Disentangling the effect of out-of-home care on child mental health.
Children in out-of-home care are consistently found to have poor mental health compared to children in the general population. However, UK research has so far failed to disentangle the impact of the care system on children's mental health outcomes from the effects of the adverse circumstances that led to their admission to care. This research investigated the association between care placement and the presence of child mental health problems after controlling for children's pre-care experiences. It also identified factors associated with mental health problems among children in care. The sample comprised three groups of children involved with child welfare services due to maltreatment, including children in out-of-home care (n = 122), reunified children (n = 82) and those who had never been in care (n = 159). The mental health of the children in the three groups was compared, using information collected from their parents/foster carers and social workers. The odds of a child in out-of-home care having a mental health problem were not significantly higher than those of a child who had never been in care (AOR = 1.24; p = 0.462). However, the odds of a child in out-of-home care having reactive attachment disorder (RAD) were significantly higher than those of a child who had never been in care (AOR=1.92; p = 0.032). These findings make an important contribution to international debates about whether placing children in care is beneficial or detrimental to their wellbeing, and highlight a range of inter-linking factors associated with the mental health of children in out-of-home care.


Crystal structure of the Schizosaccharomyces pombe U7BR E2-binding region in complex with Ubc7.
Endoplasmic reticulum (ER)-associated degradation (ERAD) is a protein quality-control pathway in eukaryotes in which misfolded ER proteins are polyubiquitylated, extracted and ultimately degraded by the proteasome. This process involves ER membrane-embedded ubiquitin E2 and E3 enzymes, as well as a soluble E2 enzyme (Ubc7 in Saccharomyces cerevisiae and UBE2G2 in mammals). E2-binding regions (E2BRs) that recruit these soluble ERAD E2s to the ER have been identified in humans and S. cerevisiae, and structures of E2-E2BR complexes from both species have been determined. In addition to sequence and structural differences between the human and S. cerevisiae E2BRs, the binding of E2BRs also elicits different biochemical outcomes with respect to E2 charging by E1 and E2 discharge. Here, the Schizosaccharomyces pombe E2BR was identified and purified with Ubc7 to resolve a 1.7 Å resolution co-crystal structure of the E2BR in complex with Ubc7. The S. pombe E2BR binds to the back side of the E2 as an α-helix and, while differences exist, it exhibits greater similarity to the human E2BR. Structure-based sequence alignments reveal differences and conserved elements among these species. Structural comparisons and biochemistry reveal that the S. pombe E2BR presents a steric impediment to E1 binding and inhibits E1-mediated charging, respectively.


Bee venom attenuates neurodegeneration and motor impairment and modulates the response to L-dopa or rasagiline in a mice model of Parkinson's disease.
This study aimed to investigate the effect of bee venom, a form of alternative therapy, on rotenone-induced Parkinson's disease (PD) in mice. Moreover, the possible modulation by bee venom of the effect of L-dopa/carbidopa or rasagiline was examined. Rotenone (1.5 mg/kg, subcutaneously; SC) was administered every other day for two weeks and at the same time mice received the vehicle (DMSO, SC), bee venom (0.065, 0.13, and 0.26 mg/kg; intradermal; ID), L-dopa/carbidopa (25 mg/kg, intraperitoneal; IP), L-dopa/carbidopa+bee venom (0.13 mg/kg, ID), rasagiline (1 mg/kg, IP) or rasagiline+bee venom (0.13 mg/kg, ID). Then, wire hanging and staircase tests were performed and mice were euthanized and brains' striata separated. Oxidative stress biomarkers namely, malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), paraoxonase-1 (PON-1), and total antioxidant capacity (TAC) were measured. Additionally, butyrylcholinesterase (BuChE), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and dopamine (DA) were evaluated. Brain histopathological changes and caspase-3- expression were done. Bee venom significantly enhanced motor performance and inhibited rotenone-induced oxidative/nitrosative stress, observed as a reduction in both MDA and NO along with increasing GSH, PON-1, and TAC. Besides, bee venom decreased MCP-1, TNF-α, and caspase-3 expression together with an increase in BuChE activity and DA content. Bee venom alone or in combination with L-dopa/carbidopa or rasagiline alleviated neuronal degeneration compared with L-dopa/carbidopa or rasagiline treatment only. Bee venom via its antioxidant and cytokine reducing potentials might be of value either alone or as adjunctive therapy in the management of PD.


Extracellular H(2)O(2) induced by oligogalacturonides is not involved in the inhibition of the auxin-regulated rolB gene expression in tobacco leaf explants.
alpha-1,4-Linked oligogalacturonides (OGs) inhibit auxin-regulated transcriptional activation of a rolB-beta-glucuronidase (GUS) gene fusion in tobacco (Nicotiana tabacum) leaf explants (D. Bellincampi, M. Cardarelli, D. Zaghi, G. Serino, G. Salvi, C. Gatz, F. Cervone, M. M. Altamura, P. Costantino, G. De Lorenzo [1996] Plant Cell 8: 477-487). In this paper we show that inhibition by OGs is very rapid, with a short lag time, and takes place even after rolB promoter activation has initiated. OGs also induce a transient and catalase-sensitive accumulation of H(2)O(2) in the leaf explant culture medium. OGs with a degree of polymerization from 12 to 15 are required for both the inhibition of the auxin-induced rolB-driven accumulation of GUS and the induction of H(2)O(2) accumulation(.) However, OG concentration for half-maximal induction of H(2)O(2) accumulation is approximately 3-fold higher than that for half-maximal inhibition of rolB promoter activity. The inhibition of rolB promoter activity is not influenced by the addition of catalase or superoxide dismutase, suggesting that H(2)O(2) and superoxide are not involved in this effect. A fungal oligo-beta-glucan elicitor induces extracellular H(2)O(2) accumulation at comparable or higher levels than those observed with OGs, but does not prevent the auxin-induced accumulation of GUS. We conclude that H(2)O(2) produced upon treatment with OGs is not involved in the inhibition of the auxin-induced expression of the rolB gene.


PIK3R1W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma.
Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1W624R and addiction of PIK3R1W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The PIK3R1W624R mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer.


Factors Influencing Need for Cosmetic Surgery among High School Girls.
The increase of cosmetic surgery procedures is partly motivated by more positive attitude toward cosmetic surgery as a means of improving physical appearance. In this study factors expected to predict need for cosmetic surgery were examined. A descriptive design was used with 321 high school girls who completed a questionnaire about sociocultural attitudes toward appearance, body image, self-esteem, and need for cosmetic surgery. Stepwise multiple regression analysis was performed to examine factors affecting need for cosmetic surgery. Bivariate correlations showed that need for cosmetic surgery was positively correlated with internalization and awareness of sociocultural attitudes toward appearance, and appearance orientation in body image and negatively correlated with self-esteem and ideal body mass index (BMI). Multiple regression showed that the predictive variables explained 22.1% in need for cosmetic surgery. The significant factors influencing need for cosmetic surgery were greater internalization and awareness of sociocultural attitudes toward appearance, better appearance evaluation and higher appearance orientation in body image, lower self-esteem, and lower ideal BMI. Overall, results of this research suggest that prevention of media influence and body image disturbances, and promotion of self-esteem are very important to young women.


Mass Spectrometry Imaging proves differential absorption profiles of well-characterised permeability markers along the crypt-villus axis.
Knowledge about the region-specific absorption profiles from the gastrointestinal tract of orally administered drugs is a critical factor guiding dosage form selection in drug development. We have used a novel approach to study three well-characterized permeability and absorption marker drugs in the intestine. Propranolol and metoprolol (highly permeable compounds) and atenolol (low-moderate permeability compound) were orally co-administered to rats. The site of drug absorption was revealed by high spatial resolution matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and complemented by quantitative measurement of drug concentration in tissue homogenates. MALDI-MSI identified endogenous molecular markers that illustrated the villi structures and confirmed the different absorption sites assigned to histological landmarks for the three drugs. Propranolol and metoprolol showed a rapid absorption and shorter transit distance in contrast to atenolol, which was absorbed more slowly from more distal sites. This study provides novel insights into site specific absorption for each of the compounds along the crypt-villus axis, as well as confirming a proximal-distal absorption gradient along the intestine. The combined analytical approach allowed the quantification and spatial resolution of drug distribution in the intestine and provided experimental evidence for the suggested absorption behaviour of low and highly permeable compounds.


Deep brain stimulation in epilepsy: what is next?
Experimental and clinical studies have suggested that epileptic seizures can be modulated or interrupted by electrical stimulations of subcortical structures that may exert a remote control on seizure generators. The aim of this review is to present these recent reports and to address the perspectives of this approach. The use of deep brain stimulation to control several motor diseases has renewed the interest of this technique for epilepsy. Several neurology and neurosurgery groups have applied this therapy to drug-resistant forms of epilepsy for which resective surgery cannot be applied. The choice of the subcortical brain structures that are targeted strongly depends on the rationale that has been developed from experimental studies using animal models. The stimulation parameters and whether deep brain stimulation for epilepsy must be continuously applied or only when a seizure occurs are a matter of debate. This article discusses the use of stimulation of the cerebellum, caudate nucleus, anterior and centromedian nucleus of the thalamus, subthalamic nucleus, and substantia nigra to treat epilepsy, in light of recent and less recent clinical and experimental data. New directions for studies are proposed for a better understanding of the mechanisms of action of this treatment.


Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than does treatment with azathioprine plus methylprednisolone in patients with proliferative lupus nephritis.
To analyze the effect of treatment with either pulse cyclophosphamide (CYC) or azathioprine (AZA) combined with methylprednisolone (MP), on serial biopsy results in patients with proliferative lupus nephritis, and to evaluate the predictive value of various histopathologic and clinical parameters with regard to disease outcome. Biopsy specimens from patients with proliferative lupus nephritis, obtained at study entry and after 2 years of therapy, were scored according to a standardized method, and results assessed in relation to disease outcome. Of the 87 patients originally enrolled, 39 underwent repeat biopsy. These patients were representative of the overall group, both at entry and at 2-year followup. The median activity index changed from 8.0 to 2.7 (no differences between the treatment groups). In the group treated with AZA plus MP (AZA group), the increase in the median chronicity index (from 2.7 to 3.8) was larger than that in the CYC group (from 2.7 to 3.0) (P = 0.050). In multivariate analyses, renal function at enrollment and after 2 years was the best predictor of renal function at the last visit, while none of the histopathologic variables (either at entry or at 2 years) added to this prediction. Comparing patients whose disease transitioned to class II with those who had persistent proliferative lupus nephritis revealed no differences between the treatment groups at either time point, and no clinical differences at 2 years. However, a higher serum creatinine level at entry and greater proteinuria at last visit were characteristic of patients who still had proliferative lupus nephritis at 2 years. These results indicate that, although both CYC and AZA are effective in reducing active lesions in lupus nephritis, progression of chronic lesions is more effectively halted by CYC. Variables assessed by repeat biopsy do not predict clinical outcome.


Distinct role of electrocardiographic criteria in echocardiographic diagnosis of left ventricular hypertrophy according to age, in the general population: the Ikaria Study.
The age-dependent performance of electrocardiographic (ECG) criteria was examined for left ventricular hypertrophy (LVH) prediction. During 2009, 570 middle-aged (54 ± 7 years, 45% men) and 507 elderly (75 ± 6 years, 45% men) inhabitants of the Ikaria Island were studied. Seven ECG criteria were calculated (Sokolow-Lyon voltage and product, sex-specific Cornell voltage and product, Gubner-Ungerleider voltage, Lewis voltage and Framingham), whereas LVH was defined as left ventricular mass indexed for body surface area (BSA) at least 125 g/m in men and at least 110 g/m in women or left ventricular mass indexed for height 49 g/m or more in men and 45 g/m or more in women. The Framingham criteria had in hierarchical order the highest, although insignificant, sensitivity among the elderly individuals, either when LVH was indexed for BSA or for height (18.4 and 16.7%, respectively). Cornell voltage and product criteria had hierarchically the highest sensitivity among middle-aged participants, either when LVH was indexed for BSA (19.0 and 23.8%, respectively) or for height (17.2 and 20.3%, respectively). In the multiadjusted analysis applied in elderly participants, Cornell voltage, its product and Framingham criteria were associated with echocardiographic detection of LVH (indexed for BSA); however, when LVH was indexed for height, the Sokolow-Lyon and Framingham criteria were associated with LVH detection. In contrast, among middle-aged individuals, the Cornell product was the only ECG criterion that was associated with LVH detection (irrespective of indexation). Age should be taken into consideration in selection of appropriate ECG criteria for LVH detection. Indexation of left ventricular mass differentiates the diagnostic ability of ECG criteria, especially in older patients.


Monocytes carrying GFAP detect glioma, brain metastasis and ischaemic stroke, and predict glioblastoma survival.
Diagnosis and monitoring of primary brain tumours, brain metastasis and acute ischaemic stroke all require invasive, burdensome and costly diagnostics, frequently lacking adequate sensitivity, particularly during disease monitoring. Monocytes are known to migrate to damaged tissues, where they act as tissue macrophages, continuously scavenging, phagocytizing and digesting apoptotic cells and other tissue debris. We hypothesize that upon completion of their tissue-cleaning task, these tissue macrophages might migrate via the lymph system to the bloodstream, where they can be detected and evaluated for their phagolysosomal contents. We discovered a blood monocyte subpopulation carrying the brain-specific glial fibrillary acidic protein in glioma patients and in patients with brain metastasis and evaluated the diagnostic potential of this finding. Blood samples were collected in a cross-sectional study before or during surgery from adult patients with brain lesions suspected of glioma. Together with blood samples from healthy controls, these samples were flowing cytometrically evaluated for intracellular glial fibrillary acidic protein in monocyte subsets. Acute ischaemic stroke patients were tested at multiple time points after onset to evaluate the presence of glial fibrillary acidic protein-carrying monocytes in other forms of brain tissue damage. Clinical data were collected retrospectively. High-grade gliomas (N = 145), brain metastasis (N = 21) and large stroke patients (>100 cm3) (N = 3 versus 6; multiple time points) had significantly increased frequencies of glial fibrillary acidic protein+CD16+ monocytes compared to healthy controls. Based on both a training and validation set, a cut-off value of 0.6% glial fibrillary acidic protein+CD16+ monocytes was established, with 81% sensitivity (95% CI 75-87%) and 85% specificity (95% CI 80-90%) for brain lesion detection. Acute ischaemic strokes of >100 cm3 reached >0.6% of glial fibrillary acidic protein+CD16+ monocytes within the first 2-8 h after hospitalization and subsided within 48 h. Glioblastoma patients with >20% glial fibrillary acidic protein+CD16+ non-classical monocytes had a significantly shorter median overall survival (8.1 versus 12.1 months). Our results and the available literature, support the hypothesis of a tissue-origin of these glial fibrillary acidic protein-carrying monocytes. Blood monocytes carrying glial fibrillary acidic protein have a high sensitivity and specificity for the detection of brain lesions and for glioblastoma patients with a decreased overall survival. Furthermore, their very rapid response to acute tissue damage identifies large areas of ischaemic tissue damage within 8 h after an ischaemic event. These studies are the first to report the clinical applicability for brain tissue damage detection through a minimally invasive diagnostic method, based on blood monocytes and not serum markers, with direct consequences for disease monitoring in future (therapeutic) studies and clinical decision making in glioma and acute ischaemic stroke patients.


Acacetin blocks kv1.3 channels and inhibits human T cell activation.
Acacetin, a natural flavonoid compound, has been proven to exert anti-inflammatory and immunomodulatory effects. Kv1.3 channels, highly expressed in human T cells, are attractive therapeutic targets to treat inflammatory and immunological disorders. The present study was designed to characterize the inhibition of Kv1.3 channels by Acacetin in human T cells and examine its role in T cell activation. Whole-cell patch-clamp was applied to record the Kv1.3 and KCa currents in human T cells; Western blot was used to detect Kv1.3 expression as well as NFAT1 and NF-κB activity; Fluo-4, CCK-8 and an ELISA kit were used to measure Ca(2+) influx, proliferation, and IL-2 secretion, respectively. Acacetin decreased the Kv1.3 current, accelerated the decay rate and negatively shifted the steady-state inactivation curves in a concentration-dependent manner. The IC50 values at +40 mV for peak and the current at end of pulse were 21.09 ± 2.75 and 3.63 ± 0.25 μmol/L, respectively. Treatment with Acacetin for 24 h significantly inhibited Kv1.3 protein expression. Additionally, paralleling Kv1.3 inhibition, Acacetin also inhibited Ca(2+) influx, the Ca(2+)-activated transcription factors NFAT1, NF-κB p65/p50 activity, and proliferation as well as IL-2 production. Small interfering RNA against Kv1.3 reduced the inhibitory effect of Acacetin on IL-2 secretion. Acacetin blocks the Kv1.3 channel and inhibits human T cell activation. This action most likely contributes to its immunomodulatory and anti-inflammatory actions.


Layered structure of room-temperature ionic liquids in microemulsions by multinuclear NMR spectroscopic studies.
Microemulsions form in mixtures of polar, nonpolar, and amphiphilic molecules. Typical microemulsions employ water as the polar phase. However, microemulsions can form with a polar phase other than water, which hold promise to diversify the range of properties, and hence utility, of microemulsions. Here microemulsions formed by using a room-temperature ionic liquid (RTIL) as the polar phase were created and characterized by using multinuclear NMR spectroscopy. (1)H, (11)B, and (19)F NMR spectroscopy was applied to explore differences between microemulsions formed by using 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)]) as the polar phase with a cationic surfactant, benzylhexadecyldimethylammonium chloride (BHDC), and a nonionic surfactant, Triton X-100 (TX-100). NMR spectroscopy showed distinct differences in the behavior of the RTIL as the charge of the surfactant head group varies in the different microemulsion environments. Minor changes in the chemical shifts were observed for [bmim](+) and [BF(4)](-) in the presence of TX-100 suggesting that the surfactant and the ionic liquid are separated in the microemulsion. The large changes in spectroscopic parameters observed are consistent with microstructure formation with layering of [bmim](+) and [BF(4)](-) and migration of Cl(-) within the BHDC microemulsions. Comparisons with NMR results for related ionic compounds in organic and aqueous environments as well as literature studies assisted the development of a simple organizational model for these microstructures.


Arterial CO2 pressure changes during hypercapnia are associated with changes in brain parenchymal volume.
The Monro-Kellie hypothesis (MKH) states that volume changes in any intracranial component (blood, brain tissue, cerebrospinal fluid) should be counterbalanced by a co-occurring opposite change to maintain intracranial pressure within the fixed volume of the cranium. In this feasibility study, we investigate the MKH application to structural magnetic resonance imaging (MRI) in observing compensating intracranial volume changes during hypercapnia, which causes an increase in cerebral blood volume. Seven healthy subjects aged from 24 to 64 years (median 32), 4 males and 3 females, underwent a 3-T three-dimensional T1-weighted MRI under normocapnia and under hypercapnia. Intracranial tissue volumes were computed. According to the MKH, the significant increase in measured brain parenchymal volume (median 6.0 mL; interquartile range 4.5, 8.5; p = 0.016) during hypercapnia co-occurred with a decrease in intracranial cerebrospinal fluid (median -10.0 mL; interquartile range -13.5, -6.5; p = 0.034). These results convey several implications: (i) blood volume changes either caused by disorders, anaesthesia, or medication can affect outcome of brain volumetric studies; (ii) besides probing tissue displacement, this approach may assess the brain cerebrovascular reactivity. Future studies should explore the use of alternative sequences, such as three-dimensional T2-weighted imaging, for improved quantification of hypercapnia-induced volume changes.


Appending Limited Clinical Data to an Administrative Database for Acute Myocardial Infarction Patients: The Impact on the Assessment of Hospital Quality.
Hospitals' risk-standardized mortality rates and outlier status (significantly higher/lower rates) are reported by the Centers for Medicare and Medicaid Services (CMS) for acute myocardial infarction (AMI) patients using Medicare claims data. New York now has AMI claims data with blood pressure and heart rate added. The objective of this study was to see whether the appended database yields different hospital assessments than standard claims data. New York State clinically appended claims data for AMI were used to create 2 different risk models based on CMS methods: 1 with and 1 without the added clinical data. Model discrimination was compared, and differences between the models in hospital outlier status and tertile status were examined. Mean arterial pressure and heart rate were both significant predictors of mortality in the clinically appended model. The C statistic for the model with the clinical variables added was significantly higher (0.803 vs. 0.773, P<0.001). The model without clinical variables identified 10 low outliers and all of them were percutaneous coronary intervention hospitals. When clinical variables were included in the model, only 6 of those 10 hospitals were low outliers, but there were 2 new low outliers. The model without clinical variables had only 3 high outliers, and the model with clinical variables included identified 2 new high outliers. Appending even a small number of clinical data elements to administrative data resulted in a difference in the assessment of hospital mortality outliers for AMI. The strategy of adding limited but important clinical data elements to administrative datasets should be considered when evaluating hospital quality for procedures and other medical conditions.


Structural and functional characterization of the acidic region from the RIZ tumor suppressor.
RIZ (retinoblastoma protein-interacting zinc finger protein), also denoted PRDM2, is a transcriptional regulator and tumor suppressor. It was initially identified because of its ability to interact with another well-established tumor suppressor, the retinoblastoma protein (Rb). A short motif, IRCDE, in the acidic region (AR) of RIZ was reported to play an important role in the interaction with the pocket domain of Rb. The IRCDE motif is similar to a consensus Rb-binding sequence LXCXE (where X denotes any amino acid) that is found in several viral Rb-inactivating oncoproteins. To improve our understanding of the molecular basis of binding of Rb to RIZ, we investigated the interaction between purified recombinant AR and the pocket domain of Rb using nuclear magnetic resonance spectroscopy, isothermal titration calorimetry, and fluorescence anisotropy experiments. We show that AR is intrinsically disordered and that it binds the pocket domain with submicromolar affinity. We also demonstrate that the interaction between AR and the pocket domain is mediated primarily by the short stretch of residues containing the IRCDE motif and that the contribution of other parts of AR to the interaction with the pocket domain is minimal. Overall, our data provide clear evidence that RIZ is one of the few cellular proteins that can interact directly with the LXCXE-binding cleft on Rb.


Residual immune dysregulation syndrome in treated HIV infection.
Antiretroviral therapy has revolutionized the course of HIV infection, improving immune function and decreasing dramatically the mortality and morbidity due to the opportunistic complications of the disease. Nonetheless, even with sustained suppression of HIV replication, many HIV-infected persons experience a syndrome characterized by increased T cell activation and evidence of heightened inflammation and coagulation. This residual immune dysregulation syndrome or RIDS is more common in persons who fail to increase circulating CD4+ T cells to normal levels and in several epidemiologic studies it has been associated with increased morbidity and mortality. These morbid and fatal events are not the typical opportunistic infections and malignancies seen in the early AIDS era but rather comprise a spectrum of cardiovascular events, liver disease, metabolic disorders, kidney disease, bone disease, and a spectrum of malignant complications distinguishable from the opportunistic malignancies that characterized the earlier days of the AIDS epidemic. While immune activation, inflammation, and coagulopathy are characteristic of untreated HIV infection and improve with drug-induced control of HIV replication, the drivers of RIDS in treated HIV infection are incompletely understood. And while inflammation, immune activation, and coagulopathy are more common in treated persons who fail to restore circulating CD4+ T cells, it is not entirely clear how these two phenomena are linked.


Prehospital plasma resuscitation associated with improved neurologic outcomes after traumatic brain injury.
Trauma-related hypotension and coagulopathy worsen secondary brain injury in patients with traumatic brain injuries (TBIs). Early damage control resuscitation with blood products may mitigate hypotension and coagulopathy. Preliminary data suggest resuscitation with plasma in large animals improves neurologic function after TBI; however, data in humans are lacking. We retrospectively identified all patients with multiple injuries age >15 years with head injuries undergoing prehospital resuscitation with blood products at a single Level I trauma center from January 2002 to December 2013. Inclusion criteria were prehospital resuscitation with either packed red blood cells (pRBCs) or thawed plasma as sole colloid resuscitation. Patients who died in hospital and those using anticoagulants were excluded. Primary outcomes were Glasgow Outcomes Score Extended (GOSE) and Disability Rating Score (DRS) at dismissal and during follow-up. Of 76 patients meeting inclusion criteria, 53% (n = 40) received prehospital pRBCs and 47% (n = 36) received thawed plasma. Age, gender, injury severity or TBI severity, arrival laboratory values, and number of prehospital units were similar (all p > 0.05). Patients who received thawed plasma had an improved neurologic outcome compared to those receiving pRBCs (median GOSE 7 [7-8] vs. 5.5 [3-7], p < 0.001). Additionally, patients who received thawed plasma had improved functionality compared to pRBCs (median DRS 2 [1-3.5] vs. 9 [3-13], p < 0.001). Calculated GOSE and DRS scores during follow-up, median 6 [5-7] months, demonstrated increased function in those resuscitated with thawed plasma compared to pRBCs by both median GOSE (8 [7-8] vs. 6 [6-7], p < 0.001) and DRS (0 [0-1] vs. 4 [2-8], p < 0.001). In critically injured trauma patients with TBI, early resuscitation with thawed plasma is associated with improved neurologic and functional outcomes at discharge and during follow-up compared to pRBCs alone. These preliminary data support the further investigation and use of plasma in the resuscitation of critically injured TBI patients. Therapeutic, level V.


Unintentional weight loss predicts decline in activities of daily living function and life-space mobility over 4 years among community-dwelling older adults.
The relationship between body mass index (BMI), weight loss, and changes in activities of daily living (ADL) function and mobility in older adults is not clear. We sought to study the relationship between BMI and weight loss on the rate of decline in ADL function and life-space mobility over a 4-year period among older African Americans and whites. The participants were 983 enrollees in the University of Alabama at Birmingham (UAB) Study of Aging, a longitudinal study of mobility among community-dwelling older adults stratified to achieve a balanced sample in terms of sex, race, and residence. Primary outcome measures were changes in ADL function and mobility assessed by the UAB Study of Aging Life-Space Assessment (LSA) which were measured every 6 months. Relative to normal weight participants, those with BMI levels in the obese range did not show more rapid ADL functional decline, but a history of unintentional weight loss predicted more rapid decline. Relative to normal-weight participants, other BMI categories were not associated with more rapid decline in LSA scores. However, unintentional weight loss predicted more rapid declines in LSA. Intentional weight loss had no relation to ADL function or LSA decline. In this population of community-dwelling older African Americans and whites, neither BMI nor intentional weight loss had an association with rate of functional decline. Unintentional weight loss had a negative relation with rate of functional decline, regardless of baseline BMI. Whether this is causal remains to be determined.


Potassium intake: the Cinderella electrolyte.
Dietary guidelines recommend intake targets for some essential minerals, based on observational and experimental evidence relating mineral intake levels to health outcomes. For prevention of cardiovascular disease, reducing sodium intake and increasing potassium intake are the principal tools. While reducing sodium intake has received greatest public health priority, emerging evidence suggests that increasing potassium intake may be a more important target for cardiovascular prevention. Increased potassium intake reduces blood pressure and mitigates the hypertensive effects of excess sodium intake, and the recent large Phase III SSaSS trial reported that increasing potassium intake (and reducing sodium intake) in populations with low potassium intake and high sodium intake, through salt substitution (25% KCl, 75%NaCl), reduces the risk of stroke in patients at increased cardiovascular risk. As key sources of potassium intake include fruit, vegetables, nuts, and legumes, higher potassium intake may be associated with healthy dietary patterns. The current review makes the case that increasing potassium intake might represent a more advantageous dietary strategy for prevention of cardiovascular disease. Future research should focus on addressing the independent effect of potassium supplementation in populations with low or moderate potassium intake, and determine effective strategies to increase potassium intake from diet.


Microbial flora of Pacific oysters (Crassostrea gigas) subjected to ultraviolet-irradiated seawater.
The ability of oysters to purge themselves of microbial contaminants was investigated by identifying the microorganisms retained by oysters after they have been subjected to ultraviolet (UV) light-treated seawater. A UV intensity of 960 muw per min per cm(2) reduced the microbial count of seawater from 263 to 13 per ml. The coliform multitube test (MPN) was reduced from a high of 17 to <0.18 per 100 ml. Over 75% of the microorganisms found in treated seawater were Acinetobacter/Moraxella, Vibrio/Pseudomonas type II, and Flavobacterium/Cytophaga. With the exception of coliforms, the microbial composition of oysters subjected to UV-treated seawater remained at levels comparable to the control oysters held in untreated seawater. Total counts ranged between 10(3) and 10(5)/g. The microorganism most frequently encountered were Flavobacterium/Cytophaga, Vibrio/Pseudomonas type II, Pseudomonas type III or IV, Acinetobacter/Moraxella, gram-positive cocci and Bacillus. Together they comprised over 90% of the flora. Coagulase-positive, deoxyribonuclease-positive, and beta-hemolytic cocci were found in some samples, as were V. parahaemolyticus, V. aliginolyticus, and Aeromonas species.


The rat ventromedial thalamic nucleus and motor control: role of N-methyl-D-aspartate-mediated excitation, GABAergic inhibition, and muscarinic transmission.
The rat ventromedial thalamic nucleus (VM) is a point of convergence of several pathways that are supposed to be involved in motor control. Cortical fibers terminating within this nucleus use an excitatory amino acid, possibly L-glutamate, as their transmitter. Excitatory amino acids are known to interact with N-methyl-D-aspartate (NMDA), kainate, and quisqualate receptors, the presence of which has been demonstrated within the thalamus, gamma-Amino-butyrate (GABA) has been identified as the transmitter of the basal ganglia afferents to the VM, whereas cerebellar afferents to the VM are supposed to release ACh acting on muscarinic receptors. The present study investigates the behavioral and motor consequences of local injections of drugs into the VM, which specifically interact with NMDA, GABA, and muscarine receptors. Both the NMDA antagonist (-)2-amino-7-phosphonoheptanoate [(-)AP7], and the GABA agonist muscimol, but not the muscarinic antagonist scopolamine, induced catalepsy and limb rigidity. Both the (-)AP7- and muscimol-induced catalepsy were antagonized by coadministration of NMDA and the GABA antagonist bicuculline. The (-)AP7-induced catalepsy was characterized as an akinetic-rigid syndrome, in which the ability to induce a phasic activation of a set of muscles is lost and replaced by exaggerated tonic muscular responses. NMDA, bicuculline, and the muscarinic agonist bethanechol induced an increase in locomotor activity. The present study provides evidence that an imbalance between NMDA-mediated excitation and GABAergic inhibition within the rat VM leads to disturbances of motility, whereas muscarinic transmission within this nucleus appears to be of minor importance.


Modeling Oxygen Tricluster Formation in Calcium Aluminosilicate Supercooled Liquids and Glasses.
Calcium aluminosilicate glasses have technological importance for a variety of industrial applications. However, the short-range structure of this glass system remains widely debated regarding the formation of oxygen triclusters. It is argued that triclusters are observed in high percentages within molecular dynamics simulations because of the high melting temperatures and correspondingly high fictive temperatures. This work explores the formation of such structural units by first simulating various compositions at different liquid temperatures to understand thermodynamic factors affecting the formation of such species. Structural results are then implemented into a statistical mechanical model which can predict the formation of triclusters at a given fictive temperature. Results show temperature and composition dependence of these structures, with aluminum charge modification favored in the peraluminous regime. It is concluded that oxygen triclusters are the preferred method of charge compensation even when extrapolating to laboratory fictive temperatures, indicating that triclusters are not a byproduct of simulation timescales.


Allele-specific expression of the IL-1 alpha gene in human CD4+ T cell clones.
A number of reports have described the monoallelic expression of murine cytokine genes. Here we describe the monoallelic expression of the human IL-1alpha gene in CD4+ T cells. Analysis of peripheral blood T cell clones derived from healthy individuals revealed that the IL-1alpha gene shows predominantly monoallelic expression. Monoallelic expression was observed in Th0, Th1, and Th2 cell clones. In addition, we demonstrate monoallelic expression in T cell clones from rheumatoid arthritis patients derived from synovial fluid of the knee joint, suggesting that the occurrence of this phenomenon is not different from that in clones derived from healthy individuals. The finding of monoallelic expression of a cytokine gene in human CD4+ T cell clones provides evidence for allele-specific silencing/activation as another layer of regulation of IL-1alpha gene expression.


Morbimortality in octogenarian patients submitted to coronary artery bypass graft surgery.
Given the progressive increase in longevity and the need of an increasingly elderly population to undergo myocardial revascularization surgery (MRS), it becomes necessary to know its risks and benefits. To evaluate the in-hospital morbimortality of patients aged 80 and older submitted to MRS and identify its predictor variables. A total of 140 consecutive cases were studied between January 2002 and December 2007. The patients' mean age was 82.5 +/- 2.2 years (range: 80-89) and 55.7% were males. In the sample,72.9% had arterial hypertension, 26.4% had diabetes, 65.7% presented severe lesion in three or more vessels and 28.6% presented a severe lesion in the left coronary trunk. An associated surgery was present in 35.7% of the cases, with aortic valve in 26.4% and mitral valve in 5.6%. The mortality rate was 14.3% (isolated MRS 10.0% vs 22.0% with associated procedure; p = 0.091) and the morbidity was 37.9% (isolated MRS 34.4% vs 44.0% with associated procedure; p = 0.35). The most frequent complications were low cardiac output (27.9%), renal dysfunction (10.0%) and prolonged ventilatory support (9.6%). At the bivariate analysis, the most important mortality predictors were sepsis (RR 10.2; 95%CI: 6.10-17.7), previous MRS (RR 8.06; 95%CI: 5.16-12.6), postoperative low cardiac output (RR 7.77; 95%CI: 3.03-19.9) and postoperative renal dysfunction (RR 7.36; 95%CI: 3.71-14.6). The morbidity predictors were extracorporeal circulation time > 120 min. (RR: 2.34; 95%CI: 1.62-3.38) and time of ischemia > 90 min. (RR: 2.29 95%CI: 1.56-3.37). The MRS in octogenarians is associated with a higher morbimortality when compared to younger patients, which, however, does not prevent the procedure if the indication is justified by clinical condition.


[Arterial blood flow in the prostate in the syndrome of chronic pelvic pain/chronic prostatitis].
Causes and mechanisms of chronic pelvic pain/chronic prostatitis (CPP/CP) syndrome are not well investigated yet. It is suggested that pain in an inflammatory form of this syndrome may be due to tissue inflammation. In the non-inflammatory form pain may result from neurogenic factors. Standard diagnostic methods in the absence of inflammation often fail to detect pathological changes in the prostate. We made duplex mapping of the prostate and obtained quantitative characteristics of arterial hemodynamics of the prostate. Control values of arterial prostatic blood flow were developed after examination of healthy volunteers. These values were compared with similar values of arterial blood flow in CPP/CP syndrome. We found a significant decrease of the peak systolic velocity in patients with non-inflammatory CPP/CP syndrome. There is a direct correlation between intensity of pain syndrome and peak systolic velocity of arterial blood flow. Thus, pain may arise from chronic prostatic ischemia.


High-sensitivity troponin T in asymptomatic severe aortic stenosis.
Background: In asymptomatic severe aortic stenosis (ASAS), treatment decisions are made on an individual basis, and case management presents a clinical conundrum. Methods: We prospectively phenotyped consecutive patients with ASAS using echocardiography, exercise echocardiography, cardiac MRI and biomarkers (NT-proBNP, high-sensitivity troponin T (hs-TnT) and ST2) (n = 58). The primary endpoint was a composite of cardiovascular death, new-onset symptoms, cardiac hospitalization, guideline-driven indication for valve replacement and cardiovascular death at 12 months. Results: During the first year, 46.6% patients met primary endpoint. In multivariable analysis, aortic regurgitation ≥2 (p = 0.01) and hs-TnT (p = 0.007) were the only independent predictors of the primary endpoint. The best cutoff value was identified as hs-TnT >10ng/L, which was associated with a ∼10-fold greater risk of the primary endpoint (HR, 9.62; 95% CI, 2.27-40.8; p = 0.002). A baseline predictive model including age, sex and variables showing p < 0.10 in univariable analyses showed an area under the curve (AUC) of 0.79(0.66-0.91). Incorporation of hs-TnT into this model increased the AUC to 0.90(0.81-0.98) (p = 0.03). Patient reclassification with the model including hs-TnT yielded an NRI of 1.28(0.46-1.78), corresponding to 43% adequately reclassified patients. Conclusions: In patients with ASAS, hs-TnT >10ng/L was associated with high risk of events within 12 months. Including hs-TnT in routine ASAS management markedly improved prediction metrics.


Chronic ifosfamide nephrotoxicity in children.
Nephrotoxicity is a frequent complication of treatment with ifosfamide in children. Although renal damage may be acute and reversible, chronic toxicity may develop with potentially serious consequences. Chronic nephrotoxicity due to ifosfamide may lead to a wide variety of subclinical and clinical manifestations. Proximal tubular dysfunction is the commonest presentation, and may lead to a Fanconi syndrome, including hypophosphataemic rickets and proximal renal tubular acidosis. Glomerular impairment is also common, whilst distal tubular impairment has been described but is relatively rare. Although full reversibility has been described occasionally, there is no information about the very long-term outcome of chronic ifosfamide nephrotoxicity. We studied a cohort of 12 children 1 and 10 years after completion of ifosfamide treatment. There was no statistically significant change in either glomerular or tubular toxicity in the group as a whole over this time period. However, marked improvements were seen in some aspects of toxicity in some patients, and deterioration was observed in others. We concluded that considerable nephrotoxicity is still present 10 years after completion of ifosfamide treatment, but that the outcome varies between individual patients. Although several risk factors for the development of chronic nephrotoxicity have been described, total ifosfamide dose, patient age at treatment, previous or concurrent cisplatin treatment, and unilateral nephrectomy are the most important. Nevertheless, it remains difficult to predict the occurrence of this toxicity with confidence. The pathogenesis of ifosfamide nephrotoxicity is poorly understood. There is an urgent need for the development and clinical investigation of nephroprotective strategies.


Analysis of FcgammaRII gene polymorphisms in Wegener's granulomatosis.
Fcgamma receptors (FcgammaRs) are potent initiators of proinflammatory reactions and tissue injury programs through the oxidative burst, degranulation and the production of a variety of proinflammatory cytokines. Direct experimental evidence indicates that translocation of ANCA target from intracellular granules to the neutrophil membrane and subsequent binding of ANCA enables FcgammaR-mediated neutrophil activation. In the presence of ANCA, these data provide a framework from which to understand the importance of ANCA class, subclass, and titer in Wegener's granulomatosis and other ANCA-positive vasculitides. The well-characterized and functionally important alleles of neutrophil FcgammaR (FcgammaRIIa-H131/R131 and FcgammaRIIIb-NA1/NA2) are possible inheritable genetic elements that may alter disease severity and/or phenotype.


PCR-mediated one-step deletion of targeted chromosomal regions in haploid Saccharomyces cerevisiae.
Chromosome rearrangements, especially chromosomal deletions, have been exploited as important resources for functional analysis of genomes. To facilitate this analysis, we applied a previously developed method for chromosome splitting for the direct deletion of a designed internal or terminal chromosomal region carrying many nonessential genes in haploid Saccharomyces cerevisiae. The method, polymerase chain reaction (PCR)-mediated chromosomal deletion (PCD), consists of a two-step PCR and one transformation per deletion event. In this paper, we show that the PCD method efficiently deletes internal regions in a single transformation. Of the six chromosomal regions targeted for deletion by this method, five regions (16 to 38 kb in length) containing 10 to 19 nonessential genes were successfully eliminated at high efficiency. The one targeted region on chromosome XIII that was not deleted was subsequently found to contain sequences essential for yeast growth. While 14 individual genes in this region have been reported to be nonessential, synthetic lethal interactions may occur among these nonessential genes. Phenotypic analysis showed that four deletion strains still exhibited normal growth while possible synthetic growth defects were observed in another strain harboring a 19-gene deletion on chromosome XV. These results demonstrate that the PCD method is a useful tool for deleting genes and for analyzing their functions in defined chromosomal regions.


Searching MEDLINE free on the Internet using the National Library of Medicine's PubMed.
Searching MEDLINE, the National Library of Medicine's premier bibliographic database covering the fields of medicine, nursing, dental medicine, the healthcare system, veterinary medicine, and the preclinical sciences, is now available free on the Internet through PubMed. This retrieval system allows users of all skill levels to obtain important medical information. Additionally, through the National Network of Libraries of Medicine (NN/LM) program, a division of NLM, user support in the form of phone, e-mail, and training is available free of charge. Those interested in having a training session for PubMed at their facility may contact the NN/LM to make arrangements.


Cross-domain generality of achievement motivation across sport and the classroom: the case of Spanish adolescents.
Drawing from contemporary social cognitive theories of achievement motivation, the relationship of personal theories of achievement (ego and task theory) with perceived ability and reported satisfaction with school and sport was examined. The cross-domain generality of these relationships in these contexts, in the case of a representative sample of adolescents between 11 and 15 years of age (N = 967, M age = 13.5, SD = 1.80; 492 girls and 475 boys) from the Valencian Community (Spain) also was examined. According to previous research in the United States (Duda & Nicholls, 1992), the findings of this study indicate a cross-domain consistency with regard to how adolescents tend to define success and their views of how achievement activities operate across sport and the classroom. However, little cross-domain generality was found for perceptions of ability and reported satisfaction. In the sport and classroom domains, a task theory was related to greater satisfaction, while an ego theory was related to greater reported boredom and low interest in the activity.


Microscale Reversed-Phase Liquid Chromatography/Capillary Zone Electrophoresis-Tandem Mass Spectrometry for Deep and Highly Sensitive Bottom-Up Proteomics: Identification of 7500 Proteins with Five Micrograms of an MCF7 Proteome Digest.
Capillary zone electrophoresis-tandem mass spectrometry (CZE-MS/MS) has been well recognized for bottom-up proteomics. It has approached 4000-8000 protein identifications (IDs) from a human cell line, mouse brains, or Xenopus embryos via coupling with liquid chromatography (LC) prefractionation. However, at least 500 μg of complex proteome digests were required for the LC/CZE-MS/MS studies. This requirement of a large amount of initial peptide material impedes the application of CZE-MS/MS for deep bottom-up proteomics of mass-limited samples. In this work, we coupled microscale reversed-phase LC (μRPLC)-based peptide prefractionation to dynamic pH-junction-based CZE-MS/MS for deep bottom-up proteomics of the MCF7 breast cancer cell proteome starting with only 5 μg of peptides. The dynamic pH-junction-based CZE enabled a 500 nL sample injection from as low as a 1.5 μL peptide sample, using up to 33% of the available peptide material for an analysis. Two kinds of μRPLC prefractionation were investigated, C18 ZipTip and nanoflow RPLC. C18 ZipTip/CZE-MS/MS identified 4453 proteins from 5 μg of the MCF7 proteome digest and showed good qualitative and quantitative reproducibility. Nanoflow RPLC/CZE-MS/MS produced over 7500 protein IDs and nearly 60 000 peptide IDs from the 5 μg of MCF7 proteome digest. The nanoflow RPLC/CZE-MS/MS platform reduced the required amount of complex proteome digests for LC/CZE-MS/MS-based deep bottom-up proteomics by 2 orders of magnitude. Our work provides the proteomics community with a powerful tool for deep and highly sensitive proteomics.


Specific expression in mouse mesoderm- and neural crest-derived tissues of a human PDGFRA promoter/lacZ transgene.
The platelet-derived growth factor alpha-receptor (PDGFR-alpha) displays a lineage-specific expression pattern in the mouse embryo and is required for normal development of mesoderm and cephalic neural crest derivatives. The purpose of the present study was to demonstrate the in vivo promoter function of genomic DNA fragments representing the 5'-flanking part of the human PDGFRA gene. 2.2, 0.9 and 0.4 kb PDGFRA promoter fragments, ligated to a lacZ reporter gene, were microinjected into fertilized mouse eggs and transgenic mouse lines were established. The expression patterns were basically similar in the 2.2 and 0.9 kb lines and overlapped grossly the endogenous Pdgfra gene expression pattern. The transgenic line with the highest expression level was chosen for detailed analysis. Expression was, as expected, mainly confined to tissues of mesodermal and neural crest origin. No expression was found in epithelial tissues of endo- or ectodermal origin. The promoter fragments were also active in neuroepithelium and in certain neuronal cell types that did not faithfully express PDGFR-alpha mRNA, while they failed to specify reporter expression in PDGFR-alpha expressing O-2A progenitor cells and other glial elements of the central nervous system. Thus, the isolated human PDGFRA promoter contains most but not all of the regulatory elements that are necessary to establish tissue specific gene expression during development.


The use of fluorescein dye as a predictor of mastectomy skin flap viability following autologous tissue reconstruction.
The skin sparing mastectomy continues to allow improvement in the esthetic outcome after immediate autologous breast reconstruction. However, native skin flap necrosis does occur and can significantly jeopardize the result. The purpose of this series was to evaluate objectively the utility of fluorescein dye as a tool to assist with evaluation of eventual flap viability or flap necrosis. Fifty consecutive periareolar mastectomy flaps were evaluated after autologous reconstruction. Patient demographics and risk factors were queried. The mastectomy skin flaps were evaluated clinically for viability and managed appropriately. Flap inset was performed. Intravenous fluorescein dye was then given, and areas of nonfluorescence were marked (size and location documented). Photodocumentation was performed intraoperatively and 1 week postoperatively. Areas of skin survival and skin necrosis were documented, and comparisons were made. The type of reconstructions included TRAM flap (n = 31), and latissimus dorsi with expander (n = 19), with an average age of 50 years (range: 38-68 years). Patient demographics included previous radiation therapy (n = 5), smoking history (n = 14), hypertension (n = 13), and previous breast scars (n = 16). Skin fluorescence corresponded with flap survival (n = 48/50), giving a positive predictive value of 96%. Two flaps (1 patient) had some skin necrosis despite full fluorescence; however, she was eventually diagnosed with hepatitis C vasculitis. Of the 21 flaps with areas of nonfluorescence, skin necrosis was present in 5 of 21, a negative predictive value of 25%. The majority of areas of nonfluorescence were less than 4 cm2 and had full flap survival (n = 16/21). Two flaps with nonfluorescence of <4 cm2 and previous radiation therapy had skin necrosis. All flaps with areas >4 cm2 had skin necrosis, unless proximally located on the skin flaps. Fluorescein dye is a sensitive test for determining native mastectomy skin flap viability after autologous reconstruction; however, viability is underpredicted. Location on the skin flaps, size of nonfluorescence, as well as history of radiation therapy should be taken into consideration. Areas of nonfluorescence <4 cm2 typically survive, except in the irradiated breast. Any area of nonfluorescence >4 cm2 typically does not survive, except when located more proximally on the flap.


Establishing the outcome indicators for the essential nursing competencies and curricula guidelines for genetics and genomics.
The translation of genetics/genomics to clinical care has implications for nurses. The Essential Nursing Competencies and Curricula Guidelines for Genetics and Genomics, established by consensus, apply to all registered nurses. Learning outcomes and clinical practice indicators have been developed to provide additional guidance. The Essentials Advisory Group (EAG) established a team to establish the Outcome Indicators. A draft was developed based on published peer-reviewed documents and syllabi. The draft underwent three layers of review: (a) critique by the EAG; (b) review by representatives at a Genetics/Genomics Toolkit for Faculty meeting; and (c) review by workshop attendees of the American Association of Colleges of Nursing's baccalaureate and master's education conferences, followed by EAG's final approval. Outcome Indicators clarify specific knowledge areas and suggest clinical performance indicators for each competency. They provide the foundation to establish a competency-based education repository with outcome indicator mapping matrixes for genetic/genomic education resources. A gap analysis of education resources identified resource deficits, and online unfolding case studies were developed. Outcome Indicators assist the academic and continuing education nurse community to prepare the nursing workforce in genetics/genomics and provide a platform from which to build tools needed to achieve this goal.


Tolerance of activated pathogenic CD4+ T cells by transcriptional targeting of dendritic cells.
We have recently shown that targeted expression of myelin oligodendrocyte glycoprotein (MOG) to dendritic cells with self-inactivating-lentivirus vectors induces antigen-specific tolerance in naive antigen-specific CD4+ T cells and protects mice from experimental autoimmune encephalomyelitis (EAE). In the present study, we demonstrate that this approach also induces tolerance of activated antigen-specific CD4+ T cells and completely protects mice from passive EAE induction. Tolerance induction did not correlate with the depletion of the preactivated antigen-specific CD4+ T cells. However, upon isolation and in vitro re-stimulation at day 6 after adoptive transfer the MOG-specific CD4+ T cells from the non-tolerized mice produced large amounts of inflammatory cytokines, whereas those from tolerized mice did not. This unresponsiveness correlated with the upregulation of regulatory molecules associated with anergy and regulatory T cells (Tregs). The in vivo depletion of Tregs resulted in EAE susceptibility of the tolerized animals, suggesting that these cells have indeed a role in tolerance induction/maintenance.


Self-assembly of an azobenzene-containing polymer prepared by a multi-component reaction: supramolecular nanospheres with photo-induced deformation properties.
In this article, we have synthesized a polymer containing regulated azobenzene groups by one-pot multi-component polymerization (MCP) based on Passerini reaction, and investigated its self-assembly behavior and photo-induced deformation properties. We found that this molecule can form spherical structures with sizes ranging from hundreds of nanometers to several micrometers when dissolved in THF. NMR and FTIR studies indicate that there are associated hydrogen bonds among the molecules in the aggregates, which are responsible for the formation of the nanospheres. By controlling the stirring rate as the THF suspension is dropped into water, the nanospheres can be sorted according to their size. In this way, we have obtained nanospheres with relatively uniform diameter. When irradiated by UV light in the aqueous medium, the nanospheres tend to aggregate into large clusters, while in dry state they are ready to merge into island-like structures, showing a good photo-induced deformation property.


Humans infested with Ixodes ricinus are exposed to a diverse array of tick-borne pathogens in Serbia.
Tick-borne pathogens (TBPs) pose a major threat to human health in Europe and the whole northern hemisphere. Despite a high prevalence of TBPs in Ixodes ricinus ticks, knowledge on the incidence of tick-borne diseases in humans infested by this tick species is limited. This study was conducted in the year 2019 on patients who presented themselves to the Pasteur Institute Novi Sad with tick infestations. Ticks (n = 31) feeding on human (n = 30) and blood samples from the same individuals were collected by physicians and a microfluidic real-time high-throughput PCR system was used to test the genomic DNA of the samples for the presence of 27 bacterial and eight parasitic microorganisms in Serbia. Except for one Rhipicephalus sanguineus s.l. adult male tick, all ticks infesting humans were morphologically identified as I. ricinus. A high proportion of ticks (74 %, 23/31) were infected with at least one of the tested TB microorganisms, being Rickettsia helvetica (54 %, 17/31) the most common pathogen, but Borrelia afzelii (9 %, 3/31), Anaplasma phagocytophilum (6 %, 2/31), Borrelia miyamotoi (6 %, 2/31), and Francisella like-endosymbiont (6 %, 2/31), Borrelia valaisiana (3 %, 1/31), Borrelia lusitaniae (3 %, 1/31), Rickettsia felis (3 %, 1/31) and Rickettsia aeschlimannii (3 %, 1/31) were also identified. Despite the high infection rate of TBPs in ticks, only two human blood samples (6 %, 2/30) tested positive for the presence of TBPs, one patient (code H12, 67 years old female) was diagnosed with Borrelia spp. and the other patient was diagnosed (code H17, 71 years old female) with R. felis infection. The tick infesting patient H12 tested positive for B. afzelii, and R. helvetica and the tick infesting patient H17 tested positive for R. felis. Upon clinical examination, both patients were diagnosed with erythema migrans. No additional discomfort was reported by the patient and no additional pathology was observed by the physician. We concluded that humans bitten by I. ricinus in Serbia are exposed to a diverse array of TBPs with clinical impact in the Serbian cohort studied.


Effects of Tomato and Soy Germ on Lipid Bioaccumulation and Atherosclerosis in ApoE-/- Mice.
Dietary patterns with cardiovascular benefits have been recommended, but the relative contributions of individual foods and food components, alone or in combination, remain undefined. Male ApoE(-/-) mice were fed either a purified AIN-93G control diet, a Western diet (WD), or a WD with 10% tomato powder (TP), 2% soy germ (SG), or the combination, for 4 wk (n = 10 per group). Plasma total cholesterol and triglycerides were measured with enzymatic colorimetric kits, and serum amyloid A (SAA) was measured by ELISA. Liver lipids were extracted with chloroform:methanol, and triglycerides, free and esterified cholesterol measured with enzymatic colorimetric kits. Expression of Cyp27a1, Cyp7a1, Abcg5, and Abcg8 in the liver was determined by quantitative polymerase chain reaction. Sections of the aortic root and aorta were cut and stained with hematoxylin and eosin (H&E) to assess extent of atherosclerotic lesions. WD-fed animals had greater liver and adipose weights, plasma cholesterol and SAA, hepatic lipids, and atherosclerosis than AIN-93G animals. TP and SG did not decrease atherosclerosis as measured by H&E-stained sections of the aortic root, aortic arch, and descending aorta. The TP diets further increased plasma cholesterol, but also led to increased expression of the Abcg5/8 transporters involved in cholesterol efflux. Addition of SG alone to the WD attenuated WD-induced increases in plasma cholesterol, liver lipids, and gonadal adipose weight. The results of this study do not support the use of either TP or SG for reduction of atherosclerosis, but suggest some beneficial effects of SG on lipid metabolism in this model of cardiovascular disease.


The MR-Base platform supports systematic causal inference across the human phenome.
Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (<ext-link ext-link-type="uri" xlink:href="http://www.mrbase.org">http://www.mrbase.org</ext-link>): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.


[Ophthalmic oncology: achievements over the last two decades].
The article describes current trends in scientific research, especially those that concern treatment of the most common cancers. The latter include malignant eyelid and conjunctiva tumors, retinoblastoma and choroidal melanoma. Relevant publications in Russian and foreign journals demonstrate a progressive advance in treatment approaches: from radical methods associated with surrounding tissue damage to local tumor destruction. Comparative analysis of the methods and their effectiveness suggest that Russian ophthalmic oncology meets state-of-the-art international criteria.


Cognitive function 5 years after randomization to coronary angioplasty or coronary artery bypass graft surgery.
Coronary bypass surgery often leads to short-term cognitive dysfunction, whereas coronary angioplasty does not. Perioperative cognitive dysfunction usually resolves, although a subgroup of surgical patients may continue to exhibit long-term cognitive dysfunction. The purpose of this study was to compare cognitive function 5 years after randomization to a strategy of either initial coronary surgery or initial angioplasty. Five centers in the Bypass Angioplasty Revascularization Investigation participated in this ancillary study. Patients with multivessel coronary disease randomized to angioplasty or surgery were eligible at the time of their 5-year clinic visit. A battery of five measures previously shown to be sensitive to perioperative changes in cognitive function was administered, including the Logical and Figural Memory Scales from the Wechsler Memory Scale, the Digit Symbol and Digit Span subtests from the Wechsler Adult Intelligence Scale, and Part B of the Reitan Trail Making Test. The 125 study patients were generally similar to the 133 patients who were eligible but did not participate, although study participants were significantly younger (P=.003). The 64 patients randomly assigned to angioplasty had baseline characteristics similar to those of 61 patients randomly assigned to surgery. Cognitive function scores were not significantly different between angioplasty or surgery patients in an intention-to-treat analysis (P=.57). There also was no difference in cognitive function scores when the data were analyzed according to whether the patient had ever undergone bypass surgery (P=.59). Long-term cognitive function is similar after coronary bypass surgery and coronary angioplasty in the majority of patients.


Cleavage of Grb2-Associated Binding Protein 2 by Viral Proteinase 2A during Coxsackievirus Infection.
Coxsackievirus type B3 (CV-B3), an enterovirus associated with the pathogenesis of several human diseases, subverts, or employs the host intracellular signaling pathways to support effective viral infection. We have previously demonstrated that Grb2-associated binding protein 1 (GAB1), a signaling adaptor protein that serves as a platform for intracellular signaling assembly and transduction, is cleaved upon CV-B3 infection, resulting in a gain-of-pro-viral-function via the modification of GAB1-mediated ERK1/2 pathway. GAB2 is a mammalian homolog of GAB1. In this study, we aim to address whether GAB2 plays a synergistic role with GAB1 in the regulation of CV-B3 replication. Here, we reported that GAB2 is also a target of CV-B3-encoded viral proteinase. We showed that GAB2 is cleaved at G238 during CV-B3 infection by viral proteinase 2A, generating two cleaved fragments of GAB2-N1-237 and GAB2-C238-676. Moreover, knockdown of GAB2 significantly inhibits the synthesis of viral protein and subsequent viral progeny production, accompanied by reduced levels of phosphorylated p38, suggesting a pro-viral function for GAB2 linked to p38 activation. Finally, we examined whether the cleavage of GAB2 can promote viral replication as observed for GAB1 cleavage. We showed that expression of neither GAB2-N1-237 nor GAB2-C238-676 results in enhanced viral infectivity, indicating a loss-of-function, rather than a gain-of-function of GAB2 cleavage in mediating virus replication. Taken together, our findings in this study suggest a novel host defense machinery through which CV-B3 infection is limited by the cleavage of a pro-viral protein.


Sex differences in androgen responsiveness in the rat brain: regional differences in the induction of aromatase activity.
The transformation of testosterone (T) to estrogens in brain tissue by cytochrome P-450 aromatase is required for the expression of sexual behaviors in adult male rats. Androgens regulate aromatase activity in the medial preoptic nucleus (MPN), as well as in a reciprocally connected group of forebrain nuclei involved in the regulation of male sexual behaviors. The levels of aromatase in these nuclei are generally greater in males than in females due to sex differences in circulating androgen levels. However, the mechanism of enzyme induction also appears to be sexually dimorphic. The current experiments were undertaken: (1) to characterize and compare the kinetic properties of aromatase in male and female rats and (2) to study sex differences in the dose-response relationship between the administered doses of T and the induction of aromatase in microdissected brain regions. Saturation analysis of aromatase activity in the MPN, bed nucleus of the stria terminalis (BNST), periventricular preoptic area (PVPOA), anterior hypothalamus (AH), and ventromedial hypothalamic nucleus (VMN) indicates that the greater aromatase activity observed in intact males reflects a sex difference in the maximal enzyme velocity, and not a sex difference in the apparent affinity of enzyme for substrate (Michaelis constant). The dose-response study of aromatase induction in the BNST, PVPOA, and VMN indicated a sex difference in aromatase activity over a range of circulating T levels varying from 0.3 to 35 ng/ml. No sex difference in inducible aromatase activity in AH was observed at any dose of T. The results of this study clearly demonstrate a sexually dimorphic effect of androgen action in the rat brain. Since T both regulates and is the substrate for aromatase in the brain, this sexual dimorphism is potentially an important limitation to the action of T in females and may relate to the enhanced expression of T-stimulated copulatory behavior in males compared to females.


Applying the zero-inflated Poisson model with random effects to detect abnormal rises in school absenteeism indicating infectious diseases outbreak.
Records of absenteeism from primary schools are valuable data for infectious diseases surveillance. However, the analysis of the absenteeism is complicated by the data features of clustering at zero, non-independence and overdispersion. This study aimed to generate an appropriate model to handle the absenteeism data collected in a European Commission granted project for infectious disease surveillance in rural China and to evaluate the validity and timeliness of the resulting model for early warnings of infectious disease outbreak. Four steps were taken: (1) building a 'well-fitting' model by the zero-inflated Poisson model with random effects (ZIP-RE) using the absenteeism data from the first implementation year; (2) applying the resulting model to predict the 'expected' number of absenteeism events in the second implementation year; (3) computing the differences between the observations and the expected values (O-E values) to generate an alternative series of data; (4) evaluating the early warning validity and timeliness of the observational data and model-based O-E values via the EARS-3C algorithms with regard to the detection of real cluster events. The results indicate that ZIP-RE and its corresponding O-E values could improve the detection of aberrations, reduce the false-positive signals and are applicable to the zero-inflated data.


Besnoitia besnoiti-induced neutrophil clustering and neutrophil extracellular trap formation depend on P2X1 purinergic receptor signaling.
Bovine besnoitiosis is a re-emerging cattle disease caused by the cyst-forming apicomplexan parasite Besnoitia besnoiti. Neutrophil extracellular trap (NET) formation represents an efficient innate immune mechanism of polymorphonuclear neutrophils (PMN) against apicomplexan parasites, including B. besnoiti. PMN purinergic signaling was proposed as a critical factor for NET formation. One important purinergic ligand is ATP, which is recognized as a danger signal and released into the extracellular space acting as an autocrine/paracrine signaling molecule. ATP-driven effects on PMN via the nucleotide P2 receptor family include chemotaxis, reactive oxygen species (ROS) production, and NET formation. So far, data on both PMN ATP concentrations and the role of ATP as a key modulator of purinergic signaling in B. besnoiti tachyzoite-triggered bovine NETosis is scarce. Current data showed that B. besnoiti tachyzoite exposure to bovine PMN neither changed total PMN ATP nor extracellular ATP quantities even though it significantly triggered NET formation. Moreover, B. besnoiti tachyzoite-exposed PMN revealed enhanced oxygen consumption rates (OCR) as quantified by the Seahorse metabolic analyzer. Exogenous supplementation of ATP or non-hydrolizable ATP (ATPγS) led to increased extracellular acidification rates (ECAR) but failed to alter tachyzoite-induced oxidative responses (OCR) in exposed PMN. In addition, exogenous supplementation of ATPγS, but not of ATP, boosted B. besnoiti tachyzoite-induced anchored NET formation. Referring to purinergic signaling, B. besnoiti tachyzoite-triggered anchored NET formation revealed P2X1 purinergic as receptor-dependent since it was blocked by the P2X1 inhibitor NF449 at an IC50 of 1.27 µM. In contrast, antagonists of P2Y2, P2Y6, P2X4, and P2X7 purinergic receptors all failed to affect parasite-driven NETosis. As an interesting finding, we additionally observed that B. besnoiti tachyzoite exposure induced PMN clustering in a P2X1-dependent manner. Thus, we identified P2X1 purinergic receptor as a pivotal molecule for both B. besnoiti tachyzoite-induced PMN clustering and anchored NET formation.


Identification of the hub genes in gastric cancer through weighted gene co-expression network analysis.
Gastric cancer is one of the most lethal tumors and is characterized by poor prognosis and lack of effective diagnostic or therapeutic biomarkers. The aim of this study was to find hub genes serving as biomarkers in gastric cancer diagnosis and therapy. GSE66229 from Gene Expression Omnibus (GEO) was used as training set. Genes bearing the top 25% standard deviations among all the samples in training set were performed to systematic weighted gene co-expression network analysis (WGCNA) to find candidate genes. Then, hub genes were further screened by using the "least absolute shrinkage and selection operator" (LASSO) logistic regression. Finally, hub genes were validated in the GSE54129 dataset from GEO by supervised learning method artificial neural network (ANN) algorithm. Twelve modules with strong preservation were identified by using WGCNA methods in training set. Of which, five modules significantly related to gastric cancer were selected as clinically significant modules, and 713 candidate genes were identified from these five modules. Then, ADIPOQ, ARHGAP39, ATAD3A, C1orf95, CWH43, GRIK3, INHBA, RDH12, SCNN1G, SIGLEC11 and LYVE1 were screened as the hub genes. These hub genes successfully differentiated the tumor samples from the healthy tissues in an independent testing set through artificial neural network algorithm with the area under the receiver operating characteristic curve at 0.946. These hub genes bearing diagnostic and therapeutic values, and our results may provide a novel prospect for the diagnosis and treatment of gastric cancer in the future.


Lack of MHC expression and retention of ultrastructural characteristics by xenograft transmissible venereal tumor cells in SCID mice.
Canine transmissible venereal tumor (CTVT) is primarily a tumor of adult dogs with a high incidence of spontaneous regression. We recently reported a xenograft model of CTVT (XTVT) in NOD/SCID mice. XTVT cells retain cytological and histological features of CTVT as well as characteristic rearranged LINE/c-MYC junction [Am. J. Vet. Res. 62 (2001) 907]. In this paper, we demonstrate that XTVT cells maintain ultrastructural characteristics of CTVT and do not express MHC classes I and II molecules.


Small interfering RNAs that deplete the cellular translation factor eIF4H impede mRNA degradation by the virion host shutoff protein of herpes simplex virus.
The herpes simplex virus (HSV) virion host shutoff (Vhs) protein is an endoribonuclease that accelerates decay of many host and viral mRNAs. Purified Vhs does not distinguish mRNAs from nonmessenger RNAs and cuts target RNAs at many sites, yet within infected cells it is targeted to mRNAs and cleaves those mRNAs at preferred sites including, for some, regions of translation initiation. This targeting may result in part from Vhs binding to the translation initiation factor eIF4H; in particular, several mutations in Vhs that abrogate its binding to eIF4H also abolish its mRNA-degradative activity, even though the mutant proteins retain endonuclease activity. To further investigate the role of eIF4H in Vhs activity, HeLa cells were depleted of eIF4H or other proteins by transfection with small interfering RNAs (siRNAs) 48 h prior to infection or mock infection in the presence of actinomycin D. Cellular mRNA levels were then assayed 5 h after infection. In cells transfected with an siRNA for the housekeeping enzyme glyceraldehyde-3-phosphate dehydrogenase, wild-type HSV infection reduced beta-actin mRNA levels to between 20 and 30% of those in mock-infected cells, indicative of a normal Vhs activity. In contrast, in cells transfected with any of three eIF4H siRNAs, beta-actin mRNA levels were indistinguishable in infected and mock-infected cells, suggesting that eIF4H depletion impeded Vhs-mediated degradation. Depletion of the related factor eIF4B did not affect Vhs activity. The data suggest that eIF4H binding is required for Vhs-induced degradation of many mRNAs, perhaps by targeting Vhs to mRNAs and to preferred sites within mRNAs.


Infiltrating mast cells correlate with angiogenesis in bone metastases from gastric cancer patients.
While gastric cancer is a well established angiogenesis driven tumor, no data has been published regarding angiogenesis stimulated by mast cells (MCs) positive for tryptase in bone metastases from gastric cancer patients (BMGCP). It is well established that MCs play a role in immune responses and more recently it was demonstrated that MCs have been involved in tumor angiogenesis. We analyzed infiltrating MCs and neovascularization in BMGCP diagnosed by histology. A series of 15 stage T3-4N2-3M1 (by AJCC for Gastric Cancer Staging 7th Edition) BMGCP from bone biopsies were selected. Tumour tissue samples were evaluated by mean of immunohistochemistry and image analysis methods in terms of MCs density positive to tryptase (MCDPT), MCs area positive to tryptase (MCAPT), microvascular density (MVD) and endothelial area (EA). A significant correlation between MCDPT, MCAPT, MVD and EA groups to each other was found by Pearson and t-test analysis (r ranged from 0.68 to 0.82; p-value ranged from 0.00 to 0.02). Our very preliminary data suggest that infiltrating MCs positive for tryptase may play a role in BMGCP angiogenesis, and could be further evaluated as a novel target of anti-angiogenic therapy.


Determination of brachial artery stiffness prior to vascular access creation: reproducibility of pulse wave velocity assessment.
Despite routine ultrasound mapping of upper extremity arteries and veins, early thrombosis and nonmaturation remain frequent complications following vascular access (VA) surgery. Besides vascular diameters, brachial artery stiffness is assumed to play an important role; however, reproducibility of measurements has never been established. The purpose of this study was to determine within-session and between-session variabilities of pulse wave velocity (PWV) assessment by using ultrasonography and blood pressure registration. Beat-to-beat changes in brachial artery diameter and pressure were obtained in 21 subjects in measurement sessions on Day 1 and Day 3. Each session consisted of three acquisitions. For each acquisition, systolic and diastolic diameter and pressure were determined and used for calculation of brachial artery PWV. Within-session variability of diameter and pressure, as well as the estimated PWV, was expressed using the intraclass correlation coefficient with corresponding coefficient of variation (CoV). Between-session variability was reported using Bland-Altman analysis in combination with CoV analysis. Significant agreement (P < 0.001) was obtained for all diameter and pressure measurements obtained on Day 1 and Day 3. Within-session CoV of pulse pressure, diastolic diameter and distension were 7.0, 1.6 and 18.3%, respectively. Subsequent estimation of local PWV resulted in a CoV of 10.6%. Between-session CoV was 15.1, 3.8 and 18.9% for pulse pressure, diastolic diameter and distension, respectively. For PWV estimation, this resulted in a CoV of 13.5%. Diameter and pressure can be recorded accurately over the cardiac cycle, and calculations of distensibility, pulse pressure and PWV show a slight to moderate degree of variation. Larger studies elaborating on interindividual differences need to determine the clinical efficacy of PWV measurements prior to VA creation.


The role of gender in the association between self-rated health and mortality among older adults in Santiago, Chile: A cohort study.
Previous studies on the role of gender in the association between self-rated health and mortality have shown contrasting results. This study was aimed to determine the importance of gender in the association between self-rated health and mortality among older people in Santiago, Chile. A 10 year follow-up of 1066 people aged 60 or more, from the Chilean cohort of the Study of Health, Ageing and Well-Being. Self-rated health was assessed in face to face interviews through a single general question, along with socio-demographic and health status information. Cox proportional hazards and flexible parametric models for survival analyses were employed. By the end of follow-up, 30.7% of women and 39.4% of men died. Adjusted hazard ratio of poor self-rated health, compared to good self-rated health, was 1.92(95% CI 1.29-2.86). In models stratified by gender, an increased risk of mortality was observed among women who rated their health as poor (HR = 2.21, 95% CI 1.43-3.40), but not among men (HR = 1.04, 95% CI 0.58-1.86). Age was associated with mortality in both groups; for men, functional limitation and underweight were also risk factors and obesity was a protective factor. Compared to older women who rated their health as good, older women who rated their health as poor had a 2 fold increased risk of mortality over the subsequent 10 years. These findings stress the importance of considering a gender perspective into health programmes, including those focused on older people, in order to address the different elements that increase, on the long run, the risk of dying among older women and men.


Heterotrimeric G proteins in the control of parathyroid hormone actions.
Parathyroid hormone (PTH) is a key regulator of skeletal physiology and calcium and phosphate homeostasis. It acts on bone and kidney to stimulate bone turnover, increase the circulating levels of 1,25 dihydroxyvitamin D and calcium and inhibit the reabsorption of phosphate from the glomerular filtrate. Dysregulated PTH actions contribute to or are the cause of several endocrine disorders. This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11 Genetic mutations affecting the activity or expression of the alpha-subunit of Gs, encoded by the GNAS complex locus, are responsible for several human diseases for which the clinical findings result, at least partly, from aberrant PTH signaling. Here, we review the bone and renal actions of PTH with respect to the different signaling pathways downstream of these G proteins, as well as the disorders caused by GNAS mutations.


Abatacept and Glomerular Diseases: The Open Road for the Second Signal as a New Target is Settled Down.
Glomerulopathy is the third most important cause of kidney disease. Proteinuria is the hallmark of glomerular damage, and a marker of progression of kidney disease, cardiovascular morbidity and mortality. Strategies to reduce proteinuria are partially successful, and despite proteinuria management, renal disease may still progress. Immunosuppression to treat glomerulopathies is nonspecific, partially effective and presents side-effects. It is critical to find safe drugs with specific podocyte molecular targets. Podocytes contain a complex array of proteins. Lymphocyte activation antigen B7-1 (CD80) is located on antigen presenting cells modulating CD4+ and CD8+ T cells by interacting with co-stimulator CD28, a glycoprotein located on T-cells, or with cytotoxic T-lymphocyte protein 4 (CTLA-4) co-inhibitor. Normally, podocytes do not express B7-1. However, certain glomerulopathies are associated with an increase on the surface of podocytes of B7-1, which reduces the ability of podocytes to attach to the surrounding glomerular basement membrane, favouring podocyturia and proteinuria. When the B7-1-CTLA-4 interaction takes place, the immune response is abrogated, while a B7-1-CD28 coupling leads to T cell activation. Abatacept binds to B7-1 by blocking the CD28 or potentiating the CTLA-4 signals. In B7-1 positive podocytes, abatacept may be a specific tool to decrease proteinuria. Selected patents are also briefly presented in this review.


Inbreeding does not alter the response to an experimental heat wave in a freshwater snail.
Global climate change affects natural populations of many species by increasing the average temperature and the frequency of extreme weather events (e.g. summer heat waves). The ability of organisms to cope with these environmental changes can, however, depend on their genetic properties. For instance, genetic load owing to inbreeding could alter organisms' responses to climate change-mediated environmental changes but such effects are often overlooked. We investigated the effects of an experimental heat wave (25°C versus 15°C) on life history (reproduction, size) and constitutive immune defence traits (phenoloxidase-like and antibacterial activity of haemolymph) in relation to inbreeding by manipulating the mating type (outcrossing, self-fertilization) in two populations of a hermaphroditic freshwater snail, Lymnaea stagnalis. High temperature increased reproduction and size of snails but impaired their immune function. In one of the two study populations, inbreeding reduced reproductive output of snails indicating inbreeding depression. Furthermore, this effect did not depend on the temperature snails were exposed to. Our results suggest that L. stagnalis snails can be negatively affected by inbreeding but it may not alter their responses to heat waves.


Bandstructure approach to near edge structure.
We review the current state of the art in EELS fingerprinting by computer simulation, focusing on the bandstructure approach to the problem. Currently calculations are made using a one electron theory, but we describe in principle the way to go beyond this to include final state effects. We include these effects within the one electron framework using the Slater transition state formula and assess the errors involved. Two examples are then given which illustrate the use of the one electron approximation within density functional theory. Our approach is to combine predicted atomic structure with predicted electronic structure to assist in fingerprinting of complex crystal structures.


Temporal Evolution of Imaging Findings in Ossified Cephalohematoma.
Cephalohematoma is collection of blood between skull and periosteum that is confined by cranial sutures. Cephalohematomas usually resorb spontaneously within the first month of life; however, if it fails to resolve, ossified cephalohematoma may form. Clinical archiving system and picture archiving and communication system were retrospectively reviewed for cases of birth-related cephalohematoma. Cases of ossified cephalohematomas identified on imaging were retrieved from this subset of patients. Cross-sectional imaging findings in patients with ossified cephalohematomas were evaluated for location, size of the hematoma, and contours of the inner lamella. Out of 115 cases of cephalohematoma, 7 cases had imaging findings consistent with ossified cephalohematoma. All ossified cephalohematomas were located parietally, with size ranging between 18 and 55 mm and the thickness of the outer rim of calcification ranging between 1.5 and 4.8 mm. The contour of inner lamella in relation to the surrounding normal cranial vault was normal in 5 cases, and inner lamella was depressed in 2 cases.Three patients had follow-up imaging available for demonstration of changes in ossified cephalohematoma. The first case was an 11 day-old boy with a cephalohematoma with no signs of calcification at the time of initial imaging. Follow-up at 2 months of age showed partial regression of hematoma cavity with marked calcification at the hematoma walls. The second case was a 3 month-old boy with ossified cephalohematoma at initial imaging. Follow-up imaging at 7 months of age showed almost total regression of hematoma cavity, and approximation of inner and outer lamella with increased thickness of the cranial vault. The third case was a 1 month-old boy with ossified cephalohematoma at initial imaging that totally resolved without residual increased bone thickness at 21-month follow-up. These 3 cases demonstrate the variability in temporal changes that may occur in ossified cephalohematomas.


The epileptology of Koolen-de Vries syndrome: Electro-clinico-radiologic findings in 31 patients.
This study was designed to describe the spectrum of epilepsy phenotypes in Koolen-de Vries syndrome (KdVS), a genetic syndrome involving dysmorphic features, intellectual disability, hypotonia, and congenital malformations, that occurs secondary to 17q21.31 microdeletions and heterozygous mutations in KANSL1. We were invited to attend a large gathering of individuals with KdVS and their families. While there, we recruited individuals with KdVS and seizures, and performed thorough phenotyping. Additional subjects were included who approached us after the family support group brought attention to our research via social media. Inclusion criteria were genetic testing results demonstrating 17q21.31 deletion or KANSL1 mutation, and at least one seizure. Thirty-one individuals were studied, aged 2-35 years. Median age at seizure onset was 3.5 years, and 9 of 22 had refractory seizures 2 years after onset. Focal impaired awareness seizures were the most frequent seizure type occurring in 20 of 31, usually with prominent autonomic features. Twenty-one patients had prolonged seizures and, at times, refractory status epilepticus. Electroencephalography (EEG) showed focal/multifocal epileptiform discharges in 20 of 26. MRI studies of 13 patients were reviewed, and all had structural anomalies. Corpus callosum dysgenesis, abnormal hippocampi, and dilated ventricles were the most common, although periventricular nodular heterotopia, focal cortical dysplasia, abnormal sulcation, and brainstem and cerebellum abnormalities were also observed. One patient underwent epilepsy surgery for a lesion that proved to be an angiocentric glioma. The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features. Multifocal epileptiform discharges are the typical EEG pattern. Structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnormal axonal guidance. Epilepsy surgery should be undertaken with care given the widespread neuroanatomic abnormalities; however, tumors are a rare, yet important, occurrence.


Distal femoral arthropometry in Nigerians and its correlation to total knee replacement implants.
Total Knee replacement (TKR) is performed to relieve pain and restore both the mechanical axis and joint line whenever indicated. Most of prostheses being used for TKR were manufactured using dimensions from Caucasians' measurements. This study documented the dimensions of distal femora of Nigerians and correlated the dimensions with different TKR prostheses. Fifty-six matured femora were measured. Dimensions of distal femora from other regions were retrieved from published articles. The dimensions of TKR prosthesis were extracted from product monographs. Analyses were done with Microsoft excel 2010 (Microsoft Corporation, Redmond, Washington, United States) and STATA version 13 (StataCorp, Texas. USA). Statistical significance was set at p ≤ 0.05. The average Mediolateral dimension was 79.3 ± 4.4 mm. The anterioposterior dimensions of the medial and lateral condyles were 63.7 ± 3.6 mm and 64.9 ± 3.3 mm respectively. There were no significant differences between the left and right distal femur. The average aspect ratio calculated was1.23 ± 0.05. There was a mismatch of aspect ratio of the distal femora and those of the prostheses. Equations that can be useful both clinically and in forensic medicine were generated. This study has provided measurements that can be considered when the designing of a suitable femoral component of total knee prosthesis for Nigerians. This study also provided equations that can be used to estimate the dimensions of the medial and the lateral condyles and femoral length from parts of distal femur in forensic medicine. Self-funded.


Clinical decision support for stroke prevention in atrial fibrillation (CDS-AF): Rationale and design of a cluster randomized trial in the primary care setting.
Atrial fibrillation (AF) is associated with substantial morbidity, in particular stroke. Despite good evidence for the reduction of stroke risk with anticoagulant therapy, there remains a significant undertreatment. The main aim of the current study is to investigate whether a clinical decision support tool for stroke prevention (CDS) integrated in the electronic health record can improve adherence to guidelines for stroke prevention in patients with AF. We will conduct a cluster randomized trial where 43 primary care clinics in the county of Östergötland, Sweden (population 444,347), will be randomized to be part of the CDS intervention or serve as controls. The CDS will alert responsible physicians of patients with AF and increased risk for thromboembolism according to the CHA2DS2VASc (Congestive heart failure, Hypertension, Age ≥ 74 years, Diabetes mellitus, previous Stroke/TIA/thromboembolism, Vascular disease, Age 65-74 years, Sex category (i.e. female sex)) algorithm without anticoagulant therapy. The primary end point will be adherence to guidelines after 1 year. The present study will investigate whether a clinical decision support system integrated in an electronic health record can increase adherence to guidelines regarding anticoagulant therapy in patients with AF.


HIV Pre-Exposure Prophylaxis: New and Upcoming Drugs to Address the HIV Epidemic.
Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) provides a critical intervention toward ending the HIV epidemic and protecting people with reasons to utilize PrEP. PrEP options continue to expand as new administration modalities offer the potential to tailor PrEP use for individual success. We have provided the evidence for new and emerging antiretroviral agents for PrEP (cabotegravir, lenacapavir, dapivirine, and broadly neutralizing antibodies), divided into pharmacology, animal model, and human data, accompanied by a summary and suggested place in therapy. Cabotegravir is a US Food and Drug Administration (FDA)-approved intramuscular injection given every 2 months with a strong body of evidence demonstrating efficacy for HIV PrEP, lenacapavir administered subcutaneously every 6 months is currently under investigation for HIV PrEP, dapivirine vaginal ring is an available PrEP option for women in certain areas of Africa, and broadly neutralizing monoclonal antibodies have been challenged in demonstrating efficacy in phase 1-2 study for HIV PrEP to date. Clinical literature for individual agents is discussed with data from major studies summarized in tables. This review provides a detailed overview of recently available and premier candidate PrEP drugs.