Contribution of tibiofemoral joint contact to net loads at the knee in gait.
Inverse dynamics analysis is commonly used to estimate the net loads at a joint during human motion. Most lower-limb models of movement represent the knee as a simple hinge joint when calculating muscle forces. This approach is limited because it neglects the contributions from tibiofemoral joint contact forces and may therefore lead to errors in estimated muscle forces. The aim of this study was to quantify the contributions of tibiofemoral joint contact loads to the net knee loads calculated from inverse dynamics for multiple subjects and multiple gait patterns. Tibiofemoral joint contact loads were measured in four subjects with instrumented implants as each subject walked at their preferred speed (normal gait) and performed prescribed gait modifications designed to treat medial knee osteoarthritis. Tibiofemoral contact loads contributed substantially to the net knee extension and knee adduction moments in normal gait with mean values of 16% and 54%, respectively. These findings suggest that knee-contact kinematics and loads should be included in lower-limb models of movement for more accurate determination of muscle forces. The results of this study may be used to guide the development of more realistic lower-limb models that account for the effects of tibiofemoral joint contact at the knee.


Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG.
3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is a recently developed PET tracer to image tumor cell proliferation. We characterized (18)F-FLT PET of brain gliomas and compared (18)F-FLT with (18)F-FDG PET in side-by-side studies of the same patients. Twenty-five patients with newly diagnosed or previously treated glioma underwent PET with (18)F-FLT and (18)F-FDG on consecutive days. Three stable patients in long-term remission were included as negative control subjects. Tracer kinetics in normal brain and tumor were measured. Uptake of (18)F-FLT and (18)F-FDG was quantified by the standardized uptake value (SUV) and the tumor-to-normal tissue (T/N) ratio. The accuracy of (18)F-FLT and (18)F-FDG PET in evaluating newly diagnosed and recurrent gliomas was compared. More than half of the patients underwent resection after the PET study and correlations between PET uptake and the Ki-67 proliferation index were examined. Patients were monitored for a mean of 15.4 mo (range, 12-20 mo). The predictive power of PET for tumor progression and survival was analyzed using Kaplan-Meier statistics. (18)F-FLT uptake in tumors was rapid, peaking at 5-10 min after injection and remaining stable up to 75 min. Hence, a 30-min scan beginning at 5 min after injection was sufficient for imaging. (18)F-FLT visualized all high-grade (grade III or IV) tumors. Grade II tumor did not show appreciable (18)F-FLT uptake and neither did the stable lesions. The absolute uptake of (18)F-FLT was low (maximum-pixel SUV [SUV(max)], 1.33) but image contrast was better than with (18)F-FDG (T/N ratio, 3.85 vs. 1.49). (18)F-FDG PET studies were negative in 5 patients with recurrent high-grade glioma who subsequently suffered tumor progression within 1-3 mo. (18)F-FLT SUV(max) correlated more strongly with Ki-67 index (r = 0.84; P < 0.0001) than (18)F-FDG SUV(max) (r = 0.51; P = 0.07). (18)F-FLT uptake also had more significant predictive power with respect to tumor progression and survival (P = 0.0005 and P = 0.001, respectively). Thirty-minute (18)F-FLT PET 5 min after injection was more sensitive than (18)F-FDG to image recurrent high-grade tumors, correlated better with Ki-67 values, and was a more powerful predictor of tumor progression and survival. Thus, (18)F-FLT appears to be a promising tracer as a surrogate marker of proliferation in high-grade gliomas.


Deptor transcriptionally regulates endoplasmic reticulum homeostasis in multiple myeloma cells.
Multiple myeloma (MM) is a malignant disorder of plasma cells characterized by active production and secretion of monoclonal immunoglobulins (IgG), thus rendering cells prone to endoplasmic reticulum (ER) stress. For this reason, MM cell survival requires to maintain ER homeostasis at basal levels. Deptor is an mTOR binding protein, belonging to the mTORC1 and mTORC2 complexes. It was reported that Deptor is overexpressed in MM cells where it inhibits mTOR kinase activity and promotes cell survival by activating Akt signaling. Here we identify Deptor as a nuclear protein, able to bind DNA and regulate transcription in MM cells. In particular, we found that Deptor plays an important role in the maintenance of the ER network, sustaining the expression of several genes involved in this pathway. In agreement with this, Deptor depletion induces ER stress and synergizes the effect of the proteasome inhibitor bortezomib (Bz) in MM cells. These findings provide important new insights in the ER stress control in MM cells.


[Medical genetic research on the Khanty population of the Ovgort rural district of the Yamal-Nenets Autonomous territory].
The results of medico-genetical studies of the Khanty from the Lower Ob river carried out by Tomsk Department of Institute of Medical Genetics of Academy of Medical Sciences of the USSR are presented. The population is characterized by a relatively high index of endogamy (0.54) and a low inbreeding coefficient (0.0011). Diseases of the polygenic mode of inheritance predominate among nosological forms of hereditary pathology.


The problem of gastroesophageal reflux.
Gastroesophageal reflux is the "postnasal drip" of the 1980s. A large variety of symptoms result from reflux: some are merely nuisances, some are life threatening. This review covers those symptoms and diseases due to acid reflux that are of importance to the otolaryngologist.


Yeast Delta 12 fatty acid desaturase: gene cloning, expression, and function.
In an effort to elucidate the molecular mechanisms of fatty acid desaturation in yeast, a complete gene encoding Delta 12 fatty acid desaturase of Saccharomyces kluyveri was cloned. The open reading frame of this gene (named Sk-FAD2) consists of 1,251 bp, encoding 416 amino acids. The deduced Sk-FAD2 protein had 37-55% identity with those from other filamentous fungi. Unlike the genes of these other fungi, S. cerevisiae expressing Sk-FAD2 was found to be capable of synthesizing the dienoic fatty acid hexadecadienoic acid as well as linoleic acid. Moreover, the Sk-FAD2-disrupted strain of S. kluyveri was unable to produce polyunsaturated fatty acids. These results suggested that Sk-FAD2 protein is a unique Delta 12 fatty acid desaturase in S. kluyveri. Analysis of transcriptional expression revealed that Sk-FAD2 was not repressed by exogenous unsaturated fatty acids but responded to low-temperature stress.


Arsenic removal by perilla leaf biochar in aqueous solutions and groundwater: An integrated spectroscopic and microscopic examination.
In this study, we examined the removal of arsenite (As(III)) and arsenate (As(V)) by perilla leaf-derived biochars produced at 300 and 700 °C (referred as BC300 and BC700) in aqueous environments. Results revealed that the Langmuir isotherm model provided the best fit for As(III) and As(V) sorption, with the sorption affinity following the order: BC700-As(III) > BC700-As(V) > BC300-As(III) > BC300-As(V) (QL = 3.85-11.01 mg g-1). In general, As removal decreased (76-60%) with increasing pH from 7 to 10 except for the BC700-As(III) system, where notably higher As removal (88-90%) occurred at pH from 7 to 9. Surface functional moieties contributed to As sequestration by the biochars examined here. However, significantly higher surface area and aromaticity of BC700 favored a greater As removal compared to BC300, suggesting that surface complexation/precipitation dominated As removal by BC700. Arsenic K-edge X-ray absorption near edge structure (XANES) spectroscopy demonstrated that up to 64% of the added As(V) was reduced to As(III) in BC700- and BC300-As(V) sorption experiments, and in As(III) sorption experiments, partial oxidation of As(III) to As(V) occurred (37-39%). However, XANES spectroscopy was limited to precisely quantify As binding with sulfur species as As2S3-like phase. Both biochars efficiently removed As from natural As-contaminated groundwater (As: 23-190 μg L-1; n = 12) despite in the presence of co-occurring anions (e.g., CO32-, PO43-, SO42-) with the highest levels of As removal observed for BC700 (97-100%). Overall, this study highlights that perilla leaf biochars, notably BC700, possessed the greatest ability to remove As from solution and groundwater (drinking water). Significantly, the integrated spectroscopic techniques advanced our understanding to examine complex redox transformation of As(III)/As(V) with biochar, which are crucial to determine fate of As on biochar in aquatic environments.


The role of intergenerational educational mobility and household wealth in adult obesity: Evidence from Wave 2 of the World Health Organization's Study on global AGEing and adult health.
Obesity has emerged as a major risk factor for non-communicable diseases in low and middle-income countries but may not follow typical socioeconomic status (SES)-related gradients seen in higher income countries. This study examines the associations between current and lifetime markers of SES and BMI categories (underweight, normal weight, overweight, obese) and central adiposity in Ghanaian adults. Data from 4,464 adults (2,610 women) who participated in the World Health Organization's Study on global AGEing and adult health (SAGE) Wave 2 were examined. Multilevel multinomial and binomial logistic regression models were used to examine associations. SES markers included parental education, individual education, intergenerational educational mobility and household wealth. Intergenerational educational mobility was classified: stable-low (low parental and low individual education), stable-high (high parental and high individual education), upwardly (low parental and high individual education), or downwardly mobile (high parental and low individual education). The prevalence of obesity (12.9%) exceeded the prevalence of underweight (7.2%) in the population. High parental and individual education were significantly associated with higher odds of obesity and central adiposity in women. Compared to the stable low pattern, stable high (obesity: OR = 3.15; 95% CI: 1.96, 5.05; central adiposity: OR = 1.75; 95% CI: 1.03, 2.98) and upwardly (obesity: OR = 1.71; 95% CI: 11.13, 2.60; central adiposity: OR = 1.60; 95% CI: 1.08, 2.37) mobile education patterns were associated with higher odds of obesity and central adiposity in women, while stable high pattern was associated with higher odds of overweight (OR = 1.88; 95% CI: 1.11, 3.19) in men. Additionally, high compared to the lowest household wealth was associated with high odds of obesity and central adiposity in both sexes. Stable high and upwardly mobile education patterns are associated with higher odds of obesity and central adiposity in women while the stable high pattern was associated with higher odds of overweight in men.


Quantitative and qualitative 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in skull base meningiomas.
Complete resection of skull base meningiomas provides patients with the best chance for a cure; however, surgery is frequently difficult given the proximity of lesions to vital structures, such as cranial nerves, major vessels, and venous sinuses. Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative assessment of protoporphyrin IX (PpIX) fluorescence following the exogenous administration of 5-aminolevulinic acid (ALA) has demonstrated utility in malignant glioma resection but limited use in meningiomas. Here the authors demonstrate the use of ALA-induced PpIX fluorescence guidance in resecting a skull base meningioma and elaborate on the advantages and disadvantages provided by both quantitative and qualitative fluorescence methodologies in skull base meningioma resection. A 52-year-old patient with a sphenoid wing WHO Grade I meningioma underwent tumor resection as part of an institutional review board-approved prospective study of fluorescence-guided resection. A surgical microscope modified for fluorescence imaging was used for the qualitative assessment of visible fluorescence, and an intraoperative probe for in situ fluorescence detection was utilized for quantitative measurements of PpIX. The authors assessed the detection capabilities of both the qualitative and quantitative fluorescence approaches. The patient harboring a sphenoid wing meningioma with intraorbital extension underwent radical resection of the tumor with both visibly and nonvisibly fluorescent regions. The patient underwent a complete resection without any complications. Some areas of the tumor demonstrated visible fluorescence. The quantitative probe detected neoplastic tissue better than the qualitative modified surgical microscope. The intraoperative probe was particularly useful in areas that did not reveal visible fluorescence, and tissue from these areas was confirmed as tumor following histopathological analysis. Fluorescence-guided resection may be a useful adjunct in the resection of skull base meningiomas. The use of a quantitative intraoperative probe to detect PpIX concentration allows more accurate determination of neoplastic tissue in meningiomas than visible fluorescence and is readily applicable in areas, such as the skull base, where complete resection is critical but difficult because of the vital structures surrounding the pathology.


Are procedures performed by dental auxiliaries safe and of comparable quality? A systematic review.
The objective of the current study was to systematically evaluate the existing evidence in relation to the safety, quality, productivity or cost-benefit, and patient satisfaction of the procedures performed by the different groups of dental providers. Due to the diversity of the procedures performed and the outcomes measured, it was not possible to create pooled estimates in a meaningful manner. Therefore, summary results of individual studies are presented and critically evaluated.


The t(2;5) chromosomal translocation is not a common feature of primary cutaneous CD30+ lymphoproliferative disorders: comparison with anaplastic large-cell lymphoma of nodal origin.
Primary cutaneous CD30+ lymphoproliferative disorders (LPDs), including lymphomatoid papulosis (LyP), anaplastic and nonanaplastic CD30+ large-cell lymphoma, and borderline cases, comprise a clinical and histologic spectrum. Primary cutaneous and primary nodal CD30+ anaplastic large-cell lymphomas (ALCLs) are distinct clinical entities that have identical morphologic features but differ in age of onset, immunophenotype, and prognosis. It can be difficult to distinguish primary cutaneous from nodal ALCLs that secondarily involve the skin, which is important because these diseases differ significantly in response to treatment and clinical outcome. The t(2;5) chromosomal translocation is highly associated with primary CD30+ ALCL of nodal origin. The possible occurrence of t(2;5) in primary cutaneous CD30+ LPDs has not been studied extensively, and it remains to be determined if expression of this translocation can be used to distinguish primary cutaneous ALCL from nodal ALCL that secondarily involves the skin. To address these issues, we studied 43 cases of cutaneous and nodal CD30+ LPDs using reverse transcriptase-polymerase chain reaction (RT-PCR) and/or immunohistochemistry. We found no evidence for the t(2; 5) translocation in 14 cases of primary cutaneous CD30+ LPDs, which included 10 cases of LyP, three cases of primary cutaneous CD30+ ALCL, and one borderline case. These findings were in marked contrast to CD30+ ALCL of nodal origin, in which 19 of 29 (66%) cases were positive for t(2;5), including all five cases with secondary skin involvement. Our results support the hypothesis that (1) primary cutaneous CD30+ LPDs (including LyP) and primary nodal ALCL are distinct diseases that differ in clinical behavior and pathogenesis and (2) differential expression of t(2;5) can help to distinguish between primary cutaneous CD30+ LPDs and ALCL of nodal origin.


Myofibrillar ATPase activity in the carp Cyprinus carpio: interactions between starvation and environmental temperature.
The myofibrillar ATPase activity of the epaxial white muscle was measured in carp Cyprinus carpio L. acclimated to 10 degrees C or 28 degrees C. As previously reported, cold acclimation was associated with an increase in the ATPase specific activity and a decrease in the thermostability. The water content of the white muscle was significantly higher in cold-acclimated fish than in warm-acclimated fish (P less than 0.002). Starvation for 10 weeks resulted in a significant increase in the white muscle water content of both warm- and cold-acclimated fish (P less than 0.002). When carp were starved, the ability of the myofibrillar ATPase to show thermal compensation disappeared. Previously acclimated fish, when starved, showed steady alterations of the myofibrillar ATPase activity to a level mid-way between the acclimated extremes. Refeeding resulted in a gradual return to the normal acclimated level.


Emerging therapies for noninfectious uveitis: what may be coming to the clinics.
Corticosteroids along with other immunomodulatory therapies remain as the mainstay of treatment tor all patients with noninfectious uveitis (NIU). However, the systemic side effects associated with the long-term use of these drugs has encouraged the development of new therapeutic agents in recent times. This review article discusses upcoming therapeutic agents and drug delivery systems that are currently being used to treat patients with NIU. These agents mediate their actions by blocking specific pathways involved in the inflammatory process. Agents discussed in this review include full or recombinant monoclonal antibodies against interleukins such as IL-17 (secukinumab), IL-l (gevokizumab), and IL-6 (tocilizumab and sarilumab), antibody fragments against inflammatory cytokines such as TNF- α (ESBA 105) and T-cell inhibitors such as fusion proteins (abatacept), and next generation calcineurin inhibitors (voclosporin). In addition, administration of immune modulatory therapies using methods such as iontophoresis (EGP-437) and intravitreal injection (sirolimus) for the treatment of NIU' uveitis has also been discussed.


Agreement between child and parent reports of 10- to 12-year-old children's meal pattern and intake of snack foods.
Dietary assessment in children is associated with misreporting, which is a problem with both child and parent reports. Therefore, it is of interest to study how children and parents report children's eating, respectively, although comparative studies are rare. The aim of the present article was to study the meal patterns and intake of certain snack foods of 10- to 12-year-old children as reported by the children and their parents, respectively, and to determine whether there was agreement between the child and parent reports. An additional aim was to study what factors might influence rater agreement. School children aged 10-12years and their parents were given parallel questionnaires regarding the children's meal pattern. Matched pairs (n=147) were analysed for agreement. Descriptive statistics were used to study all variables. Rater agreement and whether agreement depends on the age and the sex of the child, the sex of the parent and household type were analysed using ordinal regression models. Correlations between the child and parent assessments were estimated as polychoric correlations. There was a general agreement between child and parent reports, except with respect to sweets and chocolate, where children reported less frequent consumption than the parents did (P= 0.0001). The sex of the child was a significant factor regarding consumption of in-between meals (P=0.0001) and soft drinks (P=0.01). Most children had breakfast, school lunch and dinner every day, whereas it was less common to report daily consumption of in-between meals. There was a general agreement between children's and parents' reports, and most children were reported to have a regular meal pattern.


Signal transduction networks in cancer: quantitative parameters influence network topology.
Networks of fixed topology are used to summarize the collective understanding of the flow of signaling information within a cell (i.e., canonical signaling networks). Moreover, these canonical signaling networks are used to interpret how observed oncogenic changes in protein activity or expression alter information flow in cancer cells. However, creating a novel branch within a signaling network (i.e., a noncanonical edge) provides a mechanism for a cell to acquire the hallmark characteristics of cancer. The objective of this study was to assess the existence of a noncanonical edge within a receptor tyrosine kinase (RTK) signaling network based upon variation in protein expression alone, using a mathematical model of the early signaling events associated with epidermal growth factor receptor 1 (ErbB1) signaling network as an illustrative example. The abundance of canonical protein-RTK complexes (e.g., growth factor receptor bound protein 2-ErbB1 and Src homology 2 domain containing transforming protein 1-ErbB1) were used to establish a threshold that was correlated with ligand-dependent changes in cell proliferation. Given the available data, the uncertainty associated with this threshold was estimated using an empirical Bayesian approach. Using the variability in protein expression observed among a collection of breast cancer cell lines, this model was used to assess whether a noncanonical edge (e.g., Irs1-ErbB1) exceeds the threshold and to identify cell lines where this noncanonical edge is likely to be observed. Taken together, the simulations suggest that the topology of signal transduction networks within cells is influenced by quantitative parameters, such as protein expression and binding affinity. Moreover, forming this noncanonical pathway was not due solely to overexpression of the cell surface receptor but was influenced by overexpression of all members of the multiprotein complex. Multivariate alterations in expression of signaling proteins in cancer cells may activate noncanonical pathways and may rewire the signaling network within a cell.


Prescription patterns and mineral metabolism abnormalities in the cinacalcet era: results from the MBD-5D study.
Prescription patterns for hemodialysis patients with secondary hyperparathyroidism have varied widely since market introduction of cinacalcet. This study examined associations between prescription patterns and subsequent laboratory values. Using a Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients subcohort, 1716 prevalent hemodialysis patients (4048 sets for repeated measures between January 2008 and July 2009) with an intact parathyroid hormone (iPTH) level >180 pg/ml who used intravenous vitamin D receptor activator (VDRA) without cinacalcet were selected. Prescription patterns were defined based on cinacalcet administration (starting or not) and VDRA dosage change (decreased [<-25%], stable [-25% to 25%], or increased [>25%]). Proportion differences (PDs) were determined for decreasing iPTH levels by at least one category (<180, 180-299, 300-499, and ≥500 pg/ml) and for achieving target phosphorus (3.5-6.0 mg/dl) and calcium (8.4-10.0 mg/dl) levels, adjusting for potential confounders. The starting cinacalcet and increased VDRA patterns were associated with decreasing iPTH levels (PD, 0.25 and 0.13; 95% confidence intervals [95% CIs], 0.19-0.31 and 0.09-0.17, respectively); combination use had an additive association (PD, 0.34; 95% CI, 0.20-0.42). The starting cinacalcet and decreased VDRA combination was associated with simultaneously achieving target phosphorus (PD, 0.12; 95% CI: 0.04-0.20) and calcium (PD, 0.09; 95% CI, 0.01-0.17) levels. Certain combinations of cinacalcet and VDRA were associated with decreasing iPTH and achieving targets for phosphorus and calcium. Combinations may prove advantageous versus VDRA alone in managing secondary hyperparathyroidism.


The Montreal Cognitive Assessment in Veteran Postacute Care: Implications of Cut Scores.
The Montreal Cognitive Assessment (MoCA) is often used for cognitive screening across health care settings, especially in rehabilitation centers, where assessment and treatment of cognitive function is considered key for successful multidisciplinary treatment. Although the original MoCA validation study suggested a cut score of <26 to identify cognitive impairment, recent studies have suggested that lower cut scores should be applied. To examine the percentage of positive screens for cognitive impairment using the MoCA in a veteran postacute care (PAC) rehabilitation setting and to identify the most accurate MoCA cut score based on criterion neuropsychological measures. We obtained data from 81 veterans with diverse medical diagnoses who had completed the MoCA during their admission to a PAC unit. A convenience subsample of 50 veterans had also completed four criterion neuropsychological measures. Depending on the cut score used, the percentage of individuals classified as impaired based on MoCA performance varied widely, ranging from 6.2% to 92.6%. When predicting performance using a more comprehensive battery of criterion neuropsychological tests, we identified <22 as the most accurate MoCA cut score to identify a clinically relevant level of impairment and <24 to identify milder cognitive impairment. Our findings suggest that a MoCA cut score of <26 carries a risk of misdiagnosis of cognitive impairment, and scores in the range of <22 to <24 are more reliable for identifying cognitive impairment.


Effectiveness of Hands-Off Therapy in the Management of Primary Headache: A Systematic Review and Meta-Analysis.
A number of hands-off therapies have been widely reported and are used in the management of headache. This systematic review and meta-analysis aimed to assess evidence supporting these therapies on selected headache outcomes. A systematic literature search for randomized clinical trials reporting on the effects of hands-off therapies for headache was performed in two electronic databases; PubMed and Web of Science (PROSPERO: CRD42018093559). Risk of bias was assessed using the Cochrane risk of bias tool. Meta-analysis was performed using Review Manager v5.4. Thirty-five studies, including 3,403 patients with migraine, tension-type or chronic headaches were included in the review. Methodological quality of the studies ranged from poor to good. Result-synthesis revealed weak to moderate evidence for aerobic exercises, relaxation training and pain education for reducing disability. Other hands-off interventions were either weak or limited in evidence. Meta-analysis of 22 studies indicated that the effect of hands-off therapies significantly differed from one another for pain intensity, disability and quality of life (p < 0.05). Relaxation training, aerobic and active/stretching exercises had significant effect on pain intensity and disability (p < 0.05). To conclude, few hands-off therapies were effective on selected headache outcomes. Evidence to support other hands-off therapies is limited by paucity of studies.


Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-year results of a randomized clinical trial--VIP report no. 3.
To report 24-month vision and fluorescein angiographic outcomes from trials evaluating photodynamic therapy with verteporfin in patients with subfoveal choroidal neovascularization (CNV) caused by pathologic myopia. Multicenter, double-masked, placebo-controlled, randomized clinical trial at 28 ophthalmology practices in Europe and North America. Patients with subfoveal choroidal neovascular lesions caused by pathologic myopia measuring no more than 5400 micro m and best-corrected visual acuity (approximate Snellen equivalent) of 20/100 or better. Similar to methods described for 1-year results with follow-up examinations beyond 1 year, continuing every 3 months (except Photograph Reading Center evaluations only at the month 24 examination). During the second year, the same regimen (with verteporfin or placebo as applied at baseline) was used if angiography showed fluorescein leakage from CNV. The primary outcome was the proportion of eyes with fewer than 8 letters (approximately 1.5 lines) of visual acuity loss at the month 24 examination, adhering to an intent-to-treat analysis and using the last observation carried forward method to impute for any missing data. Seventy-seven of 81 patients (95%) in the verteporfin group, compared with 36 of 39 patients (92%) in the placebo group, completed the month 24 examination. At this time point, 29 of 81 verteporfin-treated patients (36%) compared with 20 of 39 placebo-treated patients (51%) lost at least 8 letters (P = 0.11). The distribution of change in visual acuity at the month 24 examination was in favor of a benefit for the cases assigned to verteporfin (P = 0.05). This included improvement by at least 5 letters (equivalent to at least 1 line) in 32 verteporfin-treated cases [40%] vs. five placebo-treated cases (13%) and improvement by at least 15 letters (equivalent to at least 3 lines) in 10 verteporfin-treated cases (12%) vs. zero placebo-treated cases. No additional photosensitivity adverse reactions or injection site adverse events were associated with verteporfin therapy in the second year of follow-up. Verteporfin therapy for subfoveal CNV caused by pathologic myopia safely maintained a visual benefit compared with a placebo therapy through 2 years of follow-up. Although the primary outcome was not statistically significantly in favor of verteporfin therapy at 2 years as it had been at 1 year of follow-up, the distribution of change in visual acuity at the month 24 examination was in favor of the verteporfin-treated group and showed that this group was more likely to have improved visual acuity through the month 24 examination. The VIP Study Group recommends verteporfin therapy for subfoveal CNV resulting from pathologic myopia based on both the 1- and 2-year results of this randomized clinical trial.


Clinicopathologic features and outcomes in patients with diffuse sclerosing variant of papillary thyroid carcinoma.
Diffuse sclerosing variant (DSV) of papillary thyroid carcinoma (PTC) is a rare variant more common among younger patients. Excluding patients with microcarcinoma, 5848 patients with PTC underwent initial surgery between 1995 and 2011. Twenty-two patients (0.4 %) were histologically diagnosed with DSV, of whom 20 (91 %) were <45 years old. We compared clinicopathologic characteristics and outcomes between patients with DSV and those with classical PTC <45 years old. Univariate analysis by the Kaplan-Meier method in relation to cause-specific survival (CSS) and disease-free survival (DFS) rates was performed with regard to the following variables: sex; anti-thyroglobulin antibody (TgAb) positivity; presence of distant metastasis; pathological lymph node metastasis; extra-thyroidal invasion; and pathological variant (classical vs. DSV). The 20 patients with DSV <45 years old comprised 18 females and 2 males. Frequencies of TgAb, pN1b, and local recurrence were higher in the DSV group than in the classical PTC group. Ten-year CSS and DFS rates for PTC patients <45 years old were 99.7 and 88.6 % in the classical PTC group and 100 and 60.5 % in the DSV group. CSS rate did not differ between groups, but DFS rate was significantly lower in the DSV group than in the classical PTC group (p < 0.0001, log-rank test). Multivariate analysis identified DSV group and pN1b as prognostic factors for recurrence in young PTC patients. Most DSV patients were young and had a background of chronic thyroiditis. Outcomes for DSV were very good, but recurrence was more common than in classical PTC.


Optical detection of synaptically induced glutamate transport in hippocampal slices.
Although it has long been believed that glial cells play a major role in transmitter uptake at synapses in the CNS, the relative contribution of glial and neuronal cells to reuptake of synaptically released glutamate has been unclear. Recent identification of the diverse glutamate transporter subtypes provides an opportunity to examine this issue. To monitor glutamate transporter activity, we optically detected synaptically induced changes of membrane potential from hippocampal CA1 field in slice preparations using a voltage-sensitive dye, RH155. In the presence of ionotropic glutamate-receptor blockers, synaptic inputs gave rise to a slow depolarizing response (SDR) in the dendritic field. The amplitude of SDR correlated well with presynaptic activities, suggesting that it was related to transmitter release. The SDR was found to be caused by the activities of glutamate transporters because it was not affected by blockers for GABAA, nACh, 5-HT3, P2X, or metabotropic glutamate receptors but was greatly reduced by dihydrokainate (DHK), a specific blocker for GLT-1 transporter, and by D, L-threo-beta-hydroxyaspartate (THA), a blocker for EAAC, GLAST, and GLT-1 transporters. When SDR was detected with RH482 dye, which stains both glial and neuronal cells, 1 mM DHK and 1 mM THA were equally effective in suppressing SDR. The SDR was very small in GLT-1 knockout mice but was maintained in gerbil hippocampi in which postsynaptic neurons were absent because of ischemia. Because GLT-1 transporters are exclusively expressed in astrocytes, our results provide direct evidence that astrocytes play the dominant role in sequestering synaptically released glutamate.


Prognostic effect of categorized tumor deposits in gastric cancer: A single-center retrospective study.
Tumor deposits are defined as all types of isolated cancer lesions without lymphocyte aggregates considered part of the lymph node. Tumor deposits have been reported as a negative prognostic factor. However, the survival significance of categorized tumor deposits is uncertain, particularly in gastric cancer. This study aimed to investigate the prognostic difference among categorized tumor deposits. Patients who underwent gastrectomy for gastric cancer were enrolled. All tumor deposits were categorized into irregular nodule, irregular nodule star, smooth nodule, and vascular/neural invasion. There are some cases with more than 2 categorized tumor deposits. These cases were categorized as tumor deposit complex in the following analysis. We performed survival analysis between the patients with and without tumor deposits, and compared the survival among each categorized tumor deposit. Of 868 patients, there were 96 (11.1%) and 772 (88.9%) patients with and without tumor deposits. Vascular/neural invasion, smooth nodule, irregular nodule, irregular nodule star, and the tumor deposits complex was observed in 6 (6.3%), 15 (15.6%), 43 (44.8%), 1 (1.0%), and 31 (32.3%) patients. Patients with tumor deposits displayed poorer survival than those without; the 3-year overall survival: tumor deposits negative = 87.0%, tumor deposits positive = 53.2% (P < .001). Survival analysis revealed tumor deposits can be a prognostic risk factor (hazard ratio: 1.9854, 95% confidence interval: 1.393-2.830, P < .01). Irregular nodule and the tumor deposits complex demonstrated the worst prognosis (irregular nodule 3-year overall survival: 51.2%, tumor deposits complex 3-year overall survival: 41.9%, P = .001), whereas smooth nodule demonstrated better prognosis (smooth nodule 3-year overall survival: 80%). Tumor deposits exerted a negative survival effect in gastric cancer. Irregular nodule and the tumor deposits complex displayed a strong prognostic effect.


Identification, genotypic relation, and clinical features of colistin-resistant isolates of Acinetobacter genomic species 13BJ/14TU from bloodstreams of patients in a university hospital.
Colistin resistance remains rare among clinical isolates of Acinetobacter species. We noted the emergence of colistin-resistant bloodstream isolates of the Acinetobacter genomic species (GS) 13BJ/14TU from patients at a university hospital between 2003 and 2011. We report here, for the first time, the microbiological and molecular characteristics of these isolates, with clinical features of Acinetobacter GS 13BJ/14TU bacteremia. All 11 available patient isolates were correctly identified as Acinetobacter GS 13BJ/14TU using partial rpoB gene sequencing but were misidentified using the phenotypic methods Vitek 2 (mostly as Acinetobacter baumannii), MicroScan (mostly as A. baumannii/Acinetobacter haemolyticus), and the API 20 NE system (all as A. haemolyticus). Most isolates were susceptible to commonly used antibiotics, including carbapenems, but all were resistant to colistin, for which it is unknown whether the resistance is acquired or intrinsic. However, the fact that none of the patients had a history of colistin therapy strongly suggests that Acinetobacter GS 13BJ/14TU is innately resistant to colistin. The phylogenetic tree of multilocus sequence typing (MLST) showed that all 11 isolates formed a separate cluster from other Acinetobacter species and yielded five sequence types. However, pulsed-field gel electrophoresis (PFGE) revealed 11 distinct patterns, suggesting that the bacteremia had occurred sporadically. Four patients showed persistent bacteremia (6 to 17 days), and all 11 patients had excellent outcomes with cleared bacteremia, suggesting that patients with Acinetobacter GS 13BJ/14TU-associated bacteremia show a favorable outcome. These results emphasize the importance of precise species identification, especially regarding colistin resistance in Acinetobacter species. In addition, MLST offers another approach to the identification of Acinetobacter GS 13BJ/14TU, whereas PFGE is useful for genotyping for this species.


Failure of an uncemented press-fit acetabular cup in primary total hip arthroplasty.
We reviewed fifteen primary total hip replacements performed using the uncemented, non-porous coated press-fit AcSys Shearer Cup. A modular titanium straight femoral stem with a 32mm head was used in all cases. The mean age of the group containing five males and 10 females was 66 years. Eight cups have been revised for aseptic loosening at a mean of seven years and the remaining four cups are radiologically loose. At revision surgery none of the cups showed any evidence of bony ingrowth. Our 10-year results with this cup indicate an unacceptably high failure rate of 80%. Absence of bony ingrowth and the lack of a secure locking mechanism between the polyethylene liner and the metal shell are the most important causes of failure. The use of a 32-mm diameter head and implantation of the cup in an open position contributed to this failure. Even though this cup is no longer manufactured, our experience suggests that all non-porous coated cups should be closely followed up. (Hip International 2002; 4: 371-7).


Influence of flexion angle of files on the decentralization of oval canals during instrumentation.
The aim of this study was to evaluate the influence of the flexion angle of files on the decentralization of root canals during instrumentation. Fifteen lower incisors were instrumented with Protaper Universal files and radiographed in two directions (mesiodistal and buccolingual) before and after instrumentation with a #15 K-file in position for evaluating the flexion angle of files. The specimens were also scanned before and after instrumentation using micro-computed tomography to obtain the canal area and the distance from the center position of the file to the canal walls. Sections located 1.0 mm (end of the canal), 3.0 mm (apical third), 9.0 mm (middle third), and 15.0 mm (cervical third) from the apex were verified. After instrumentation, the flexion angles of files decreased by an average of 0.76º in the buccolingual direction and 1.92º in the mesiodistal direction (p < 0.001); the canal area increased by an average of 0.58, 0.37, 0.23 and 0.13 mm(2) from the cervical to the end of the root canal (p < 0.001). Non-instrumented areas were observed on the buccal and lingual walls, and effective action of files was determined on the mesial and distal walls. The sections from the end of the canal showed canal deviation toward the lingual wall, whereas the other sections showed deviation toward the buccal wall. The flexion angles of files influence the final shape of the root canal, resulting in file decentralization along the pathway of the canal.


Serum Cholesterol and Impact of Age on Coronary Heart Disease Death in More Than 4 Million Veterans.
Background The lipid hypothesis postulates that lower blood cholesterol is associated with reduced coronary heart disease (CHD) risk, which has been challenged by reports of a U-shaped relation between cholesterol and death in recent studies. We sought to examine whether the U-shaped relationship is true and to assess the impact of age on this association. Method and Results We conducted a prospective cohort study of 4 467 942 veterans aged >18 years, with baseline outpatient visits from 2002 to 2007 and follow-up to December 30, 2018, in the Veterans Health Administration electronic health record system. We observed a J-shaped relation between total cholesterol (TC) and CHD mortality after a comprehensive adjustment of confounding factors: flat for TC <180 mg/dL, and greater risk was present at higher cholesterol levels. Compared with veterans with TC between 180 and 199 mg/dL, the multiadjusted hazard ratios (HRs) for CHD death were 1.03 (95% CI, 1.02-1.04), 1.07 (95% CI, 1.06-1.09), 1.15 (95% CI, 1.13-1.18), 1.25 (95% CI, 1.22-1.28), and 1.45 (95% CI, 1.42-1.49) times greater among veterans with TC (mg/dL) of 200 to 219, 220 to 239, 140 to 259, 260 to 279 and ≥280, respectively. Similar J-shaped TC-CHD mortality patterns were observed among veterans with and without statin use at or before baseline. Conclusions The cholesterol paradox, for example, higher CHD death in patients with a low cholesterol level, was a reflection of reverse causality, especially among older participants. Our results support the lipid hypothesis that lower blood cholesterol is associated with reduced CHD. Furthermore, the hypothesis remained true when TC was low due to use of statins or other lipid-lowering medication.


Rate and Predictors of Intractable Status Migrainosus among Patients Aged 13-18 Years.
To assess associations for intractable status migrainosus in the pediatric inpatient setting. A retrospective cohort study of 1,805 patients presenting to the pediatric hospital in Dayton, Ohio with status migrainosus from 2017 to 2022, was performed. Among 1,805 patients, 159 received 3 lines of sequentially more aggressive abortive migraine treatment and were included in this analysis. Responders and non-responders were categorized based on a visual analogue scale (VAS) of pain scores from time of admission to discharge with responders having a reduction of 50% or greater in VAS. Patient demographic information, migraine history, headache type, medication history, self-reported pain, anxiety level and co-morbidities were assessed. Out of 159 patients, 125 (78.6%) achieved the target pain control with decrease in VAS pain score by ≥ 50% from the baseline. The remaining 34/159 (21.4%) patients remained refractory to treatment. Non-responder patients had a longer hospital stay (6.1 days) and greater readmission rate within 7 days (17.6%) compared to responders (4.7 days and .8% respectively). Among the non-responder patients, 14/34 (41.2%) had attention-deficit/hyperactivity disorder (ADHD) compared to the responder group in which 17/125 (13.6%) had ADHD. Among patients who had comorbidity of anxiety, non-responders had greater severe generalized anxiety disorder (GAD-7 ≥15) (6/14, 42.9%) than responders (2/39, 5.1%). ADHD and severe GAD are associated with poorer response to treatment in pediatric patients with refractory migraine admitted for inpatient therapy. This study highlights the prolonged hospital stay and modest clinical outcomes seen with intractable migraine in 13-18-year-old pediatric patients.


Molecular analysis of pancreatic juice: a helpful tool to differentiate benign and malignant pancreatic tumors?
Chronic pancreatitis is an important predisposing condition leading to pancreatic carcinoma. As the differential diagnosis between these diseases may be difficult in 1 patient, the detection of specific tumor markers in pancreatic juice is an attractive diagnostic tool. Many studies have investigated tumor-mediated molecular alterations of the pancreatic juice, as k-ras mutations, telomerase reactivation, or promoter methylation of the tumor-suppressor genes p16INK4a and p14ARF. In this overview, we summarize these studies and conclude that molecular analysis of pancreatic juice is not useful for everyday care today. The high specificity of molecular alterations in pancreatic cancer in some pilot studies is waiting to be reproduced in large prospective trials, and has the potential to be a strong complementary marker of malignancy in patients with a pancreatic mass of uncertain dignity.


Apolipoprotein M and Sphingosine-1-Phosphate Receptor 1 Promote the Transendothelial Transport of High-Density Lipoprotein.
Objective: ApoM enriches S1P (sphingosine-1-phosphate) within HDL (high-density lipoproteins) and facilitates the activation of the S1P1 (S1P receptor type 1) by S1P, thereby preserving endothelial barrier function. Many protective functions exerted by HDL in extravascular tissues raise the question of how S1P regulates transendothelial HDL transport. Approach and Results: HDL were isolated from plasma of wild-type mice, Apom knockout mice, human apoM transgenic mice or humans and radioiodinated to trace its binding, association, and transport by bovine or human aortic endothelial cells. We also compared the transport of fluorescently-labeled HDL or Evans Blue, which labels albumin, from the tail vein into the peritoneal cavity of apoE-haploinsufficient mice with (apoE-haploinsufficient mice with endothelium-specific knockin of S1P1) or without (control mice, ie, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1) endothelium-specific knockin of S1P1. The binding, association, and transport of HDL from Apom knockout mice and human apoM-depleted HDL by bovine aortic endothelial cells was significantly lower than that of HDL from wild-type mice and human apoM-containing HDL, respectively. The binding, uptake, and transport of 125I-HDL by human aortic endothelial cells was increased by an S1P1 agonist but decreased by an S1P1 inhibitor. Silencing of SR-BI (scavenger receptor BI) abrogated the stimulation of 125I-HDL transport by the S1P1 agonist. Compared with control mice, that is, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1, apoE-haploinsufficient mice with endothelium-specific knockin of S1P1 showed decreased transport of Evans Blue but increased transport of HDL from blood into the peritoneal cavity and SR-BI expression in the aortal endothelium. Conclusions: ApoM and S1P1 promote transendothelial HDL transport. Their opposite effect on transendothelial transport of albumin and HDL indicates that HDL passes endothelial barriers by specific mechanisms rather than passive filtration.


Experimental Models of Hospital-Acquired Infections after Traumatic Brain Injury: Challenges and Opportunities.
Patients hospitalized after a moderate or severe traumatic brain injury (TBI) are at increased risk of nosocomial infections, including bacterial pneumonia and other upper respiratory tract infections. Infections represent a secondary immune challenge for vulnerable TBI patients that can lead to increased morbidity and poorer long-term prognosis. This review first describes the clinical significance of infections after TBI, delving into the known mechanisms by which a TBI can alter systemic immunological responses towards an immunosuppressive state, leading to promotion of increased vulnerability to infections. Pulmonary dysfunction resulting from respiratory tract infections is considered in the context of neurotrauma, including the bidirectional relationship between the brain and lungs. Turning to preclinical modeling, current laboratory approaches to study experimental TBI and lung infections are reviewed, to highlight findings from the limited key studies to date which have incorporated both insults. Then, practical decisions for the experimental design of animal studies of post-injury infections are discussed. Variables associated with the host animal, the infectious agent (e.g., species, strain, dose, and administration route), as well as the timing of the infection relative to the injury model, are important considerations for model development. Together, the purpose of this review is to highlight the significant clinical need for increased preclinical research into the two-hit insult of a hospital-acquired infection after TBI to encourage further scientific enquiry in the field.


Effective use of computer simulations in an introductory neuroscience laboratory.
Introductory Neuroscience courses are being offered more regularly at diverse institutions. On the other hand, the creation of an independent laboratory curriculum for introductory neuroscience courses puts a strain on financial and human resources of a small college. A solution to this situation might be presented through the use of relevant simulation software in order to eliminate the binding of resources; but nevertheless, provide sufficient, effective, and engaging education to students. This paper suggests the use of a combination of different software during Introductory Neuroscience laboratory sessions, which are finely tuned with the material presented during lecture. Two student cohorts were evaluated and compared using three types of measures: exam grades, course evaluations, and software evaluations. The results show that the use of software simulations had a positive effect on the performance of students on exams, and on the favorability of course ratings. The findings suggest the use of software simulations for Introductory Neuroscience courses to be beneficial for the learning experience of the students.


The level of antibody against E6 HPV 16 oncoprotein in blood sera of women with chronic HPV 16 infection and cervical cancer.
The aim of this study was to estimate of the role of chronic HPV 16 infection and the presence of anti E6 HPV 16 in the initiation of the cancerogenesis process of cervical cancer. The study included two groups of patients. The first group comprised 323 women observed for three consecutive years (1998-2000), in whom the presence of HPV 16 viruses was estimated by PCR, and the level of anti E6 HPV 16 antibodies was estimated in the plasma with ELISA. A similar test was performed in a group of 46 patients with cervical intraepithelial neoplasia (CIN), 91 patients with invasive cervical cancer and 22 women after hysterectomy and RTG-therapy. In 32 patients, chronic HPV 16 infection showed a steady rise in the mean absorbance level of anti E6 HPV 16 antibodies from 0.04 in 1998 to 0.06 in 2000, while in HPV-negative women the mean absorbance value was 0.03-0.04. Mean absorbance value in patients with CIN III and invasive cancer rose with advancing stage of the cancer process and lowered after completion of oncological treatment. The values were 0.14, 0.33 and 0.13, respectively. The persistence of chronic HPV 16 infection and accompanying steady rise in absorbance index caused by an increase in the level of antiviral antibodies are a clear warning signal preceding in time the histological process of cancerogenesis.


Physical activity and other health-risk behaviors during the transition into early adulthood: a longitudinal cohort study.
Research consistently demonstrates that physical activity declines with age. However, such declines do not occur linearly. The transition into early adulthood is one period in which disproportionate declines in physical activity have been evident, but much of our understanding of such declines among young adults has been based on either cross-sectional data or prospective studies that focus exclusively on college/university students. The purpose of the current study was to use multilevel modeling to discern patterns of physical activity based on gender and educational trajectory among a nationally representative cohort of Canadian adolescents (N=640; ages at baseline, 12-15 years). Examinations of smoking and binge drinking also were conducted as a basis for comparison. Drawn from seven cycles of the National Population Health Survey (NPHS), participants were interviewed every 2 years from 1994-1995 to 2006-2007; data analysis was conducted in 2010. Overall, there was a 24% decrease in physical activity (equivalent to 1 MET/day) across the 12-year period. A significant three-way time X gender X educational trajectory interaction (coefficient= -0.189, SE=0 .09, p<0.05) emerged in the physical activity analysis; main effects in time(2) (coefficient= -0.114, SE=0.01, p<0.01) and time(3) (coefficient=0.028, SE=0.01, p<0.01) were significant for binge drinking and smoking, respectively. Physical activity decline was evident during young adults' transition into early adulthood, with declines being steepest among men who entered a college/university. Although there were increases in several health-risk behaviors during adolescence, individuals tend to grow out of binge drinking and smoking as they mature.


Attitude towards the Practice of Female Genital Cutting among School Boys and Girls in Somali and Harari Regions, Eastern Ethiopia.
Introduction. Female genital cutting (FGC) is a harmful traditional practice that violates women's rights and threatens their health. Although much work has been done to tackle this practice in Ethiopia, the prevalence remains very high in Somali and Harari regions. This study aims to investigate the attitude towards FGC of young people (boys and girls) in Somali and Harari regions of Eastern Ethiopia. Methods. A cross-sectional quantitative study was carried out in Somali and Harari regions from October to December 2015. Two districts were purposely selected from the two regions, and a stratified random sampling technique was employed to select 480 subjects from the randomly selected schools. Results. Out of 480 questionnaires distributed, 478 (99.6%) respondents filled the questionnaires and returned them. The finding of the study reveals that 86% of study participants condemn the practice of FGC. Almost 59% of male participants from both study areas preferred to marry uncircumcised girls. Being a female and being a Muslim are significantly associated with the support toward the continuation of the FGC (P < 0.05). Conclusion. Although the study demonstrates a positive attitude towards the abandonment of FGC, there is a need to increase the knowledge about the position of Islam in FGC and to educate women about the harmful effect of FGC.


[Lupus nephropathy. Treatment with the indomethacin-hydroxychloroquine combination and comparison with corticoids].
The authors report their comparative experience of the treatment of proliferative lupus glomerulonephritis using prednisone (16 patients) or the indomethacin-hydroxychloroquine association (12 patients). Prednisone in high dosage was associated in this series with 9 deaths and in 6 patients, with renal failure or an extra-renal complication. By contrast, the indomethacin-hydroxychloroquine association proved to be highly effective, without side-effect. In the endocapillary glomerulonephritis group (8 cases) the authors obtained 7 durable remissions (36.3 months on average) and 1 temporary remission of 24 months, with an average length of treatment of 45.8 months. In the extracapillary glomerulonephritis group (4 cases) the authors obtained 1 remission, 2 improvements and I death, with an average length of treatment of 16.8 months. This combination has a highly significant anti-proteinuric and anti-haematuric action, with a constant efficiency on renal function and on the extra-renal signs of lupus. Its effect is less constant on the immunological disorders. Study of iterative renal biopsies confirms this favourable impression. According to these results, the authors propose a provisional scheme of management of proliferative lupus glomerulonephritis.


Our doctors are joining a labor union!
Are physicians going to join a union at your hospital, multi-specialty group, or HMO? Having recently lived through such an experience, the author shares the lessons that he has learned. This article outlines what physician executives need to do to prepare for the increasingly likely eventuality of physicians at their hospitals making a push for unionization. The best way to avoid a union is to manage people fairly, communicate with them constantly, and develop consensus for difficult decisions whenever possible. But if a petition lands on your desk, it is crucial to understand the laws governing union campaigns and the possible outcomes. From how to respond to a petition to election campaign strategies to the negotiation phase, physician executives need to be prepared for the very real possibility of physicians at their organizations deciding to unionize.


The Veterans Affairs Cardiac Risk Score: Recalibrating the Atherosclerotic Cardiovascular Disease Score for Applied Use.
Accurately estimating cardiovascular risk is fundamental to good decision-making in cardiovascular disease (CVD) prevention, but risk scores developed in one population often perform poorly in dissimilar populations. We sought to examine whether a large integrated health system can use their electronic health data to better predict individual patients' risk of developing CVD. We created a cohort using all patients ages 45-80 who used Department of Veterans Affairs (VA) ambulatory care services in 2006 with no history of CVD, heart failure, or loop diuretics. Our outcome variable was new-onset CVD in 2007-2011. We then developed a series of recalibrated scores, including a fully refit "VA Risk Score-CVD (VARS-CVD)." We tested the different scores using standard measures of prediction quality. For the 1,512,092 patients in the study, the Atherosclerotic cardiovascular disease risk score had similar discrimination as the VARS-CVD (c-statistic of 0.66 in men and 0.73 in women), but the Atherosclerotic cardiovascular disease model had poor calibration, predicting 63% more events than observed. Calibration was excellent in the fully recalibrated VARS-CVD tool, but simpler techniques tested proved less reliable. We found that local electronic health record data can be used to estimate CVD better than an established risk score based on research populations. Recalibration improved estimates dramatically, and the type of recalibration was important. Such tools can also easily be integrated into health system's electronic health record and can be more readily updated.


Surface-Charge-Switchable Nanoclusters for Magnetic Resonance Imaging-Guided and Glutathione Depletion-Enhanced Photodynamic Therapy.
Photodynamic therapy (PDT) is an effective noninvasive therapeutic method that employs photosensitizers (PSs) converting oxygen to highly cytotoxic singlet oxygen (1O2) under light irradiation. The conventional PDT efficacy is, however, compromised by the nonspecific delivery of PSs to tumor tissue, the hypoxic tumor microenvironment, and the reduction of generated 1O2 by the intracellular antioxidant glutathione (GSH). Herein, an intelligent multifunctional synergistic nanoplatform (CMGCC) for T1-weighted magnetic resonance (MR) imaging-guided enhanced PDT is presented, which consists of nanoparticles composed of catalase (CAT) and manganese dioxide (MnO2) that are integrated within chlorin-e6-modified glycol chitosan (GC) polymeric micelles. In this system, (1) GC polymers with pH-sensitive surface charge switchability from neutral to positive could improve the PS accumulation within the tumor region, (2) CAT could effectively reoxygenate the hypoxic tumor via catalyzing endogenous hydrogen peroxide to O2, and (3) MnO2 could consume the intracellular GSH while simultaneously producing Mn2+ as a contrast agent for T1-weighted MR imaging. The CMGCC particles possess uniform size distribution, well-defined structure, favorable enzyme activity, and superior 1O2 generation ability. Both in vitro and in vivo experiments demonstrate that the CMGCC exhibit significantly enhanced PDT efficacy toward HeLa cells and subcutaneous HeLa tumors. Our study thereby demonstrates this to be a promising synergistic theranostic nanoplatform with highly efficient PDT performance for cancer therapy.


Genomic fingerprinting of Haemophilus somnus by a combination of PCR methods.
Twenty-three isolates of Haemophilus somnus were typed by repetitive extragenic palindromic (REP) element-based PCR, enterobacterial repetitive intergenic consensus (ERIC)-based PCR, and PCR ribotyping. A total of 11 types were distinguished by REP-PCR, 13 types were distinguished by ERIC-PCR, and 5 types were distinguished by PCR ribotyping. PCR ribotyping produced a relatively simple pattern and a small number of distinct types, whereas REP- and ERIC-PCR both produced more complex banding patterns but increased the discrimination between strains. Clearly distinguishable profiles were obtained for respiratory and genital isolates of H. somnus by all three typing methods. The results suggest that a combination of all three primer sets provides a high-resolution fingerprinting method for epidemiological studies of H. somnus and for its differentiation from related species.


Morphological variation in vanishing Mexican desert fishes of the genus Characodon (Goodeidae).
This study investigated a rapidly vanishing group of fishes in the genus Characodon (including Characodon lateralis and Characodon audax) from the upper Rio Mezquital drainage in Mexico. Using specimens from museum collections, morphological variation was assessed to quantify body shape differentiation among historic (i.e. extirpated and extant) collection sites. In both sexes, body shape (particularly head shape, the proportion of the caudal peduncle and the position and size of dorsal and anal fins) varied significantly among populations and species. Variation among collection sites could at least partially be attributed to geography, as the presence of distinct hydrographic units and a major waterfall coincided with major body shape differences. These results are discussed in the light of previously published molecular genetic analyses, as they have direct implications for taxonomic problems and the need for conservation measures for these endangered fishes.


[AIDS and hemophilia in pediatrics: report of a case].
It is reported the case of a 12-year-old white school boy with diagnosis of degree III hemophilia A since he was 2 months old that had received innumerable transfusions of cryoprecipitate and several of blood. In 1999, he was diagnosed hepatitis C and, at the end of 2000, HIV infection. There was a high possibility of having acquired them both by the blood and hemoderivative transfusions received. As very low figures of TCD4 lymphocytes (4%) with 54 cells/mm3 were corroborated on conducting immunological studies, it was classified as group B-3 AIDS, according to the classification established by the CDC of Atlanta, in 1994. He was indicated antiretroviral treatment with tritherapy (d4T, 3TC and Nelfinavir). This case was reported to call the attention of doctors at the time of indicating treatment with antivirals or protease-inhibitors to fight AIDS in pediatric cases with diagnosis of hemophilia, since some of them may cause spontaneous bleeding episodes.


Behavioural treatment of urinary incontinence and encopresis in children with learning disabilities: transfer of stimulus control.
Urinary and faecal incontinence present a considerable problem in people with learning disabilities, despite the general effectiveness of behavioural techniques in continence training. Children with learning disabilities and obsessional behaviour may be particularly resistant to toilet training, even where relatively cognitively able, and often despite a substantial degree of control over their eliminatory functions. Their resistance may be more appropriately regarded as a challenging behaviour and their incontinence better explained by factors other than a simple failure to learn. A 'stimulus-control' hypothesis proposes that the child's nappy (diaper)/potty/underwear has developed strong stimulus control over the elimination response. This report describes three case studies in which treatment-resistant children, aged between 8 and 12 years, with mild or moderate learning disabilities, were successfully treated for nappy-dependent nocturnal encopresis or diurnal urinary incontinence. The children were routine case referrals for whom previous attempts to train bowel or bladder control had failed. Behavioural techniques, such as 'shaping' (gradually increasing the proximity to the toilet), 'fading' (reducing the presence of the nappy), and rewards for eliminating, effected successful transfer of stimulus control over elimination from nappy to toilet. Treatment times varied, depending on the degree of the child's obsession and resistance to change.


[Development and dissemination of malignant tumors, and hemostasis].
Strong circumstantial evidence suggests that the activation of the hemostatic system is involved in the growth and spread of malignant tumors. Nevertheless, the considerable experimental and clinical data presently available cannot be interpreted in one specific direction. The presence of a fibrin and/or a platelet thrombus in the environment of tumor cells only represents the visible end product of a complex biochemical and biophysical process during which other phenomena like haemodynamic changes and the generation of many biologically active enzymes occur. In the interpretation of experimental studies and clinical trials of anticoagulants in cancer disease, a wider concept of the hemostatic process and its multiple interactions with other biological systems is needed. The complement system, adhesive glycoproteins of the cell surface, chemotaxis, growth factors and prostaglandins are some examples of factors which interact with the hemostatic system as well as with the pathology of cancer. The definite pathogenic connection between the clinically observed hypercoagulability of patients with malignant disease and the biology of tumor growth and tumor dissemination remains unclear. Agents which modify hemostatic reactions must be evaluated in specific tumor categories using carefully controlled prospective trials. The results of such studies on tumor regression and also on longevity will permit to assess the efficacy of these agents as adjuvant therapy in the treatment of cancer.


A systematic review of food protein-induced enterocolitis syndrome from the last 40 years.
To provide a complete, exhaustive summary of current literature relevant to food protein-induced enterocolitis syndrome (FPIES). Data have been extracted from PubMed and Science Direct databases. Following the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, a literature search for peer-reviewed journal articles in English through January 1975 with updates through October 2016 was conducted. Relevant publications were reviewed that included pediatric and adult populations. Information on the study design, sample, intervention, comparators, outcome, timeframe, and risk of bias were abstracted for each article. Of 135 reviewed reports, 52 were included in this systematic review. In accordance with the age at onset, clinical features, and offending foods, it is possible to distiguish different types of FPIES. An immune systemic involvement can occur in patients with FPIES. In addition to the most common causative foods (cow's milk, soy, and rice), any food can potentially cause FPIES. Although specific diagnostic tests are not available, open food challenge remains the gold standard for FPIES diagnosis. Moreover, because of the lack of randomized clinical trials and of use of different adopted methods, confounding factors might mask critical findings, leading to poor knowledge of this pleiotropic clinical entity. Multicenter studies are needed to better develop an evidence-based approach to pathophysiology, prevalence, diagnosis, and natural history of the disease.


[Inhalation techniques in the treatment of asthma].
In the pharmacological treatment of asthma, the most suitable way is by inhalation, since this enables us to achieve a greater concentration of medicine in the affected organ than systemic medication, and besides the latter's secondary effects are minimized. The suitable use of inhalers and hence their efficacy depends on very different factors. Some of those of a merely technical kind are as follows: A suitable volume of inhalation. The rhythm of inhalation. The length of the inspiratory apnea following administration of the medicine. The coordination between the inspiration of the aerosol and activation of the device, in the case of the metered dose inhaler (MDI). One of the reasons for the incorrect use of MDI aerosols is the lack of coordination between activation of the device and inspiration. This has led to the design of different devices that avoid the need for this coordination, such as: inhalation chambers and devices for inhaling dry dust. It has also been suggested in the literature that the causes of these mistakes are to be found in the health professionals not knowing, or not suitably teaching the patients how to handle the devices. In spite of being designed to facilitate correct administration, suitable knowledge of the technique of their use by the patient is required.


Dorsomedial forebrain ablations and home loft association behavior in homing pigeons.
In a series of experiments which involved only short distance experimental releases (800 m or less and within view of the home loft), it was demonstrated that dorsomedial forebrain ablated pigeons generally failed to reassociate with their home loft if the postablation experimental release took place soon postablation or if during the time between ablation and experimental release they were kept away from their home loft. In contrast, if dorsomedial forebrain ablated pigeons were allowed to recover at their home loft prior to experimental release, they succeeded in associating with their home loft in a manner similar to controls. However, only postablation exposure to a pigeon's own loft was sufficient to permit continued home loft association. Pigeons from one loft failed to associate with a foreign postablation recovery loft when released within sight of it. The results show that dorsomedial forebrain ablations result in pigeons which no longer succeed in associating with their home loft; recovery from failed home loft association behavior is possible with postablation exposure to the home loft, and a pigeon's previous association with a loft was a precondition if postablation association was to be affected. The results suggest that dorsomedial forebrain ablated pigeons retain something like a 'home loft trace' which they can use to mediate retrieval and reformation of the recognition properties needed for proper home loft association.


Drosophila CLOCK target gene characterization: implications for circadian tissue-specific gene expression.
CLOCK (CLK) is a master transcriptional regulator of the circadian clock in Drosophila. To identify CLK direct target genes and address circadian transcriptional regulation in Drosophila, we performed chromatin immunoprecipitation (ChIP) tiling array assays (ChIP-chip) with a number of circadian proteins. CLK binding cycles on at least 800 sites with maximal binding in the early night. The CLK partner protein CYCLE (CYC) is on most of these sites. The CLK/CYC heterodimer is joined 4-6 h later by the transcriptional repressor PERIOD (PER), indicating that the majority of CLK targets are regulated similarly to core circadian genes. About 30% of target genes also show cycling RNA polymerase II (Pol II) binding. Many of these generate cycling RNAs despite not being documented in prior RNA cycling studies. This is due in part to different RNA isoforms and to fly head tissue heterogeneity. CLK has specific targets in different tissues, implying that important CLK partner proteins and/or mechanisms contribute to gene-specific and tissue-specific regulation.


[ultrastructural localization of adenylate cyclase activity in the smooth muscle cells of the wall of the aorta and the kidney].
As the data on estimation of adenylate cyclase activity in the aortic and nephric tissue have demonstrated the product of histochemical reaction is localized in sarcolemmic vesicles of the aortic wall smooth muscle and on the plasmic membrane of the brush border microvilli in the proximal tubules of the kidney. From our knowledge on how some hormones affect the cell via the intracellular mediator cAMP, which is formed from Atp at activation of the adonylate cyclase system, it is possible to suggest that sarcolemmic vesicles of the smooth muscle cells and separate parts in plasmolemma of the brush border of the proximal tubules correspond to the adenylate cyclase system in the receptory zones where the hormones interact with the cell. It is interesting to note topographic coincidence in one ultrastructure--sarcolemmic vesicules--of the adenylate cyclase system and a sarcolemmic area through which calcium ions (the primary regulator of contractility) are excreted at relaxing action of beta-adrenergetics on the smooth muscles.


Lessons learned from employee fitness programs at the Marshfield Clinic.
To describe and evaluate employee fitness programs at the Marshfield Clinic. A 16-week program was offered to employees from April-July 2004, and a 12-week program was offered from August-November, 2004. Weekly e-mails included suggestions to increase physical activity and eat a healthy diet. Incentives were offered for meeting program goals. A total of 1129 employees signed up for the first program (approximately 18% of all employees) and 610 for the second program. More than 95% of the participants in both programs were female. The activity program goal was met by 231 (20.5%) participants in the first program and 31% (n = 190) of participants in the second program. There was a significant increase in the percent of people with good or excellent fitness levels from baseline (46.4%, 95% CL = 40.5, 52.3) to follow-up (70.7%, 95% CL = 65.3, 76.0) in the first program. In the second program, there was a significant association between the number of program goals met and self-report of having increased energy, better weight control, and feeling better overall and about body image. Emphasis in future programs should be placed on increasing employee participation. Program evaluation could be expanded to include health care costs and employee absenteeism.


Biomechanical Evaluation of Different Fixation Methods for Mandibular Anterior Segmental Osteotomy Using Finite Element Analysis, Part Two: Superior Repositioning Surgery With Bone Allograft.
In this study, the biomechanical behavior of different fixation methods used to fix the mandibular anterior segment following various amounts of superior repositioning was evaluated by using Finite Element Analysis (FEA). The three-dimensional finite element models representing 3 and 5 mm superior repositioning were generated. The gap in between segments was assumed to be filled by block bone allograft and resignated to be in perfect contact with the mandible and segmented bone. Six different finite element models with 2 distinct mobilization rate including 3 different fixation configurations, double right L (DRL), double left L (DLL), or double I (DI) miniplates with monocortical screws, correspondingly were created. A comparative evaluation has been made under vertical, horizontal and oblique loads. The von Mises and principal maximum stress (Pmax) values were calculated by finite element solver programme. The first part of our ongoing Finite Element Analysis research has been addressed to the mechanical behavior of the same fixation configurations in nongrafted models. In comparison with the findings of the first part of the study, it was concluded that bone graft offers superior mechanical stability without any limitation of mobilization and less stress on the fixative appliances as well as in the bone.


[Effect of a magnetic field on the fluorescence yield of Rhodopseudomonas sphaeroides cells of the wild strain and strain R-26. Relationship to temperature].
Fluorescence yield of Rhodopseudomonas sphaeroides cells whose primary acceptor is chemically reduced depends on the magnetic field tension. The maximal value of relative magnetic effect and the field value, at which the effect amounts to a half of the maximal value for R. sphaeroides wild strain and R-26, equal 3.6 and 1.1%; 260 and 120 G correspondingly at 295 K. An effect of th magnetic field on fluorescence yield for R. sphaeroides wild strain at the medium potential 300 mV was observed. The values of relative magnetic effect were shown to change within the temperature range 295-120 K. The results obtained are discussed in terms of the relationship between these parameters and the velocity constant values of the radical paris recombination (P 870(+) . Bph(-) . in singlet and triplet states and the value of metabolic interaction in the radical pairs (P 870(+) . Bph(-) .) and (Bph(-) . --X(-) .).


In vitro downregulation of matrix metalloproteinase-9 in rat glial cells by CCR5 antagonist maraviroc: therapeutic implication for HIV brain infection.
Matrix metalloproteinases (MMPs) released by glial cells are important mediators of neuroinflammation and neurologic damage in HIV infection. The use of antiretroviral drugs able to combat the detrimental effect of chronic inflammation and target the exaggerated MMP activity might represent an attractive therapeutic challenge. Recent studies suggest that CCR5 antagonist maraviroc (MVC) exerts immunomodulant and anti-inflammatory activity beyond its anti-HIV properties. We investigated the in vitro effect of MVC on the activity of MMPs in astrocyte and microglia cultures. Primary cultures of rat astrocytes and microglia were activated by exposure to phorbol myristate acetate (PMA) or lypopolysaccharide (LPS) and treated in vitro with MVC. Culture supernatants were subjected to gelatin zymography and quantitative determination of MMP-9 and MMP-2 was done by computerized scanning densitometry. MMP-9 levels were significantly elevated in culture supernatants from both LPS- and PMA-activated astrocytes and microglia in comparison to controls. The treatment with MVC significantly inhibited in a dose-dependent manner the levels and expression of MMP-9 in PMA-activated astrocytes (p<0,05) and, to a lesser extent, in PMA-activated microglia. By contrast, levels of MMP-2 did not significantly change, although a tendency to decrease was seen in PMA-activated astrocytes after treatment with MVC. The inhibition of levels and expression of MMP-9 in PMA-activated glial cells did not depend on cytotoxic effects of MVC. No inhibition of MMP-9 and MMP-2 were found in both LPS-activated astrocytes and microglia. The present in vitro study suggests that CCR5 antagonist compounds, through their ability to inhibit MMP-9 expression and levels, might have a great potential for the treatment of HIV-associated neurologic damage.


Diabetes insipidus associated with metastatic pancreatic carcinoma in a dog.
Diabetes insipidus was diagnosed in a dog with metastatic pancreatic carcinoma. Histologic examination of the pituitary gland revealed extensive invasion of the pars intermedia and neurohypophysis by metastatic tumor cells.


Prevalence of congenital heart diseases in children with Down syndrome in Mansoura, Egypt: a retrospective descriptive study.
The pattern and risk factors for congenital heart diseases (CHD) in children with Down syndrome (DS) vary over time. To update knowledge of the prevalence, types, trends and associated factors for CHD in children with DS in the Egyptian Delta. A retrospective hospital record-based descriptive study. A tertiary care center in Mansoura, Egypt during a period of 14 years from 2003 up to 2016. We studied children with genetically proven DS. Relevant sociodemographic factors, medical history, clinical examination, karyotype and echocardiographic data were statistically analyzed. Prevalence, types and risk factors of CHD in DS. The prevalence of overall, isolated and multiple CHD in 1720 children with DS were 36.9%, 29% and 8%, respectively. Isolated defects accounted for 78.4% of all CHD. Ventricular septal defect, atrioventricular septal defect and atrial septal defect were the most frequent isolated defects. There was a downward trend in the prevalence of overall CHD (from 56.2% to 25.0%) and isolated CHD (from 56.2% to 19.8%). The logistic regression model predicted 65.7% of CHD and revealed that passive maternal smoking, lack of folic acid/multivitamin supplementation and parental consanguinity were the independent predictors of CHD in children with DS with adjusted odds ratios of 1.9, 1.8 and 1.9, respectively. More than one-third of children with DS have CHD with ventricular septal defect, which is the most common. Avoidance of passive maternal smoking and consanguineous marriage together with maternal folic acid supplementation could contribute to further reduction of CHD in children with DS. Single-center study and retrospective.


Parameters affecting the efficient delivery of mesoporous silica nanoparticle materials and gold nanorods into plant tissues by the biolistic method.
Applying nanotechnology to plant science requires efficient systems for the delivery of nanoparticles (NPs) to plant cells and tissues. The presence of a cell wall in plant cells makes it challenging to extend the NP delivery methods available for animal research. In this work, research is presented which establishes an efficient NP delivery system for plant tissues using the biolistic method. It is shown that the biolistic delivery of mesoporous silica nanoparticle (MSN) materials can be improved by increasing the density of MSNs through gold plating. Additionally, a DNA-coating protocol is used based on calcium chloride and spermidine for MSN and gold nanorods to enhance the NP-mediated DNA delivery. Furthermore, the drastic improvement of NP delivery is demonstrated when the particles are combined with 0.6 μm gold particles during bombardment. The methodology described provides a system for the efficient delivery of NPs into plant cells using the biolistic method.


Dorsal versus ventral hippocampal contributions to trace and contextual conditioning: differential effects of regionally selective NMDA receptor antagonism on acquisition and expression.
The dorsal and ventral subregions of the hippocampus likely play dissociable roles in some forms of learning. For example, we have previously demonstrated that temporary inactivation of ventral, but not dorsal, hippocampus dramatically impaired the acquisition of trace fear conditioning, while temporary inactivation of dorsal, but not ventral, hippocampus impaired spatially guided reinforced alternation (Czerniawski et al. (2009) Hippocampus 19:20-32). Importantly, emerging data suggest that lesions, temporary inactivation, and NMDA receptor antagonism within these subregions can produce quite different patterns of behavioral effects when administered into the same region. Specifically, while neither lesions nor temporary inactivation of dorsal hippocampus impair the acquisition of trace fear conditioning, learning in this paradigm is severely impaired by pre-training administration of the NMDA receptor antagonist dl-2-phosphonovaleric acid (APV) in dorsal hippocampus; the effect of NMDA receptor antagonism within ventral hippocampus on the acquisition and expression of trace conditioning, or on learning in general, has not yet been systematically explored. The present study extends our previous work examining the differential effect of lesions or inactivation of the dorsal and ventral hippocampal subregions by systematically examining the effect of regionally selective pre-training or pre-testing administration of APV on the acquisition and expression of trace and contextual fear conditioning. The results of these studies demonstrate that while pre-training NMDA receptor antagonism within either the dorsal or ventral subregion of the hippocampus impaired the acquisition of both trace and contextual conditioning, pre-testing NMDA receptor antagonism within ventral, but not dorsal, hippocampus impaired the expression of previously-acquired trace and contextual fear conditioning. These data suggest that selectively manipulating the integrity of individual subregions may result in compensatory mechanisms that can support learning, and that NMDA-dependent plasticity within both dorsal and ventral hippocampus is normally required for the acquisition and maintenance of memory in trace and contextual fear conditioning.


In vitro and in vivo antitumoral effects of combinations of polyphenols, or polyphenols and anticancer drugs: perspectives on cancer treatment.
Carcinogenesis is a multistep process triggered by genetic alterations that activate different signal transduction pathways and cause the progressive transformation of a normal cell into a cancer cell. Polyphenols, compounds ubiquitously expressed in plants, have anti-inflammatory, antimicrobial, antiviral, anticancer, and immunomodulatory properties, all of which are beneficial to human health. Due to their ability to modulate the activity of multiple targets involved in carcinogenesis through direct interaction or modulation of gene expression, polyphenols can be employed to inhibit the growth of cancer cells. However, the main problem related to the use of polyphenols as anticancer agents is their poor bioavailability, which might hinder the in vivo effects of the single compound. In fact, polyphenols have a poor absorption and biodistribution, but also a fast metabolism and excretion in the human body. The poor bioavailability of a polyphenol will affect the effective dose delivered to cancer cells. One way to counteract this drawback could be combination treatment with different polyphenols or with polyphenols and other anti-cancer drugs, which can lead to more effective antitumor effects than treatment using only one of the compounds. This report reviews current knowledge on the anticancer effects of combinations of polyphenols or polyphenols and anticancer drugs, with a focus on their ability to modulate multiple signaling transduction pathways involved in cancer.


Altered inhibition-related frontolimbic connectivity in obsessive-compulsive disorder.
Recent studies have shown that response inhibition is impaired in patients with obsessive-compulsive disorder and their unaffected siblings, suggesting that these deficits may be considered a cognitive endophenotype of obsessive-compulsive disorder. Structural and functional neural correlates of altered response inhibition have been identified in patients and siblings. This study aims to examine the functional integrity of the response inhibition network in patients with obsessive-compulsive disorder and their unaffected siblings. Forty-one unmedicated patients with obsessive-compulsive disorder, 17 of their unaffected siblings and 37 healthy controls performed a stop signal task during functional magnetic resonance imaging. Psycho-physiological interaction analysis was used to examine functional connectivity between the following regions of interest: the bilateral inferior frontal gyri, presupplementary motor area, subthalamic nuclei, inferior parietal lobes, anterior cingulate cortex, and amygdala. We then used dynamic causal modeling to investigate the directionality of the networks involved. Patients, and to a lesser extent also their unaffected siblings, show altered connectivity between the inferior frontal gyrus and the amygdala during response inhibition. The follow-up dynamic causal modeling suggests a bottom-up influence of the amygdala on the inferior frontal gyrus in healthy controls, whereas processing occurs top-down in patients with obsessive-compulsive, and in both directions in siblings. Our findings suggest that amygdala activation in obsessive-compulsive disorder interferes differently with the task-related recruitment of the inhibition network, underscoring the role of limbic disturbances in cognitive dysfunctions in obsessive-compulsive disorder.


Amplitude of Accommodation in Patients with Multiple Sclerosis.
Purpose: To evaluate the effect of multiple sclerosis (MS) on the amplitude of accommodation (AA) and retinal nerve fiber layer (RNFL) thickness.Materials and Methods: A total of 25 MS patients with visual-evoked potential (VEP) abnormalities (MS/+VEP Group), 25 MS patients without VEP abnormalities (MS/-VEP Group), and 25 controls (Control Group) were enrolled. Only findings from the right eye of the participants were included in the analysis. Each participant underwent a pattern-reversal visual-evoked potential (PVEP) recording, an RNFL thickness analysis by optic coherence tomography (OCT) in all quadrants, and a measurement of amplitude of accommodation (AA) with minus lens technique. The AA and the RNFL thickness were compared between the groups.Results: The mean age and sex distributions did not differ significantly across the groups (p= .788, p= .906, respectively). The mean AA was 5.36 ± 0.7 D in MS/+VEP group, 6.06 ± 1.4 D in MS/-VEP group, and 6.4 ± 0.9 D in control group (p= .002). The difference in the mean AA values between MS/+VEP and control groups were significant (p = .002). AA was significantly correlated with age, P100 latency and amplitude values in MS/+VEP group (r = -0.832, p < .001; r = -0.596, p = .002 and r = 0.498, p = .011, respectively). In a multivariable regression model, age and P100 latency were significant parameters for affecting AA in patients with MS (p < .001 and p = .001). In another multivariable regression model, age and average RNFL thickness were significant parameters for affecting AA in patients with MS (p < .001 and p = .010).Conclusions: We found that the AA was lower in MS patients with VEP abnormalities compared to age-matched healthy individuals. P100 latency was a significant parameter for predicting AA in MS/+VEP group. These results suggest that MS patients with VEP abnormalities might experience presbyopia earlier in life than people without MS, probably due to the chronic demyelination of neural pathways.


AcpA, a member of the GPR1/FUN34/YaaH membrane protein family, is essential for acetate permease activity in the hyphal fungus Aspergillus nidulans.
In a previous study, alcS, a gene of the Aspergillus nidulans alc cluster, was shown to encode a protein that belongs to the GPR1/FUN34/YaaH membrane protein family. BLAST screening of the A. nidulans genome data identified additional genes encoding hypothetical proteins that could belong to this family. In this study we report the functional characterization of one of them, AN5226. Its expression is induced by ethanol and ethyl acetate (two inducers of the alc genes) and is mediated by the specific transcriptional activator of genes of the acetate-utilization pathway FacB. Growth of a null mutant (DeltaAN5226) is notably affected when acetate is used as sole carbon source at low concentration and in a high pH medium, i.e. when protonated acetate, the form that can enter the cell by passive diffusion, is present in low amounts. Consistently, expression of AN5226 is also induced by acetate, but only when the latter is present at low concentrations. (14)C-labelled acetate uptake experiments using germinating conidia demonstrate an essential role for AN5226 in mediated acetate transport. To our knowledge this report is the first to provide evidence for the identification of an acetate transporter in filamentous fungi. We have designated AN5226 as acpA (for acetate permease A).


Overexpression of a citrus NDR1 ortholog increases disease resistance in Arabidopsis.
Emerging devastating diseases, such as Huanglongbing (HLB) and citrus canker, have caused tremendous losses to the citrus industry worldwide. Genetic engineering is a powerful approach that could allow us to increase citrus resistance against these diseases. The key to the success of this approach relies on a thorough understanding of defense mechanisms of citrus. Studies of Arabidopsis and other plants have provided a framework for us to better understand defense mechanisms of citrus. Salicylic acid (SA) is a key signaling molecule involved in basal defense and resistance (R) gene-mediated defense against broad-spectrum pathogens. The Arabidopsis gene NDR1 (NON-RACE-SPECIFIC DISEASE RESISTANCE 1) is a positive regulator of SA accumulation and is specifically required for signaling mediated by a subset of R genes upon recognition of their cognate pathogen effectors. Our bioinformatic analysis identified an ortholog of NDR1 from citrus, CsNDR1. Overexpression of CsNDR1 complemented susceptibility conferred by the Arabidopsis ndr1-1 mutant to Pseudomonas syringae strains and also led to enhanced resistance to an oomycete pathogen Hyaloperonospora arabidopsidis. Such heightened resistance is associated with increased SA production and expression of the defense marker gene PATHOGENESIS RELATED 1 (PR1). In addition, we found that expression of PR1 and accumulation of SA were induced to modest levels in citrus infected with Candidatus Liberibacter asiaticus, the bacterial pathogen associated with HLB disease. Thus, our data suggest that CsNDR1 is a functional ortholog of Arabidopsis NDR1. Since Ca. L. asiaticus infection only activates modest levels of defense responses in citrus, we propose that genetically increasing SA/NDR1-mediated pathways could potentially lead to enhanced resistance against HLB, citrus canker, and other destructive diseases challenging global citrus production.


Correction of Italian under-reporting in the first COVID-19 wave via age-specific deconvolution of hospital admissions.
When the COVID-19 pandemic first emerged in early 2020, healthcare and bureaucratic systems worldwide were caught off guard and largely unprepared to deal with the scale and severity of the outbreak. In Italy, this led to a severe underreporting of infections during the first wave of the spread. The lack of accurate data is critical as it hampers the retrospective assessment of nonpharmacological interventions, the comparison with the following waves, and the estimation and validation of epidemiological models. In particular, during the first wave, reported cases of new infections were strikingly low if compared with their effects in terms of deaths, hospitalizations and intensive care admissions. In this paper, we observe that the hospital admissions during the second wave were very well explained by the convolution of the reported daily infections with an exponential kernel. By formulating the estimation of the actual infections during the first wave as an inverse problem, its solution by a regularization approach is proposed and validated. In this way, it was possible to compute corrected time series of daily infections for each age class. The new estimates are consistent with the serological survey published in June 2020 by the National Institute of Statistics (ISTAT) and can be used to speculate on the total number of infections occurring in Italy during 2020, which appears to be about double the number officially recorded.


Preferential activation of helper/inducer T lymphocytes in autoimmune chronic active hepatitis.
We found a significant increase of activated circulating T lymphocytes expressing interleukin 2 receptor (IL-2r) (mean +/- s.e.m. 11.0 +/- 1.1%) or DR antigen (5.0 +/- 0.49%) in patients with autoimmune chronic active hepatitis (CAH) starting in childhood when compared to healthy controls (0.14 +/- 0.09%, P less than 0.001 and 2.8 +/- 0.06%, P less than 0.01). Patients with liver disorders due to Wilson's disease (IL-2r 0.64 +/- 0.25%, DR 3.5 +/- 0.22%) or alpha-1-antitrypsin deficiency (IL-2r 0.1 +/- 0.06%, DR 2.8 +/- 0.35%) had levels similar to controls. Levels of both IL-2r and DR positive T lymphocytes were higher in patients with uncontrolled CAH (IL-2r 18.0 +/- 1.01%; DR 6.3 +/- 0.78%) than in patients with inactive disease (IL-2r 3.2 +/- 1.4%, P less than 0.001; DR 3.0 +/- 0.13%, P less than 0.01). In patients with active disease levels of IL-2r positive cells were higher than DR positive cells (P less than 0.001). Only 21% of activated T cells coexpressed the two markers of activation. Sixty-seven percent of IL-2r positive T lymphocytes were helper/inducer and 25% suppressor/cytotoxic, while 66% of the DR positive T cells were suppressor/cytotoxic and 31% helper/inducer. The finding that the highest levels of activated T lymphocytes are present in patients with uncontrolled CAH suggests that these cells are involved in its pathogenesis. The preferential increase of activated helper/inducer cells might explain the enhanced immune reactivity characteristic of autoimmune CAH.


Role of brain kallikrein-kinin system in regulation of adrenocorticotropin release.
We evaluated whether the brain kallikrein-kinin system plays a role in the regulation of adrenocorticotropin (ACTH) release in rats. Intracerebroventricular (icv) injection of bradykinin (0.24 nmol) increased plasma immunoreactive ACTH (irACTH) levels (from 93 +/- 4 to 200 +/- 12 pg/ml, P less than 0.01). This effect was prevented by icv kinin antagonist at 15.4 nmol/h (from 98 +/- 5 to 108 +/- 6 pg/ml; not significant). The antagonist did not alter the increase in plasma irACTH levels induced by icv corticotropin-releasing factor (CRF), arginine vasopressin, or prostaglandin E2. Melittin (7 nmol/h icv) increased plasma irACTH from 95 +/- 4 to 268 +/- 7 pg/ml (P less than 0.01). This effect was prevented by icv kinin antagonist (15.4 nmol/h), kallikrein antibodies (13 pmol/h), or indomethacin (0.28 mmol/h). ACTH response to melittin was not altered by antagonists of CRF or vasopressin. Intra-arterial injection of insulin (0.3 IU/kg body wt) reduced plasma glucose levels to a similar extent in rats given icv kinin antagonist or vehicle; the ACTH response to insulin-induced hypoglycemia was slightly less in rats given kinin antagonist than in those given vehicle (55 +/- 5 vs. 86 +/- 4 pg/ml, P less than 0.05). The brain kallikrein-kinin system may play a role in the regulation of ACTH secretion in stimulated conditions.