylated Asp8 and the C(6) phosphoryl group near the carboxylate group of Asp10. This result suggests a novel two-base mechanism for phosphoryl group transfer in a phosphorylated sugar.


Dorsal root ganglionectomy for failed back surgery syndrome: a 5-year follow-up study.
Dorsal root ganglionectomy has been suggested as a method for the treatment of chronic intractable radicular pain, with theoretical advantages over dorsal rhizotomy, which does not interrupt ventral root afferents. The indications for these procedures in patients with persistent pain following lumbosacral spine surgery are not well established. Long-term results have been reported infrequently, and no published series has a mean follow-up period of more than 30 months. The authors have reviewed their experience with a series of 13 patients with failed back surgery syndrome, in whom dorsal root ganglionectomy was performed. Patients were selected on the basis of clinical presentation and diagnostic root blocks suggesting a monoradicular pain syndrome. Follow-up data were obtained at a mean of 5.5 years following dorsal root ganglionectomy. Follow-up interviews to assess outcome were conducted by a disinterested third party. Treatment "success" (at least 50% sustained relief of pain and patient satisfaction with the result) was recorded in two patients at 2 years after surgery and in none at 5.5 years. Equivocal success (at least 50% relief, without clearcut patient satisfaction) was recorded in one patient at 2 and at 5.5 years postoperatively. Improvements in activities of daily living were recorded in a minority of patients. Loss of sensory and motor function was reported frequently by patients. A minority of patients had reduced or eliminated analgesic intake. These results suggest that dorsal root ganglionectomy has a limited role in the management of failed back surgery syndrome, and that methods to select patients to receive this procedure should be refined or alternative approaches should be considered.


Spatial heterogeneity and kinetic regulation of arsenic dynamics in mangrove sediments: the Sundarbans, Bangladesh.
The biogeochemistry of arsenic (As) in sediments is regulated by multiple factors such as particle size, dissolved organic matter (DOM), iron mobilization, and sediment binding characteristics, among others. Understanding the heterogeneity of factors affecting As deposition and the kinetics of mobilization, both horizontally and vertically, across sediment depositional environments was investigated in Sundarban mangrove ecosystems, Bengal Delta, Bangladesh. Sediment cores were collected from 3 different Sundarbans locations and As concentration down the profiles were found to be more associated with elevated Fe and Mn than with organic matter (OM). At one site chosen for field monitoring, sediment cores, pore and surface water, and in situ diffusive gradients in thin films (DGT) measurements (which were used to model As sediment pore-water concentrations and resupply from the solid phase) were sampled from four different subhabitats. Coarse-textured riverbank sediment porewaters were high in As, but with a limited resupply of As from the solid phase compared to fine-textured and high organic matter content forest floor sediments, where porewater As was low, but with much higher As resupply. Depositional environment (overbank verses forest floor) and biological activity (input of OM from forest biomass) considerably affected As dynamics over very short spatial distances in the mosaic of microhabitats that constitute a mangrove ecosystem.


High heritability is compatible with the broad distribution of set point viral load in HIV carriers.
Set point viral load in HIV patients ranges over several orders of magnitude and is a key determinant of disease progression in HIV. A number of recent studies have reported high heritability of set point viral load implying that viral genetic factors contribute substantially to the overall variation in viral load. The high heritability is surprising given the diversity of host factors associated with controlling viral infection. Here we develop an analytical model that describes the temporal changes of the distribution of set point viral load as a function of heritability. This model shows that high heritability is the most parsimonious explanation for the observed variance of set point viral load. Our results thus not only reinforce the credibility of previous estimates of heritability but also shed new light onto mechanisms of viral pathogenesis.


Introduction: Infertility etiology and offspring health.
This issue's of Views and Reviews considers the origins of lifetime health established around the time of conception in some prevalent conditions related to infertility. Reviews will look at the effects of advanced paternal and maternal age, the influence of the severe sperm factor, and the impact of some endocrinopathies commonly seen in infertile couples, especially women, like polycystic ovary syndrome, under- and overweight, diabetes, and thyroid disorders. The aim of this Views and Reviews section is to summarize current evidence on the consequences of these conditions on postnatal health to encourage research in this field and the need to develop strategies and preventative measures to reduce or prevent unfavorable outcomes in future generations.


Ribosome rescue by tmRNA requires truncated mRNAs.
tmRNA targets ribosomes, stalled either on truncated mRNAs or on mRNAs with slowly read sense or stop codons, tags the newly synthesized peptide chains for degradation and allows for their release by a class-1 release factor. We have studied in vitro how the rate of trans-transfer of a peptide from the P-site tRNA to tmRNA and the efficiency by which tmRNA competes with peptide release factors depend on the length of the mRNA downstream from the P-site. We show that the rate and efficiency of tmRNA action decrease rapidly with increasing down stream length and approach zero when it exceeds 15 bases. We demonstrate that tmRNA action is strongly stimulated by RelE cleavage of mRNA in the A site. We conclude that tmRNA action in vivo must always be preceded by mRNA truncation, and suggest that cleavage of ribosome bound mRNAs is a common element in different bacterial stress responses.


Relation of Soil Water Movement and Sulfide Concentration to Spartina alterniflora Production in a Georgia Salt Marsh.
It is proposed that differences in plant height and productivity of the salt-marsh cordgrass Spartina alterniflora are the result of a dynamic interaction among tidal water movement, dissolved iron and sulfide concentrations in marsh soils, and bacterial sulfate reduction. Tidal water movement regulates the input of iron into marsh soils and the drainage of sulfide-containing interstitial water, and thereby controls the concentration of dissolved sulfide formed as a result of bacterial sulfate reduction. Near tidal creeks, where water movement and plant height and production are greatest, sulfide concentrations are lowest; in more elevated regions of marsh, where water movement andplant production are least, sulfide concentrations are highest. Plant height and productivity may be limited by the effects of sulfide on nutrient uptake.


Search for an H-dibaryon with a mass near 2mΛ in Υ(1S) and Υ(2S) decays.
We report the results of a high-statistics search for H dibaryon production in inclusive Υ(1S) and Υ(2S) decays. No indication of an H dibaryon with a mass near the M(H)=2m(Λ) threshold is seen in either the H→Λpπ(-) or ΛΛ decay channels and 90% confidence level branching-fraction upper limits are set that are between one and two orders of magnitude below the measured branching fractions for inclusive Υ(1S) and Υ(2S) decays to antideuterons. Since Υ(1S,2S) decays produce flavor-SU(3)-symmetric final states, these results put stringent constraints on H dibaryon properties. The results are based on analyses of 102 million Υ(1S) and 158 million Υ(2S) events collected with the Belle detector at the KEKB e(+)e(-) collider.


The effects of two novel objects on the behavior of singly caged adult rhesus macaques.
Six female and six male adult rhesus macaques were given sticks and nylon balls as an attempt at simple cage enrichment. A latin square design was used to compare behavior during separate 4-week periods with each object and during a control period with no object. Frequency and duration of 15 different behaviors were recorded. Resting was the most common activity which decreased slightly in duration when the stick or nylon ball was present (P less than 0.02). The mean duration of stick use was longer than that of the nylon ball (P less than 0.01). No other behaviors changed significantly, including the frequency of abnormal behaviors such as self-abuse, stereotypic acts, and bizarre postures. Generally, these objects were used infrequently and led to few changes in the behavior of singly-caged adult rhesus macaques. However, they did appear to stimulate activity for some individuals.


Peritoneal catheter for continuous drainage of ascites in advanced cancer patients.
Advanced cancer patients with refractory ascites do not often respond to dietary sodium restriction and diuretics. While paracentesis is effective, the condition invariably recurs, necessitating repeated procedures. A continuous peritoneal drainage by an indwelling catheter has been reported to be hugely beneficial symptomatically, avoiding the hazards and disadvantages of multiple repeated procedures and direct and indirect costs. Forty patients with advanced cancer patients admitted to an acute pain relief and palliative care unit, who presented symptomatic ascites, were recruited for continuous drainage of peritoneal fluid. A central venous catheter set for Seldinger technique was used. Technical failure was defined as an unsuccessful drainage of fluid through the catheter. Immediate and late complications, including hypotension, haemorrhage, tube blockage, dislodgment and sepsis were recorded. Record of daily drainage during admission were noted. At time of discharge, patients were asked to rate their global symptom burden as improved, unchanged or worsened. The follow-up was performed with frequent phone contacts or day-hospital admission in case of problems. The mean patients' age was 68 years, and 21 were men. Patients were receiving unsuccessfully a mean dose of furosemide of 32 mg/day. The technique was not painful and was easily accepted by patients. Insertion was technically successful in almost all patients. Mean admission time was 5.5 days (range 2-14), and the mean drained volume during admission was 8,499 ml (range 800-20,700), 2,850 ml (300-4,200) being drained on the first 24 h. No immediate complications were recorded. Six patients died during admission. The mean survival was 38.9 days (range 1-120). Of the 34 patients who were discharged home, 22 patients stated that symptom burden had improved, while in 10 patients symptom burden did not change or worsened, probably due to the advanced status of diseases and multiple contributing factors. Five, two, and one patients required skin sutures at 1, 2 and 3 months, respectively. About one third of patients had mechanical problems, some of them requiring a catheter replacement. No infection was recorded. In conclusion, a permanent peritoneal catheter was a valuable method to remove abdominal fluids and reduce symptom burden attributable to ascites and was also easy to use at home. Complication rate was acceptable and balanced by the benefits of the technique which avoided frequent paracentesis and associated complications.


Eukaryotic release factor 1-2 affects Arabidopsis responses to glucose and phytohormones during germination and early seedling development.
Germination and early seedling development are coordinately regulated by glucose and phytohormones such as ABA, GA, and ethylene. However, the molecules that affect plant responses to glucose and phytohormones remain to be fully elucidated. Eukaryotic release factor 1 (eRF1) is responsible for the recognition of the stop codons in mRNAs during protein synthesis. Accumulating evidence indicates that eRF1 functions in other processes in addition to translation termination. The physiological role of eRF1-2, a member of the eRF1 family, in Arabidopsis was examined here. The eRF1-2 gene was found to be specifically induced by glucose. Arabidopsis plants overexpressing eRF1-2 were hypersensitive to glucose during germination and early seedling development. Such hypersensitivity to glucose was accompanied by a dramatic reduction of the expression of glucose-regulated genes, chlorophyll a/b binding protein and plastocyanin. The hypersensitive response was not due to the enhanced accumulation of ABA. In addition, the eRF1-2 overexpressing plants showed increased sensitivity to paclobutrazol, an inhibitor of GA biosynthesis, and exogenous GA restored their normal growth. By contrast, the loss-of-function erf1-2 mutant exhibited resistance to paclobutrazol, suggesting that eRF1-2 may exert a negative effect on the GA signalling pathway. Collectively, these data provide evidence in support of a novel role of eRF1-2 in affecting glucose and phytohormone responses in modulating plant growth and development.


Effect of microstructure of low carbon steels on ultrasonic attenuation.
The ultrasonic attenuation in low carbon steel with 0.04 wt% C to 0.80 wt% C was measured over a frequency range of 5 to 15 MHz, and the effects of the carbon content and normalizing temperature were analyzed. In pure iron, the attenuation is determined from the average grain size, which increases as the normalizing temperature increases; there is a noticeable effect caused by a few large grains. In the case of the hypoeutectoid steels, the proeutectoid ferrite grain, the size of which depends on prior austenite grain size, acts as the main scatterer. The prior austenite grain size increases as the carbon content decreases and the normalizing temperature increases. The colony is responsible for scattering in the eutectoid steel; scattering by pearlite is greater than that by ferrite.


[Life cycle of Proprioseiopsis cannaensis (Muma) (Acari: Phytoseiidae) on different types of food].
Several annual and perennial crops are severely attacked by mites from the family Eriophyidae, Tenuipalpidae and Tetranychidae. A suitable alternative commonly used in several countries for the control of these pest mites involve the use of predatory mites in the family Phytoseiidae. The phytoseiid fauna in the Brazilian natural vegetation is very rich, but nothing is known about the biology of most of these species, as it is the case with Proprioseiopsis cannaensis (Muma). The objective of this study was to determine biological parameters of P. cannaensis fed on pest mite species such as Phyllocoptruta oleivora (Ashmead) (Eriophyidae), Brevipalpus phoenicis (Geijskes) (Tenuipalpidae) and Tetranychus urticae Koch (Tetranychidae). To enable a comparison for different food sources, one of the treatments consisted of pollen from Typha angustifolia L. The study was conducted in the laboratory at 25+/-1 masculineC, 80+/-10% RH and Photophase of 12 h. Proprioseiopsis cannaensis did not complete the development when it was fed on P. oleivora. Its fecundity was very low with all other food sources (maximum of 3.3 eggs/female with pollen of T. angustifolia). The values of r m for P. cannaensis were -0.05, -0.09 and 0.002 when fed on B. phoenicis, T. urticae and pollen respectively. The unsatisfactory results from the four types of food sources do not permit us to conclude that P. cannaensis utilizes mites from the family Eriophyidae, Tenuipalpidae, Tetranychidae or pollen from different plant species as principal sources of food in nature.


Vascular-related NAC-DOMAIN7 is involved in the differentiation of all types of xylem vessels in Arabidopsis roots and shoots.
The Arabidopsis thaliana NAC domain transcription factor, vascular-related NAC-DOMAIN7 (VND7), plays a pivotal role in regulating the differentiation of root protoxylem vessels. In order to understand the mechanisms underscoring the function of VND7 in vessel differentiation in more detail, we conducted extensive molecular analyses in yeast (Saccharomyces cerevisiae), Arabidopsis, and Nicotiana tabacum L. cv. Bright Yellow 2 (tobacco BY-2) cells. The transcriptional activation activity of VND7 was confirmed in yeast and Arabidopsis, and the C-terminal region was shown to be required for VND7 transcriptional activation. Expression of the C-terminus-truncated VND7 protein under the control of the native VND7 promoter resulted in inhibition of the normal development of metaxylem vessels in roots and vessels in aerial organs, as well as protoxylem vessels in roots. The expression pattern of VND7 overlapped that of VND2 to VND5 in most of the differentiating vessels. Furthermore, a yeast two-hybrid assay revealed the ability of VND7 to form homodimers and heterodimers with other VND proteins via their N-termini, which include the NAC domain. The heterologous expression of VND7 in tobacco BY-2 cells demonstrated that the stability of VND7 could be regulated by proteasome-mediated degradation. Together these data suggest that VND7 regulates the differentiation of all types of vessels in roots and shoots, possibly in cooperation with VND2 to VND5 and other regulatory proteins.


Mitochondrial ROS Induced Lysosomal Dysfunction and Autophagy Impairment in an Animal Model of Congenital Hereditary Endothelial Dystrophy.
The Slc4a11 knock out (KO) mouse model recapitulates the human disease phenotype associated with congenital hereditary endothelial dystrophy (CHED). Increased mitochondrial reactive oxygen species (ROS) in the Slc4a11 KO mouse model is a major cause of edema and endothelial cell loss. Here, we asked if autophagy was activated by ROS in the KO mice. Immortalized cell lines and mouse corneal endothelia were used to measure autophagy and lysosome associated protein expressions using Protein Simple Wes immunoassay. Autophagy and lysosome functions were examined in wild type (WT) and KO cells as well as animals treated with the mitochondrial ROS quencher MitoQ. Even though autophagy activation was evident, autophagy flux was aberrant in Slc4a11 KO cells and corneal endothelium. Expression of lysosomal proteins and lysosomal mass were decreased along with reduced nuclear translocation of lysosomal master regulator, transcription factor EB (TFEB). MitoQ reversed aberrant lysosomal functions and TFEB nuclear localization in KO cells. MitoQ injections in KO animals reduced corneal edema and decreased the rate of endothelial cell loss. Mitochondrial ROS disrupts TFEB signaling causing lysosomal dysfunction with impairment of autophagy in Slc4a11 KO corneal endothelium. Our study is the first to identify the presence as well as cause of lysosomal dysfunction in an animal model of CHED, and to identify a potential therapeutic approach.


Screening for developmental problems at primary care level: a field programme in San Isidro, Argentina.
Information on prevalence and type of problems of psychomotor development (PPD) is necessary for implementation of specific care programmes at field level. With the purpose of obtaining this information, a screening test, the Prueba Nacional de Pesquisa (PRUNAPE) for PPD was implemented in three health centres in San Isidro, a city near Buenos Aires, attended by different socio-economic groups: centres A and B were located in the inner city, and C in a middle-class area. The test was administered by three previously trained paediatricians to 839 apparently healthy children aged 0-5 years. The failure rates were 24%, 19% and 16% in centres A, B and C respectively (20% in total). Out of the 170 children failing the test and referred to hospital for diagnosis and treatment, only 96 complied and went through a series of studies carried out by a previously prepared multidisciplinary team. With the exception of children who failed the Battelle test [classified as Global Developmental Delay (GDD)], final diagnoses were classified according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition: GDD (60 children), pervasive developmental disorders (11), communication disorders (10), motor disorders (6, of whom 2 were with cerebral palsy), attention deficit disorders (5), attachment disorders (2), normal children (3). Co-morbidity was present in 22 affected children. Forty-three per cent of children failing the test did not attend hospital or did not complete studies because of major social and family problems, the family not living in the area, or the parents preferring to consult their own paediatrician. Health centres and children not selected in a randomised way, and a significant proportion of them not complying with the indication of hospital referral were major sources of bias, so that PPD prevalences, positive and negative predictive values should be interpreted with great caution. Further studies accounting for these sources of bias are needed to confirm the observed prevalence of PPD. Training of health personnel, at hospital and health centre level, priority settings, and operational research to evaluate effectiveness of treatments and care delivery systems at field level are necessary in Argentina for optimal use of limited healthcare resources.


Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice.
Genomic imprinting is regulated by differential methylation of the paternal and maternal genome. However, it remains unknown how parental imprinting is established during gametogenesis. In this study, we demonstrate that Dnmt3L, a protein sharing homology with DNA methyltransferases, Dnmt3a and Dnmt3b, but lacking enzymatic activity, is essential for the establishment of maternal methylation imprints and appropriate expression of maternally imprinted genes. We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells, suggesting that Dnmt3L may regulate genomic imprinting via the Dnmt3 family enzymes. Consistent with this model, we show that [Dnmt3a(-/-), Dnmt3b(+/-)] mice also fail to establish maternal methylation imprints. In addition, both Dnmt3a and Dnmt3L are required for spermatogenesis. Together, our findings suggest that Dnmt3L may cooperate with Dnmt3 family methyltransferases to carry out de novo methylation of maternally imprinted genes in oocytes.


Leader-Following Consensus for High-Order Nonlinear Stochastic Multiagent Systems.
This paper considers the distributed consensus tracking problem for a class of high-order stochastic multiagent systems with uncertain nonlinear functions under a fixed undirected graph. Through the recursive method, the novel nonlinear distributed controllers are designed. By constructing a kind of special form for the virtual controller in the first step of recursive design, we realize that the state variables of every agent are separated except the outputs of the adjacency agents. The designed controller of each agent only depends on its own state variables and the outputs of the adjacent multiagents. With the proposed method, it is not required any more that the orders of the agents are same. This makes the designed controller be easier to be implemented and the proposed method be applicable for a wider class of multiagent systems. The efficiency of the design approach is illustrated by a simulation example.


Dimethyl sulfoxide-induced enhancement of 7,12-dimethylbenz(a)anthracene metabolism and DNA binding in differentiating mouse epidermal cell cultures.
Mouse epidermal cells in primary culture differentiate rapidly over a 2-week period leading to keratinization and sloughing of most of the plated cells. Cell replication was partially synchronized in these cultures with peaks of DNA synthesis at the 2nd and 8th day. The ability of epidermal cells to metabolize 7,12-dimethylbenz[a]anthracene and the subsequent binding of activated products to epidermal DNA was a function of the culture time. Constitutive and induced levels of aryl hydrocarbon hydroxylase in cells cultured for 10 days were half of those in cells grown for 3 days. Likewise, 7,12-dimethylbenz[a]anthracene binding to epidermal DNA was two- to fourfold lower in 10-day than 3-day cultures. This decrease in metabolism and binding between 3-day and 10-day cultures could be eliminated by the inclusion of 1.25% dimethyl sulfoxide in the culture medium during the entire culture period.


Possible mechanism for mianserin induced neutropenia associated with saturable elimination kinetics.
Two cases of mianserin induced neutropenia associated with prolonged elimination of the drug were studied. In each case the pharmacokinetic profile suggested saturable elimination kinetics, and the temporal relation of mianserin concentrations and the neutrophil count suggested a direct toxic effect of mianserin on the bone marrow. Until further studies are carried out the plasma mianserin concentration and neutrophil count should be measured in any patient who develops an infection while taking this drug.


Role of cyclooxygenase 2 and endothelial nitric oxide synthetase in preclinical atherosclerosis.
Cyclooxygenase-2 and endothelial nitric oxide (NO) synthase enzymes may have a role in developing preclinical atherosclerosis. Designed groups were as follows: smoke exposed rats before and during pregnancy, only before pregnancy, and controls. Cross-sectional samples of abdominal aorta were examined immunohistochemically. Cyclooxygenase-2 and eNOS expression was evaluated semi-quantitatively through staining extent (focal, diffuse) and staining intensity. Diffuse COX-2 expression was detected in study groups. Endothelial NO synthase expression was diffuse in study groups. COX-2 and eNOS may contribute to the formation of preatherosclerotic lesions in offspring of rats exposed to cigarette smoke through inflammatory response.


[The transsexual enigma. Apropos of the work of Jan Morris "Enigma"].
The fixity of the therapeutic demand of the transsexual renders it refractory to psychotherapeutic analysis, which always tries to reveal an other demand behind the explicit demand. But the transsexual wants nothing else than to obtain from the medical wf his intime conviction to belong to the opposite sex despite his non equivoqual hormonal anatomic and genetic sex. As a consequence, he demands surgical correction of this mistake of nature. The author wants to draw from J. Morris's remarquable work, both on human and literary grounds, the essential axis of the deep problems of the transsexual: the precocious apparition of the conviction which becomes irreversible, the concern to have it accredited by scientists, a desexualised verbalisation with a rich claim for gender (psychological sex), the impact of the desire of the mother on the future of the subject, the necessary idealisation of the mother (virgin cult), the problem of castration, the link between identity and recognition by the other. The psychotherapeutic failure gives rise to an important theoretical lesson which is clearly illustrated in the transsexual: one can not conound penis and phallus (Lacan), because if the transexxual is ready to live without the former, it is to obtain (or become) the latest.


Association of decreased myonectin levels with metabolic and hormonal disturbance in polycystic ovary syndrome.
Myonectin is a myokine involving in glucose and lipid metabolisms. Polycystic ovary syndrome (PCOS) is a metabolic and reproductive disorder associated with insulin resistance. Our aims were to discover whether myonectin levels were altered in PCOS women comparing to controls and to determine the link of myonectin with hormonal-metabolic parameters in PCOS women. The current research was designed as a case-control study. Seventy-two subjects with PCOS and 72 age- and body mass index (BMI)-matched subjects as controls were enrolled into the study. Circulating myonectin levels were measured by ELISA. Myonectin levels were significantly lower in PCOS subjects compared to controls (6.77 ± 1.96 vs. 9.14 ± 2.87 ng/ml, p< .001). Myonectin exhibited an inverse association with BMI, insulin resistance, free androgen index (FAI) and triglycerides whereas it showed a positive association with high-density lipoprotein cholesterol (HDL-C) in women with PCOS. Logistic regression analysis revealed that decreased myonectin levels were parallel with increased probability of having PCOS risk. Decreased myonectin levels were associated with metabolic and hormonal disturbances in PCOS women, suggesting that myonectin may play a role in pathophysiology of PCOS.


Male chest correction. Pectoral implants and gynecomastia.
Implants have been developed in different sizes and shapes to mimic the pectoralis major muscle and its nipple-areolar complex below it. These soft, solid silicone implants have the approximate dimensions in height, length, and thickness as the muscle the implant is to mimic. Some improvements in the treatment of breast hypertrophy have also allowed a better result in the surgery of gynecomastia. The challenge of obtaining a smooth and flat result has been helped by the technique of liposuction with circum-areolar excision.


A review of collaborative partnerships as a strategy for improving community health.
Collaborative partnerships (people and organizations from multiple sectors working together in common purpose) are a prominent strategy for community health improvement. This review examines evidence about the effects of collaborative partnerships on (a) community and systems change (environmental changes), (b) community-wide behavior change, and (c) more distant population-level health outcomes. We also consider the conditions and factors that may determine whether collaborative partnerships are effective. The review concludes with specific recommendations designed to enhance research and practice and to set conditions for promoting community health.


Neuroblastoma presented with polyhydramniosis.
Neuroblastoma is the most common extracranial solid tumor in pediatric age group. Clinical presentation of neuroblastoma is mostly related to origin of the tumor, extent of disease, and the presence of paraneoplastic syndromes. Here the authors report a neonate with neuroblastoma with an atypical presentation, diagnosed with postnatal abdominal ultrasonography performed due to polyhydramniosis in her mother during pregnancy.


Sound direction modifies the inhibitory as well as the excitatory frequency tuning characteristics of single neurons in the frog torus semicircularis (inferior colliculus).
Single-unit recordings were made from the frog inferior colliculus to determine whether or not the direction-dependent sharpening of a unit's free-field excitatory frequency-threshold curve (FTCe) was accompanied by a broadening of its inhibitory frequency-threshold curve (FTCi). To determine the FTCi, a two-tone-suppression paradigm was employed. The unit's FTCis and FTCes were collected at three azimuths: contralateral to the recording site, ipsilateral to the recording site, and frontal midline. The result showed that: (1) most inferior colliculus neurons (95%) displayed two-tone suppression, (2) the majority (54%) of neurons displayed stronger two-tone-suppression leading to broader FTCis when the sound was presented from the ipsilateral side than from the contralateral side, (3) for some neurons, the borders of the FTCes and FTCis were closely aligned, and this juxtaposition persisted at all sound azimuths (namely, when a change in sound direction produced a narrowing of a unit's FTCe, its FTCi was broadened concomitantly). For the remaining neurons, however, direction-dependent sharpening of the FTCe was not accompanied by an increase in two-tone-suppression. The neural mechanisms that underlie the direction-dependent changes in the FTCes and FTCis are discussed.


Laboratory testing for recent alcohol consumption: comparison of ethanol, methanol, and 5-hydroxytryptophol.
The ratio of 5-hydroxytryptophol to 5-hydroxyindole-3-acetic acid (5HTOL/5HIAA) in urine was compared with concentrations of ethanol and methanol as a way to monitor recent alcohol consumption. During detoxification of alcohol-dependent subjects, ethanol persisted longer in urine than in breath or plasma. Blood and urinary methanol remained increased for 2-6 h after blood ethanol had returned to background concentrations, whereas 5HTOL/5HIAA remained increased for 6-15 h. In healthy volunteers who had ingested alcohol (range 3-98 g) the previous afternoon or evening, 87% (for men) and 59% (for women) of all drinking occasions exceeding 7 g of alcohol were identified by an increased 5HTOL/5HIAA in the first morning urine void. This compared with 32% and 12%, respectively, identified by analysis of ethanol (>200 micromol/L). No gender difference in the excretion pattern of 5HTOL/5HIAA was seen. The results demonstrate that 5HTOL/5HIAA provides a specific and more sensitive method to detect recent alcohol consumption than does ethanol or methanol.


Regulation of cyclic AMP phosphodiesterase from Mucor rouxii by phosphorylation and proteolysis. Interrelationship of the activatable and insensitive forms of the enzyme.
DEAE-cellulose chromatography of mycelial extracts of Mucor rouxii grown to mid-exponential phase resolves two types of low-Km cyclic AMP phosphodiesterase (EC 18.104.22.168; PDE): PDE I, highly activatable (4-6-fold) by phosphorylation or proteolysis, and PDE II, unresponsive to activation. The enzymic profile of PDE activity obtained from germlings shows only PDE I activity, whereas PDE activity from mycelia grown to stationary phase is eluted from the DEAE-cellulose column at the position of PDE II, and like PDE II is unresponsive to activation. Endogenous proteolysis or controlled trypsin treatment transforms PDE I into PDE II. The insensitive forms of PDE exhibit a slightly smaller sedimentation coefficient than the activatable forms, as judged by sucrose-gradient centrifugation. The basal activity of the highly activatable form of PDE is elevated almost to the value in the presence of trypsin on storage at 4 degrees C in the absence of proteinase inhibitors. Benzamidine, leupeptin, antipain or EGTA prevents the activation produced by storage. PDE I remains strongly activatable by phosphorylation and proteolysis after resolution by polyacrylamide-gel electrophoresis.


Combined modality treatment of small cell carcinoma of the lung.
Ninety patients with extensive and 61 with limited small cell carcinoma of the lung were treated with three courses of intravenous chemotherapy (cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate) followed by radiotherapy to intrathoracic disease, and a second three-drug oral combination consisting of lomustine, procarbazine, and methotrexate for one year. Among the 147 patients who were evaluated, 55 of 66 (83%) with limited disease and 53 of 81 (65%) with extensive disease showed response after three courses of chemotherapy. The complete response rate in patients with limited disease prior to radiotherapy was 24%, but increased to 58% when evaluated following radiotherapy. The median survival was 47 weeks for patients with limited disease and 36 weeks for those with extensive disease. A 24% two-year survival is projected for complete responders. Important prognostic factors for survival are performance status, extent of disease, and sex, with female subjects doing somewhat better than male subjects. Among patients with limited disease, 45% failed within the CNS despite the use of chemotherapeutic agents that cross the blood-brain barrier. The initial induction regimen and radiotherapy were well tolerated; the oral three-drug combination was more toxic and did not prevent CNS metastases.


Cyclin/CDK regulates the nucleocytoplasmic localization of the human papillomavirus E1 DNA helicase.
Cyclin-dependent kinases (CDKs) play key roles in eukaryotic DNA replication and cell cycle progression. Phosphorylation of components of the preinitiation complex activates replication and prevents reinitiation. One mechanism is mediated by nuclear export of critical proteins. Human papillomavirus (HPV) DNA replication requires cellular machinery in addition to the viral replicative DNA helicase E1 and origin recognition protein E2. E1 phosphorylation by cyclin/CDK is critical for efficient viral DNA replication. We now show that E1 is phosphorylated by CDKs in vivo and that phosphorylation regulates its nucleocytoplasmic localization. We identified a conserved regulatory region for localization which contains a dominant leucine-rich nuclear export sequence (NES), the previously defined cyclin binding motif, three serine residues that are CDK substrates, and a putative bipartite nuclear localization sequence. We show that E1 is exported from the nucleus by a CRM1-dependent mechanism unless the NES is inactivated by CDK phosphorylation. Replication activities of E1 phosphorylation site mutations are reduced and correlate inversely with their increased cytoplasmic localization. Nuclear localization and replication activities of most of these mutations are enhanced or restored by mutations in the NES. Collectively, our data demonstrate that CDK phosphorylation controls E1 nuclear localization to support viral DNA amplification. Thus, HPV adopts and adapts the cellular regulatory mechanism to complete its reproductive program.


Amiloride interacts with renal alpha- and beta-adrenergic receptors.
We have used radioligand binding techniques to assess whether amiloride and certain analogues of amiloride (ethylisopropyl amiloride and benzamil) can bind to adrenergic receptors in the kidney. We found that amiloride could compete for [3H]rauwolscine (alpha 2-adrenergic receptors), [3H]prazosin (alpha 1-adrenergic receptors), and [125I]iodocyanopindolol (beta-adrenergic receptors) binding in rat renal cortical membranes with inhibitor constants of 13.6 +/- 5.7, 24.4 +/- 7.4, and 83.6 +/- 13.5 microM, respectively. Ethylisopropyl amiloride and benzamil were from 2- to 25-fold more potent than amiloride in competing for radioligand binding sites in studies with these membranes. In addition, amiloride and the two analogues competed for [3H]prazosin sites on intact Madin-Darby canine kidney cells and amiloride blocked epinephrine-stimulated prostaglandin E2 production in these cells. We conclude that amiloride competes for binding to several classes of renal adrenergic receptors with a rank order of potency of alpha 2 greater than alpha 1 greater than beta. Binding to, and antagonism of, adrenergic receptors occurs at concentrations of amiloride that are lower than previously observed "nonspecific" interactions of this agent.


Prevalence of Violence Victimization and Perpetration During Middle and High School in Underresourced, Urban Communities.
This study describes rates of violence victimization, perpetration, and witnessing in 6th-11th grade for a multisite sample (N = 3,466) of predominantly Black and Hispanic middle- and high-school students from urban areas with high rates of crime and economic disadvantage. Students completed surveys in middle and high school assessing teen dating violence, stalking, sexual violence and harassment, bullying, cyberbullying, and physical violence perpetration and victimization, as well as witnessing violence. The highest prevalence rates are observed most often in 8th or 9th grade. Youth reported high rates of witnessing serious assault and severe community violence throughout adolescence. These findings suggest that efforts to prevent violence among youth living in under-resourced communities need to start early and address community-level socioeconomic disparities.


Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic.
As the world is witnessing the epidemic of COVID-19, a disease caused by a novel coronavirus, SARS-CoV-2, emerging genetics and clinical evidences suggest a similar path to those of SARS and MERS. The rapid genomic sequencing and open access data, together with advanced vaccine technology, are expected to give us more knowledge on the pathogen itself, including the host immune response as well as the plan for therapeutic vaccines in the near future. This review aims to provide a comparative view among SARS-CoV, MERS-CoV and the newly epidemic SARS-CoV-2, in the hope to gain a better understanding of the host-pathogen interaction, host immune responses, and the pathogen immune evasion strategies. This predictive view may help in designing an immune intervention or preventive vaccine for COVID-19 in the near future.


Hypoxic pulmonary vasoconstriction in reptiles: a comparative study of four species with different lung structures and pulmonary blood pressures.
Low O2 levels in the lungs of birds and mammals cause constriction of the pulmonary vasculature that elevates resistance to pulmonary blood flow and increases pulmonary blood pressure. This hypoxic pulmonary vasoconstriction (HPV) diverts pulmonary blood flow from poorly ventilated and hypoxic areas of the lung to more well-ventilated parts and is considered important for the local matching of ventilation to blood perfusion. In the present study, the effects of acute hypoxia on pulmonary and systemic blood flows and pressures were measured in four species of anesthetized reptiles with diverse lung structures and heart morphologies: varanid lizards (Varanus exanthematicus), caimans (Caiman latirostris), rattlesnakes (Crotalus durissus), and tegu lizards (Tupinambis merianae). As previously shown in turtles, hypoxia causes a reversible constriction of the pulmonary vasculature in varanids and caimans, decreasing pulmonary vascular conductance by 37 and 31%, respectively. These three species possess complex multicameral lungs, and it is likely that HPV would aid to secure ventilation-perfusion homogeneity. There was no HPV in rattlesnakes, which have structurally simple lungs where local ventilation-perfusion inhomogeneities are less likely to occur. However, tegu lizards, which also have simple unicameral lungs, did exhibit HPV, decreasing pulmonary vascular conductance by 32%, albeit at a lower threshold than varanids and caimans (6.2 kPa oxygen in inspired air vs. 8.2 and 13.9 kPa, respectively). Although these observations suggest that HPV is more pronounced in species with complex lungs and functionally divided hearts, it is also clear that other components are involved.


Expert variability provides perspective on the strengths and weaknesses of citizen-driven intertidal monitoring program.
Citizen scientist programs are a means to efficiently conduct large-scale surveys of ecosystems or managed species, provided that concerns over the quality and use of data generated by nonexperts can be addressed. This study presents actions taken in a citizen science program to assure data quality and demonstrates the validity of citizen-generated data. In this case the accuracy of data collected by secondary school students as citizens in a program that quantitatively sampled benthic rocky intertidal communities at 13 sites on Maui, Molokai, Oahu, and Hawai'i island during the years 2004-2007 was evaluated. In 2007, two independent research teams collected data simultaneously with students at five sites on eight sampling dates. Comparisons of Shannon diversity and Bray-Curtis similarity values computed and simulated from student and researcher collected data revealed that nonexpert students accurately collect community-level data within the range of the variation that occurs between researchers. Students were, however, likely to misidentify cryptic and rare species. These findings have direct implications for the conservation goals of the monitoring program as the assessment reveals that students are likely to misidentify early alien introductions but are able to monitor the abundances of native and introduced species once they become established. The validity assessment designed for this investigation is unique in that it directly compares consistent errors made by citizens in data collection to expert variability to identify usage limitations and can be a guide for future studies that involve the efforts of trained volunteers.


Evaluation of frequency of paediatric oral liquid medication dosing errors by caregivers: amoxicillin and josamycin.
To study reconstitution and preparation dosing errors of liquid oral medications given by caregivers to children. A prospective observational study was carried out in the departments of general paediatrics and emergency paediatrics at the Robert-Debré Children's University Hospital. An interview with caregivers involved (1) practical reconstitution and preparation of an oral liquid medication from a prescription drawn at random (amoxicillin (Clamoxyl, dosing spoon) or josamycin (Josacine, dose-weight pipette)) and (2) a questionnaire about their use. One hundred caregivers were included. Clamoxyl and Josacine were incorrectly reconstituted in 46% (23/50) and 56% (28/50) of cases, respectively, with a risk of underdosing of Clamoxyl (16/23) and overdosing of Josacine (23/28). Dose preparation with the dosing spoon was incorrect in 56% of cases, and in 10% of cases with the dose-weight pipette. Female sex, native French speaker, and age were significantly associated with correct reconstitution. Male sex and medication were significantly associated with correct preparation. This study highlights the high incidence of errors made by caregivers in reconstituting and preparing doses of these liquid oral medicines, which are associated with considerable risks of over- and underdosing. Factors associated with these errors have been identified which could help health professionals to optimise their strategy for educating families about the use of liquid oral medications and the need to check that they understand these instructions.


Is the unfolded state the Rosetta Stone of the protein folding problem?
Solving the protein folding problem is one of the most challenging tasks in the post genomic era. Identification of folding-initiation sites is very important in order to understand the protein folding mechanism. Detection of residual structure in unfolded proteins can yield important clues to the initiation sites in protein folding. A substantial number of studied proteins possess residual structure in hydrophobic regions clustered together in the protein core. These stable structures can work as seeds in the folding process. In addition, local preferences for secondary structure in the form of turns for beta-sheet initiation and helical turns for alpha-helix formation can guide the folding reaction. In this respect the unfolded states, studied at increasing structural resolution, can be the Rosetta Stone of the protein folding problem.


New quantum structures.
Structures in which electrons are confined to move in two dimensions (quantum wells) have led to new physical discoveries and technological applications. Modification of these structures to confine the electrons to one dimension (quantum wires) or release them in the third dimension, are predicted to lead to new electrical and optical properties. This article discusses techniques to make quantum wires, and quantum wells of controlled size and shape, from compound semiconductor materials, and describes some of the properties of these structures.


Breastfeeding practice and associated factors among female nurses and midwives at North Gondar Zone, Northwest Ethiopia: a cross-sectional institution based study.
Health care workers have a duty to promote and support breastfeeding among their clients. Although their ability to do this may be influenced by their knowledge and personal experience; little is known about breastfeeding practices and the perceived barriers. The objective of this study was to assess the breastfeeding practices and the associated factors among female nurses and midwives in North Gondar Zone; Northwest Ethiopia. An institution based cross-sectional study design was conducted in 2013 among 178 nurses and midwives. In this study exclusive breastfeeding refers to breastfeeding exclusively for the first six months of a child's life. Bivariate and multivariate logistic regressions were performed to identify the presence and strength of association. Odds ratios with 95% confidence interval were computed to determine the level of significance. Exclusive breastfeeding rate among respondents was found to be 35.9%. Nearly half (49.4%) of the respondents exclusively breastfed for only 3 months or less. The mean duration exclusive breastfeeding was 4.1 ± 1.7 months. Older women (AOR = 2.8; 95% CI 2.16, 3.24), rural residence (AOR = 3.01; 95% CI 2.65, 3.84), being midwife (AOR = 2.01; 95% CI 1.83, 2.56), a women who gave birth through vaginal delivery (AOR = 2.0; 95% CI 1.68, 2.87), multiparous women (AOR = 2.20; 95% CI 1.74, 2.67) and resumption of work after 3 months (AOR = 1.61; 95% CI 1.24, 2.35) were independently associated with exclusive breastfeeding. Though respondents had adequate knowledge on breastfeeding, the practice of exclusive breastfeeding was low. Maternal age, place of residence, profession, mode of delivery, parity and the time before resuming work were factors associated with exclusive breastfeeding. Appropriate education concerning breastfeeding, directed at nurses and midwives is required to enhance exclusive breastfeeding and duration of breastfeeding.


Environmental forcing and predator consumption outweigh the nonconsumptive effects of multiple predators on oyster reefs.
The ability to predict how predators structure ecosystems has been shown to depend on identifying both consumptive effects (CEs) and nonconsumptive effects (NCEs) of predators on prey fitness. Prey populations may also be affected by interactions between multiple predators across life stages of the prey and by environmental factors such as disturbance. However, the intersection of these multiple drivers of prey dynamics has yet to be empirically evaluated. We addressed this knowledge gap using eastern oysters (Crassostrea virginica), a species known to suffer NCEs, as the focal prey. Over 4 months, we manipulated orthogonally the life stage (none, juvenile, adult, or both) at which oysters experienced simulated predation (CE) and exposure to olfactory cues of a juvenile oyster predator (crab), adult predator (conch), sequentially the crab and then the conch, or none. We replicated this experiment at three sites along an environmental gradient in a Florida (USA) estuary. For both juvenile and adult oysters, survival was reduced solely by CEs, and variation in growth was best explained by among-site variation in water flow, with a much smaller and negative effect of predator cue. Adults exposed to conch cue exhibited reduced growth (an NCE), but this effect was outweighed by a positive CE on growth: Surviving oysters grew faster at lower densities. Finally, conch cue reduced larval settlement (another NCE), but this was swamped by among-site variation in larval supply. This research highlights how strong environmental gradients and predator CEs may outweigh the influence of NCEs, even in prey known to respond to predator cues. These findings serve as a cautionary tale for the importance of evaluating NCE processes over temporal scales and across environmental gradients relevant to prey demography.


[Finding of O-mannosyl glycan in mammals and congenital muscular dystrophies due to glycosylation defects].
Most proteins within living organisms contain glycans. Glycan structures can modulate the biological properties and function of glycoproteins. Developments in glycobiology have revealed a new type of glycosidic linkage to the peptide portion, the O-mannosyl linkage in mammals, although heretofore it had been thought to be specific to yeast. One of the best known O-mannosyl-modified glycoproteins is dystroglycan, which is a central component of dystrophinglycoprotein complex isolated from skeletal muscle membranes. We identify and characterize a glycosyltransferase, UDP-N-acetylglucosamine: protein O-mannose beta 1,2-N-acetylglucosaminyltransferase (POMGnT1), involved in the biosynthesis of mammalian type O-mannosyl glycans. Finally, we find that the POMGnT1 gene is responsible for muscle-eye-brain disease (MEB). MEB is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities and brain malformation (type II lissencephaly). Like MEB, recent data suggest that the aberrant protein glycosylation of a specific glycoprotein, alpha-dystroglycan, is the primary cause of some forms of congenital muscular dystrophy. Here I review the new insight into glycobiology of muscular dystrophy and neuronal migration disorder.


A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation.
Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumour type is now classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System (CNS) tumours. However, the H3.3-K27M subgroup still appears clinically and molecularly heterogeneous. Recent publications reported that rare patients presenting a co-occurrence of H3.3K27M with BRAF or FGFR1 alterations tended to have a better prognosis. To better study the role of these co-driver alterations, we assembled a large paediatric and adult cohort of 29 tumours H3K27-altered with co-occurring activating mutation in BRAF or FGFR1 as well as 31 previous cases from the literature. We performed a comprehensive histological, radiological, genomic, transcriptomic and DNA methylation analysis. Interestingly, unsupervised t-distributed Stochastic Neighbour Embedding (tSNE) analysis of DNA methylation profiles regrouped BRAFV600E and all but one FGFR1MUT DMG in a unique methylation cluster, distinct from the other DMG subgroups and also from ganglioglioma (GG) or high-grade astrocytoma with piloid features (HGAP). This new DMG subtype harbours atypical radiological and histopathological profiles with calcification and/or a solid tumour component both for BRAFV600E and FGFR1MUT cases. The analyses of a H3.3-K27M BRAFV600E tumour at diagnosis and corresponding in vitro cellular model showed that mutation in H3-3A was the first event in the oncogenesis. Contrary to other DMG, these tumours occur more frequently in the thalamus (70% for BRAFV600E and 58% for FGFR1MUT) and patients have a longer overall survival with a median above three years. In conclusion, DMG, H3 K27 and BRAF/FGFR1 co-altered represent a new subtype of DMG with distinct genotype/phenotype characteristics, which deserve further attention with respect to trial interpretation and patient management.


ATP catabolism by tissue nonspecific alkaline phosphatase contributes to development of ARDS in influenza-infected mice.
Influenza A viruses are highly contagious respiratory pathogens that are responsible for significant morbidity and mortality worldwide on an annual basis. We have shown previously that influenza infection of mice leads to increased ATP and adenosine accumulation in the airway lumen. Moreover, we demonstrated that A1-adenosine receptor activation contributes significantly to influenza-induced acute respiratory distress syndrome (ARDS). However, we found that development of ARDS in influenza-infected mice does not require catabolism of ATP to adenosine by ecto-5'-nucleotidase (CD73). Hence, we hypothesized that increased adenosine generation in response to infection is mediated by tissue nonspecific alkaline phosphatase (TNAP), which is a low-affinity, high-capacity enzyme that catabolizes nucleotides in a nonspecific manner. In the current study, we found that whole lung and BALF TNAP expression and alkaline phosphatase enzymatic activity increased as early as 2 days postinfection (dpi) of C57BL/6 mice with 10,000 pfu/mouse of influenza A/WSN/33 (H1N1). Treatment at 2 and 4 dpi with a highly specific quinolinyl-benzenesulfonamide TNAP inhibitor (TNAPi) significantly reduced whole lung alkaline phosphatase activity at 6 dpi but did not alter TNAP gene or protein expression. TNAPi treatment attenuated hypoxemia, lung dysfunction, histopathology, and pulmonary edema at 6 dpi without impacting viral replication or BALF adenosine. Treatment also improved epithelial barrier function and attenuated cellular and humoral immune responses to influenza infection. These data indicate that TNAP inhibition can attenuate influenza-induced ARDS by reducing inflammation and fluid accumulation within the lung. They also further emphasize the importance of adenosine generation for development of ARDS in influenza-infected mice.


Distinction between dry and raw milk using monoclonal antibodies prepared against dry milk proteins.
It is well established that the heating process during the preparation of dry milk (DMLK) causes structural changes in some milk proteins. However, because such changes are subtle, whether they can be detected by an immunochemical approach remains questionable. The present study attempted to develop a sensitive mAb that might distinguish the DMLK from freshly prepared raw milk. To test this possibility, we immunized mice with commercially prepared DMLK and produced a panel of mAb. From 900 hybridomas screened using an ELISA, 4 clones were found to be specific to DMLK; the other 68 clones recognized both DMLK and raw milk. In contrast to polyclonal antibodies, only the specific mAb could detect the DMLK spiked into the raw milk at as low as 5% in concentration (vol/vol). Western blot analysis shows that these specific mAb were all directed against beta-lactoglobulin (LG) and LG-milk protein conjugates. These mAb reacted with raw milk heated at 95 degrees for 15 min; the reaction with LG-conjugates, however, was abolished when treated with reducing reagent. Thus, results suggests that a new antigenic epitope was exposed in a heating process, and the thio group of LG cross linked with other protein moiety played a provocative role in mAb recognition. A hypothetical model with respect to the interaction between the mAb and DMLK is proposed and discussed.


Clinical potential of aclidinium bromide in chronic obstructive pulmonary disease.
Three long-acting muscarinic antagonists (LAMAs) are now available in Europe, providing clinicians and patients with a choice of interventions, which is important in COPD, which is clinically a heterogeneous disease. The first LAMA, tiotropium, has been widely used over the last decade as a once-daily maintenance therapy in stable COPD to improve patients' health-related quality of life and to reduce the risk of exacerbations. Administered via the HandiHaler(®) device, it is safe and well tolerated. Another new once-daily LAMA, glycopyrronium, has also been shown to improve health status and reduce exacerbations, and is well tolerated. The subject of this review is a third LAMA, aclidinium bromide, which was approved as a twice-daily maintenance bronchodilator treatment. In the pivotal Phase III clinical trials, patients receiving aclidinium achieved significantly greater improvements in lung function, reductions in breathlessness, and improvements in health status compared with placebo, for up to 24 weeks. In continuation studies, these improvements were sustained for up to 52 weeks. Pooled data showed exacerbation frequency was significantly reduced with aclidinium versus placebo. Preclinical and pharmacological studies demonstrating low systemic bioavailability and a low propensity to induce cardiac arrhythmias were translated into a favorable tolerability profile in the clinical trial program - the adverse event profile of aclidinium was similar to placebo, with a low incidence of anticholinergic and cardiac adverse events. While additional studies are needed to evaluate its full clinical potential, aclidinium is an important part of this recent expansion of LAMA therapeutic options, providing clinicians and patients with an effective and well-tolerated COPD treatment.


Pseudoangiomatous stromal hyperplasia. A case for bilateral mastectomy in a 12-year-old girl.
Pseudoangiomatous stromal hyperplasia (PASH) is a benign proliferation of breast stromal cells with a complex pattern of interanastomosing spaces lined by myofibroblasts and is most commonly seen in women of child-bearing age. PASH is a frequent incidental microscopic finding in breast biopsies. Nodular PASH, however, resulting in a clinically appreciable mass and rapid growth is a rare entity, with only four such patients cited in the literature. Surgical excision results in a cure in the majority of cases, with a recurrence rate of approximately 7-22%. We report a case of a 12-year-old girl with nodular PASH who presented with bilateral breast enlargement refractory to surgical excisions, eventually requiring bilateral mastectomies. To our knowledge, our patient is the youngest patient to have nodular PASH and to undergo bilateral mastectomies.


MPEA--metabolite pathway enrichment analysis.
We present metabolite pathway enrichment analysis (MPEA) for the visualization and biological interpretation of metabolite data at the system level. Our tool follows the concept of gene set enrichment analysis (GSEA) and tests whether metabolites involved in some predefined pathway occur towards the top (or bottom) of a ranked query compound list. In particular, MPEA is designed to handle many-to-many relationships that may occur between the query compounds and metabolite annotations. For a demonstration, we analysed metabolite profiles of 14 twin pairs with differing body weights. MPEA found significant pathways from data that had no significant individual query compounds, its results were congruent with those discovered from transcriptomics data and it detected more pathways than the competing metabolic pathway method did. The web server and source code of MPEA are available at http://ekhidna.biocenter.helsinki.fi/poxo/mpea/.


Does TMS Influence Verbal Function and Treat the Language Decline in Schizophrenia? Finding Answers via Systematic Review of Current Research.
rTMS is an adequately safe intervention that is approved for treatment of various neuropsychiatric conditions. There is ongoing research on the application of rTMS for the treatment of resistant auditory verbal hallucinations (AVH) in schizophrenia (SZ), and also for alleviating negative and cognitive symptoms in patients with chronic SZ states. Language decline, as a part of thought, language and communication disorders, is one of the key symptoms of SZ, having a significant bearing on decreased social/interpersonal functioning of these patients. In this regard rTMS may be a promising treatment approach, while serving as an important research tool in the field of SZ studies. The aim of our present study was to compile and evaluate the existing data on whether rTMS affects verbal function in SZ patients, and if rTMS has any efficacy for the treatment of language disturbances in SZ spectrum disorders. Our systematic search over the PubMed database revealed a total of 200 articles, of which 21 met criteria for inclusion in this analysis. We have reviewed in detail the study designs, inclusion and exclusion criteria, rTMS protocols and cognitive (in particular, speech/language domain) assessments reported in these articles. The 21 studies focused on two key topic clusters: (i) low-frequency rTMS treatment of AVH in SZ, and (ii) high-frequency rTMS treatment of negative and cognitive SZ symptoms. The majority of study participants presented with chronic and treatment-resistant states. Most of the low-frequency rTMS studies did not show any difference in verbal test measures in SZ in response to treatment. Less than a half of high-frequency rTMS studies reported a delayed positive effect on language cognitive domains in SZ. There were sporadic reports on dropouts associated with a decline in scores for auditory verbal learning tests. Our systematic review found rTMS to be generally safe in relation to verbal/speech function, and suggested that verbal memory tests could serve as a measure of safety of this treatment procedure in SZ patients. Speech effects of rTMS have only been registered over long-term observation periods, such that time-frame which should be considered as an important factor for future studies. In our project "Innovative Neuropsychiatry Research Bank: Priority-2030" we plan to clarify (i) efficient rTMS protocols targeting neurocognitive improvement in SZ, and (ii) the cohort of SZ patients with a particular cognitive endophenotype and language profile amenable to treatment with rTMS, with a focus on language scores.


Preference for human papillomavirus-based cervical cancer screening: results of a choice-based conjoint study in Zambia.
The objective of this study was to assess the conditions under which Zambian women with a history of cervical cancer screening by visual inspection with acetic acid might switch to human papillomavirus-based testing in the future. We conducted a choice-based conjoint survey in a sample of women recently screened by visual inspection in Lusaka, Zambia. The screening attribute considered in hypothetical-choice scenarios included screening modality, sex and age of the examiner, whether screening results would be presented visually, distance from home to the clinic, and wait time for results. Of 238 women in the sample, 208 (87.4%) provided responses sufficiently reliable for analysis. Laboratory testing on a urine sample was the preferred screening modality, followed by visual screening, laboratory testing on a self-collected vaginal specimen, and laboratory testing on a nurse-collected cervical specimen. Market simulation suggested that only 39.7% (95% CI = 33.8-45.6) of the respondents would prefer urine testing offered by a female nurse in her 30s over visual inspection of the cervix conducted by a male nurse in his 20s if extra wait time were as short as 1 hour and the option of viewing how their cervix looks like were not available. Our study suggests that, for some women, the level of preference for human papillomavirus-based screening strategies may depend highly on the process and conditions of service delivery.


Regulation of Classical Pathway of Complement Activation by Interferons.
Though complement activation in normal physiological conditions is under regulation of special proteins relevant to complement system, there is a number of other humoral factors, which may also act as activators or inhibitors of complement activation due to significant increase in their concentration during inflammation. Administration of interferons in rheumatic patients leads to pronounced changes in immune response including complement system. It is very likely that interferons may be regulators of complement activation. In this connection, influence of recombinant alpha2b- and gamma-interferon on C5-convertase formation was investigated. We have obtained stabilized and bound on sheep erythrocyte membrane C3-convertase with prolonged period of half-inactivation and ability of transformation into C5-convertase in the presence of employed interferons. Addition of interferons to the model system caused inhibition of complement activation and abrogation of complement-induced hemolysis. Inhibition constants were found to be 133000 and 170000 IU/ml for alpha2b- and gamma-interferon, respectively. Despite, these values are higher than natural serum interferon concentrations, it is possible that under inflammation local synthesis of interferons may by performed by attracted leukocytes. In this case it seems difficult to define concentration of interferons as well as revealed by us interferon inhibition of complement activation in situ. This inhibition has not been previously described and represents a new mechanism of interferon action. Binding of activated C3b complement component to interferons is probably of great physiological importance leading to constraint of complement cascade activation as well as to inactivation of excessive interferon quantity.


Long-term progression of rhythm and conduction disturbances in pacemaker recipients: findings from the Pacemaker Expert Programming study.
Knowledge of the long-term progression of rhythm disorders requiring pacemaker implantation could have significant implications for the choice of device and its management during follow-up. Accordingly, we conducted an observational study to analyse the long-term progression of rhythm disorders requiring pacemaker implantation. This multicentre, observational study enrolled 1810 pacemaker patients (age 71.6 ± 13.3 years, men 53.8%) consecutively evaluated during scheduled pacemaker follow-up visits. To evaluate the long-term progression of rhythm disorders, we analysed the patient's rhythm disorders at the time of device implantation and during follow-up. After pacemaker implantation, the rhythm disorders were reassessed and recorded at each scheduled pacemaker follow-up visit, and the spontaneous rhythm was analysed during pacemaker interrogation. During a median follow-up of 61.6 months, we observed a progression of the primary rhythm disorder in 295 patients (16.3%; worsening of the preexisting rhythm disorder in 7.7%; occurrence of a new rhythm disorder added to the preexisting one in 8.6%). Specifically, the cumulative per-year risks of developing the following disorders were: atrioventricular block (AVB) in patients implanted for sinus node disease (SND), 0.3%; permanent atrial fibrillation in SND patients, 2.9%; SND in AVB patients, 0.7%; and persistent AVB in patients implanted for chronic bifascicular block 3.0%. Our results revealed that rhythm disorders requiring pacemaker implantation show long-term progression in a significant number of cases. In many cases, the progression is substantial and may require a change in pacing mode.


Neurologic Clinical Signs in Cattle With Astrovirus-Associated Encephalitis.
Evidence of neurotropic astroviruses has been established using novel genetic methods in cattle suffering from viral encephalitis of previously unknown origin. To describe the clinical signs observed in cattle with astrovirus-associated encephalitis. Eight cattle (4 cows, 3 heifers, and 1 bull of 4 different breeds) admitted to the Clinic for Ruminants for neurologic disease and 1 cow investigated in the field. Cases were selected based on neuropathologic diagnosis of nonsuppurative encephalitis, positive in situ hybridization result for astrovirus, and availability of the results of physical and neurologic evaluations. Laboratory results were evaluated if available. The most frequently observed clinical signs were decreased awareness of surroundings (7), cranial nerve dysfunction (5), and recumbency (5). The cow seen in the field was the only animal that had severe behavioral changes. Cell counts in cerebrospinal fluid (CSF) were increased in 4 animals, and protein concentration was increased in 3 of 5 specimens. In 1 case, the presence of astrovirus could be identified in a CSF sample by reverse transcriptase polymerase chain reaction. Other laboratory abnormalities were nonspecific. Astrovirus infection may be an important differential diagnosis in cattle with clinical signs of brain disease and should be considered after exclusion of other causes. The clinical and epidemiological relevance of encephalitis associated with astrovirus infection should be further investigated.


Streptomyces luridiscabiei sp. nov., Streptomyces puniciscabiei sp. nov. and Streptomyces niveiscabiei sp. nov., which cause potato common scab disease in Korea.
Three plant-pathogenic isolates of Streptomyces spp., isolated from potatoes with common scab disease lesions in Korea, are described as novel species. Morphological and physiological properties of these isolates were distinct from those of previously described Streptomyces species. Strain S63(T) has yellow-white, smooth, cylindrical spores that are borne in monoverticillus flexuous spore-chains. Strain S77(T) has purple-red, spiny spores that are borne in simple rectus flexuous spore-chains. Strain S78(T) has white, smooth, cylindrical spores that are borne in simple rectus flexuous spore-chains. These three isolates differed from known pathogenic strains by analysis of 16S rRNA gene sequences in a previous study. Furthermore, genetic uniqueness of our isolates was confirmed by sequencing of the 16S-23S internal transcribed spacer (ITS) region, which indicated that isolates S63(T) and S78(T) belong to the genus Streptomyces and have low homology to other Streptomyces species (less than 71.2 and 75.7 %, respectively). The 16S-23S ITS region of strain S77(T) was not amplified by these primer sets. DNA-DNA hybridization results for all three isolates show distant relationships to previously described Streptomyces species; therefore, on the basis of polyphasic evidence, the names Streptomyces luridiscabiei sp. nov. for strain S63(T) (=LMG 21390(T)=KACC 20252(T)), Streptomyces puniciscabiei sp. nov. for strain S77(T) (=LMG 21391(T)=KACC 20253(T)) and Streptomyces niveiscabiei sp. nov. for strain S78(T) (=LMG 21392(T)=KACC 20254(T)) are proposed.


Novel vaccination approach for dengue infection based on recombinant immune complex universal platform.
Dengue infection is on the rise in many endemic areas of the tropics. Vaccination remains the most realistic strategy for prevention of this potentially fatal viral disease but there is currently no effective vaccine that could protect against all four known serotypes of the dengue virus. This study describes the generation and testing of a novel vaccination approach against dengue based on recombinant immune complexes (RIC). We modelled the dengue RIC on the existing Ebola RIC (Phoolcharoen, et al. Proc Natl Acad Sci USA 2011;108(Dec (51)):20695) but with a key modification that allowed formation of a universal RIC platform that can be easily adapted for use for other pathogens. This was achieved by retaining only the binding epitope of the 6D8 ant-Ebola mAb, which was then fused to the consensus dengue E3 domain (cEDIII), resulting in a hybrid dengue-Ebola RIC (DERIC). We expressed human and mouse versions of these molecules in tobacco plants using a geminivirus-based expression system. Following purification from the plant extracts by protein G affinity chromatography, DERIC bound to C1q component of complement, thus confirming functionality. Importantly, following immunization of mice, DERIC induced a potent, virus-neutralizing anti-cEDIII humoral immune response without exogenous adjuvants. We conclude that these self-adjuvanting immunogens have the potential to be developed as a novel vaccine candidate for dengue infection, and provide the basis for a universal RIC platform for use with other antigens.


Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts.
Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in cell membranes that regulate phosphorylation cascades originating from membrane-bound proteins. In this study, we tested whether alteration of the cholesterol content of lipid rafts in prostate cancer (PCa) cell membranes affects cell survival mechanisms in vitro and in vivo. Simvastatin, a cholesterol synthesis inhibitor, lowered raft cholesterol content, inhibited Akt1 serine-threonine kinase (protein kinase Balpha)/protein kinase B (Akt/PKB) pathway signaling, and induced apoptosis in caveolin- and PTEN-negative LNCaP PCa cells. Replenishing cell membranes with cholesterol reversed these inhibitory and apoptotic effects. Cholesterol also potentiated Akt activation in normal prostate epithelial cells, which were resistant to the apoptotic effects of simvastatin. Elevation of circulating cholesterol in SCID mice increased the cholesterol content and the extent of protein tyrosine phosphorylation in lipid rafts isolated from LNCaP/sHB xenograft tumors. Cholesterol elevation also promoted tumor growth, increased phosphorylation of Akt, and reduced apoptosis in the xenografts. Our results implicate membrane cholesterol in Akt signaling in both normal and malignant cells and provide evidence that PCa cells can become dependent on a cholesterol-regulated Akt pathway for cell survival.


Transformation by retroviral vectors of bone marrow-derived mesenchymal cells induces mitochondria-dependent cAMP-sensitive reactive oxygen species production.
Retroviral vectors are used in human gene therapy trials to stably introduce therapeutic genes in the genome of patients' cells. Their applicability, however, is frustrated by the limited viability of transformed cells and/or by risks linked to selection of oncogene-mutated clones. The reasons for these drawbacks are not yet completely understood. In this study, we show that LXSN-NeoR gene/interleukin-7-engineered mesenchymal stromal cells exhibited a marked enhancement of reactive oxygen species production compared with untransfected cells. This effect resulted to be independent on the product of the gene carried by the retroviral vehicle as it was reproducible in cells transfected with the empty vector alone. Stable transfection of mesenchymal stromal cells with the different retroviral vectors pBabe-puro and PINCO-puro and the lentiviral vector pSico PGK-puro caused similar redox imbalance, unveiling a phenomenon of more general impact. The enhanced production of reactive oxygen species over the basal level was attributable to mitochondrial dysfunction and brought back to altered activity of the NADH-CoQ oxidoreductase (complex I) of the respiratory chain. The oxidative stress in transfected mesenchymal stem cells was completely reversed by treatment with a cAMP analog, thus pointing to alteration in the protein kinase A-dependent signaling pathway of the host cell. Transfection of mesenchymal stromal cells with a PINCO-parental vector harboring the green fluorescent protein gene as selection marker in place of the puromycin-resistance gene resulted in no alteration of the redox phenotype. These novel findings provide insights and caveats to the applicability of cell- or gene-based therapies and indicate possible intervention to improve them. Disclosure of potential conflicts of interest is found at the end of this article.


Diagnosis and treatment of hidden lesions in "mild" cervical spondylotic myelopathy patients with apparent symptoms.
Patients with apparent symptoms of cervical spondylotic myelopathy (CSM) may only show a mild compressive lesion in ordinary magnetic resonance imaging (MRI). The aim of this study was to investigate the characteristics of CSM patients with "hidden" lesions on kinetic MRI and to determine an effective treatment.Thirty-one patients with obvious spinal cord compression only on kinetic MRI were included in our study. A variety of parameters were calculated from MRI of the cervical spine at different postures. The anterior cervical decompression and fusion (ACDF) procedure were used for treatment of CSM. To evaluate the effect of surgery, a further 31 age- and gender-matched ordinary CSM patients that received ACDF procedures were enrolled as the control group.The diameter of the cervical cord at the narrowest level in extension was significantly lower than that in the neutral posture (P < .01). The percentage of spinal cord compression was 34.6%. The diameter of the cervical canal at the narrowest level in the extension posture was significantly lower than that in the neutral posture (P < .01). The percentage of cervical canal stenosis was 43.6%. The anteroposterior diameter of the cervical canal in the case group was significantly lower than that in the control group (P < .01). However, the recovery rate of the Japanese Orthopaedic Association score at final follow-up was comparable between the case group and the control group (P = .53).Kinetic MRI is useful for the diagnosis of CSM with hidden lesions. ACDF is an effective procedure for treatment of CSM.


Hu-ets-1 and Hu-ets-2 genes are transposed in acute leukemias with (4;11) and (8;21) translocations.
Human probes identifying the cellular homologs of the v-ets gene, Hu-ets-1 and Hu-ets-2, and two panels of rodent-human cell hybrids were used to study specific translocations occurring in acute leukemias. The human ets-1 gene was found to translocate from chromosome 11 to 4 in the t(4;11)(q21;23), a translocation characteristic of a subtype of leukemia that represents the expansion of a myeloid/lymphoid precursor cell. Similarly, the human ets-2 gene was found to translocate from chromosome 21 to chromosome 8 in the t(8;21)(q22;q22), a nonrandom translocation commonly found in patients with acute myeloid leukemia with morphology M2 (AML-M2). Both translocations are associated with expression different from the expression in normal lymphoid cells of ets genes, raising the possibility that these genes play a role in the pathogenesis of these leukemias.


Fungal keratitis: changing pathogens and risk factors.
To describe changes in demographics and pathogens for fungal keratitis cases diagnosed at the Massachusetts Eye and Ear Infirmary. Patient demographics, clinical and laboratory findings, treatment and outcomes of 46 cases of culture-proven fungal keratitis diagnosed from January 2004 through November 2007 were compared with 23 cases of fungal keratitis previously collected over a similar period from January 1999 through November 2002. During 2004-2007, the rate of fungal keratitis was 1.0 cases per month, an increase from the baseline rate of 0.5 cases per month during 1999-2002. The proportion of cases caused by filamentous fungi increased from 30% (1999-2002) to 65% (2004-2007) (P = 0.01). Soft contact lens wear accounted for 41% of fungal keratitis cases in 2004-2007, as compared with 17% in 1999-2002. The majority of patients (70%) received oral antifungal treatment in addition to topical amphotericin B and natamycin. Seventeen patients (40%) required therapeutic keratoplasty. Patients with a history of corneal transplant had the highest rate of therapeutic keratoplasties (67%) and had the poorest visual outcome (40% counting fingers or less). In the contact lens group, 94% of patients maintained vision of at least 20/40 and only 12% required surgery to control the infection. There has been an increase in fungal keratitis in the Boston area and a change in the causative pathogens and risk factors for infection. Filamentous fungi now account for the majority of fungal keratitis cases, whereas yeasts were the predominant pathogen in the past. Soft contact lens wear is currently the most common risk factor for development of fungal keratitis.


[Marginal fit changes in implant-supported prosthetic bars by electroerosive processing].
The aim of the study was to evaluate the marginal fit changes in implant supported prosthetic bars by electroerosive processing. The experimental model included 9 bars supported by 2, 4 and 6 implant analogues (3 bars for each number of supports). Marginal gap size was assessed by digital microscopy before and after electroerosive processing conducted in 3 stages (10, 8 and 5 minutes long). Electroerosive processing proved to be useful tool for marginal fit correction.


How covalence breaks adsorption-energy scaling relations and solvation restores them.
It is known that breaking the scaling relations between the adsorption energies of *O, *OH, and *OOH is paramount in catalyzing more efficiently the reduction of O2 in fuel cells and its evolution in electrolyzers. Taking metalloporphyrins as a case study, we evaluate here the adsorption energies of those adsorbates on the metal centers Cr, Mn, Fe, Co, Ni and Cu, using H, F, OH, NH2, CH3, and BH2 as ring ligands. We show that covalence systematically breaks scaling relations under vacuum by strengthening certain M-OOH bonds. However, covalence modifies adsorbate solvation in solution depending on the degree of covalence of the metal-adsorbate bonds. The two effects have similar magnitudes and opposite signs, such that scaling relations are restored in solution. Thus, solvation is a crucial ingredient that must be taken into account in studies aimed at breaking scaling relations in solution. Our findings suggest that the choice of metal and ligand determines the catalytic activity within the limits imposed by scaling relations, whereas the choice of an appropriate solvent can drive such activity beyond those limits.


Effects of rituximab in two patients with dysferlin-deficient muscular dystrophy.
The administration of rituximab (RTX) in vivo results in B-cell depletion, but evidence for multiple mechanisms of action have been reported. Surprisingly, B cell depletion produced a response in patients with polymyositis, which is characterized as a T cell-mediated autoimmune disorder with biopsy findings similar to Miyoshi myopathy (MM). Indeed, in dysferlinopathies, there is evidence of immune system involvement including the presence of muscle inflammation and a down regulation of the complement inhibitory factor, CD55. Two patients were treated with four weekly infusions of RTX 375 mg/m2. To measure the improvement in muscle strength after treatment, the isometric hand grip maximal voluntary contraction (MVC) was measured by load cell four times during treatment, and again after one year. In order to assess the reproducibility of our grip assessment, we determined the hand MVC analysis in 16 healthy subjects. Moreover, we measured the number of B cells present in patients by flow cytometric analysis during the course of treatment. The analysis of B cell number during the course of treatment showed that CD20- and CD19-positive cells were depleted to 0-0.01%. The decrease in B cells was followed by an improvement in the mobility of the pelvic and shoulder girdles as shown by the MRC%. The MVC values of both patients began at values lower than normal whereas during treatment patients had improved percentage of muscle strength. The strength peak in both patients coincided with the minimum B cell values. There were no severe adverse events associated with an infusion of RTX. We consider the increase in muscle strength observed in both treated patients to be a consequence of their treatment with RTX. To our knowledge, these are the first cases of increased muscle strength in patients with MM. Furthermore, the results of this study indicate that B cell depletion with RTX may be useful in the treatment of patients affected by MM, suggesting a possible role for B cells in the pathophysiology of this muscle disorder.


Ion uptake pathways in European sea bass Dicentrarchus labrax.
Ion uptake mechanisms are diverse in fish species, certainly linked to duplication events that have led to the presence of a multitude of paralogous genes. In fish, Na+ uptake involves several ion transporters expressed in different ionocyte subtypes. In the European sea bass Dicentrarchus labrax, several key transporters potentially involved in Na+ uptake have been investigated in seawater (SW) and following a 2 weeks freshwater (FW) acclimation. Using gel electrophoresis, we have shown that the Na+/H+-exchanger 3 (nhe3, slc9a3) is expressed in gills and kidney at both salinities. Quantitative realtime PCR analysis showed a significantly higher nhe3 expression in fresh water (FW) compared to SW. Its apical localization in a subset of gill ionocytes in freshwater-acclimated fish supports the role of NHE3 in Na+ uptake. Interestingly, NHE3-immunopositive cells also express basolateral Na+/K+/2Cl- cotransporter 1 (NKCC1) and are mainly localized in gill lamella. Among the three nhe2 (slc9a2) paralogs, only nhe2c shows differential branchial expression levels with higher mRNA levels in SW than in FW. The increased branchial expression of the ammonia transporter rhcg1 (Rhesus protein), nhe3 and cytoplasmic carbonic anhydrase (cac) in FW could indicate the presence of a functional coupling between ion transporters to form a Na+/NH4+ exchange complex. Acid-sensing ion channel 4 (asic4) seems not to be expressed in sea bass gills. Na+/Cl- cotransporter (ncc2a or ncc-like) is about three times more expressed in FW compared to SW suggesting coupled Na+ and Cl- uptake in a subset of gill ionocytes. Besides the main pump Na+/K+-ATPase, branchial NCC2a and NHE3 may be key players in ion uptake in sea bass following a long-term freshwater challenge.