Review of Caffeine-Related Fatalities along with Postmortem Blood Concentrations in 51 Poisoning Deaths.
Publications reporting concentrations of caffeine in postmortem blood were reviewed if the cause of death was attributed to overdosing (poisoning) with drugs. Age and gender of the deceased, the manner of death (accident, suicide or undetermined) and types of co-ingested drugs were evaluated in relation to the concentrations of caffeine in blood (N = 51). The mean age (±SD) of the victims was 39 ± 17.8 years (range 18-84 years) and most were female (N = 31 or 61%). The difference in mean age of males (42 ± 17.2 years) and females (37 ± 18.3 years) was not statistically significant (t = 0.811, P = 0.421). The mean (±SD), median and range of caffeine concentrations in postmortem blood were 187 ± 96 mg/L (180 mg/L) and 33-567 mg/L, respectively. The median concentration of caffeine in males (161 mg/L) was not significantly different from that of females (182 mg/L), z = 1.18, P = 0.235. There was no correlation between the age of the deceased and the concentration of caffeine in postmortem blood (R2 = 0.026, P > 0.05). Manner of death was classified as suicide in 51% of cases (median blood-caffeine 185 mg/L), accidental in 16% (median 183 mg/L) or undetermined in 33% (median 113 mg/L). The median concentration of caffeine in blood was lower when manner of death was undetermined compared with suicide or accidental (P = 0.023). Although other drugs, including ethanol, antidepressants, antipsychotics, benzodiazepines and/or ephedrine, were often identified in postmortem blood, the predominant psychoactive substance was caffeine. The deceased had ingested caffeine in tablet or powder form and it does not seem likely that toxic concentrations of caffeine can be achieved from over-consumption of caffeinated beverages alone.


Natural product terpenoids in Eocene and Miocene conifer fossils.
Numerous saturated and aromatic hydrocarbons, but not polar compounds, originating from plants and microorganisms (biomarkers) have been reported in sediments, coals, and petroleum. Here we describe natural product terpenoids found in two fossil conifers, Taxodium balticum (Eocene) and Glyptostrobus oregonensis (Miocene). A similar terpenoid pattern is also observed in extant Taxodium distichum. The preservation of characteristic terpenoids (unaltered natural products) in the fossil conifers supports their systematic assignment to the Cypress family (Cupressaceae sensu lato). The results also show that fossil conifers can contain polar terpenoids, which are valuable markers for (paleo)chemosystematics and phylogeny.


Allelic association between dinucleotide repeats at the monoamine oxidase loci and schizophrenia.
Two X-linked microsatellites, (AC)n repeats at the monoamine oxidase (MAO) A locus and (TG)n repeats at the MAO-B locus, were typed by using a PCR-based procedure in 89 nuclear families consisting of mothers, fathers and female affected offspring with schizophrenia or mothers and male affected offspring. A haplotype-based haplotype relative risk (HHRR) approach was applied to detect allelic association of these two microsatellites with schizophrenia. In the families of male patients, a significant difference in frequency distribution was found between transmitted and non-transmitted (TG)n repeats (chi(2) = 15.13, df = 6, P = 0.019), and Fisher's exact test showed that allelic frequency of the transmitted (TG)(24) was significantly higher than that of the non-transmitted (TG)(24) (Fisher's P = 0.003). However, no significant differences in frequency distribution between mother- or father-transmitted and non-transmitted (TG)n repeats were found in the families of female patients. No significant differences in frequency distribution were found between transmitted and non-transmitted (AC)n repeats in the families of either male patients or female patients. The present study suggests that the MAO-B gene may be associated with schizophrenia, and the underlying genetic mechanism of schizophrenia may differ between male and female schizophrenic individuals.


Cerebral monitoring during carotid endarterectomy--a comparison between electroencephalography, transcranial cerebral oximetry and carotid stump pressure.
Various modalities are used for cerebral monitoring during carotid endarterectomy (CEA). The aim of this study was to evaluate whether transcranial cerebral oximetry (TCO) and carotid stump pressure (SP) are as accurate as electroencephalography (EEG) for monitoring cerebral ischaemia during carotid cross-clamping. One hundred consecutive patients who underwent CEA were studied with continuous and simultaneous EEG and TCO. SP was measured for each patient. The percentage decrease of oxygenation on TCO was calculated during cross-clamping and surgery. EEG findings were used as the benchmark to detect cerebral ischaemia and were the indication for insertion of a temporary shunt. The relationship with TCO was observed in terms of percentage decrease in oxygenation. A total of 6 patients were shunted on the basis of their EEG changes. TCO changed more than 20% in these 6 patients, but an additional 12 patients had TCO changes with a normal EEG. This correlated with a decrease in blood pressure (BP) and was corrected by increasing the BP. The positive predictive values (PPVs) and negative predictive values (NPVs) for shunting based on TCO (as compared with EEG) were 33% and 100% respectively. Thirty-four patients had SP <50 mmHg, of whom 4 were shunted based on EEG changes. Two of 66 patients with SP >50 mmHg were shunted based on EEG changes. If a shunting policy had been based on a SP of 50 mmHg, 30 patients would have been shunted unnecessarily (PPV 12%), whereas the non-requirement for a shunt was predicted correctly in 64 of 66 patients (NPV 97%). There were 2 major strokes: 1 contralateral on day 3 in a patient with bilateral severe stenoses, and 1 ipsilateral in a nonshunted patient with normal EEG, TCO and SP >50 mmHg. Compared with EEG, TCO is a practical and non-invasive monitoring system with a high sensitivity (100%) but a low specificity. TCO is more sensitive to a drop in BP and responds earlier to these changes than EEG. SP should not be used as the sole predictor for shunting during CEA.


Multivariate analysis of prognostic features in malignant pleural effusions from breast cancer patients.
To identify prognostic indicators in breast cancer patients with malignant pleural effusions, we analyzed the cytopathologic features of 57 fluids representing the first pathologic diagnosis of a distant metastasis in these women. The specimens were analyzed prior to reviewing the clinical records. The median survival of 55 patients who died of the disease was five months following the effusion diagnosis (range, 1-114). Univariate analysis identified three cytopathologic features that correlated with relatively prolonged survival: arrangement of tumor cells in spheroids, slight nuclear atypia and low mitotic rate. Women whose tumor cells formed spheroids survived a median of 24.5 months as compared to 4 months for women with all other architectural patterns (P = .004). Multivariate analysis revealed that slight nuclear atypia and low mitotic rate strongly correlated with spheroid formation. Since breast cancers that form spheroids in effusions portend a relatively favorable prognosis, we recommend that cytopathologists comment on this pattern when reporting on metastatic breast carcinoma in pleural fluids.


Spectrum of common and uncommon causes of knee joint hyaline cartilage degeneration and their key imaging features.
Hyaline cartilage lining the surfaces of diarthrodial joints is an important construct for transmission of load and to reduce friction between the bones. Normal wear and tear accounts for about 3-5 percent knee cartilage loss ever year in otherwise healthy people after the age of 30 years. Several conditions and diseases lead to premature cartilage degeneration. Standardized description of cartilage loss, detailed evaluation of the joint health and determining the underlying etiology of cartilage loss are important for effective reporting, multidisciplinary communications and patient management. In this article, the authors discuss normal and abnormal imaging appearances of the hyaline cartilage of knee with focus on using controlled terminology and MRI classifications. The reader will benefit and learn key MR imaging features of a spectrum of common and uncommon conditions and diseases affecting the knee cartilage, such as trauma, secondary injury associated with meniscus and ligament injury related instability, arthritis, ischemia, idiopathic, and hereditary conditions including Matrix metalloproteinase-2 (MMP-2) mutations and mucopolysaccharidosis type IX disease with illustrative case examples.


Decreased Level of Neurotrophic Factor Neuritin 1 in Women with Ovarian Endometriosis after Receiving Gonadotropin-Releasing Hormone Agonist Treatment.
This study aimed to investigate the effect of gonadotropin-releasing hormone agonist (GnRHa) treatment on the expression of neuritin 1 (NRN1) in women with ovarian endometriosis. We collected tissues and serum from women with endometriosis treated with (n = 45) or without (n = 37) GnRHa. NRN1 mRNA and protein levels were measured using qPCR and Western blot. Immunolocalization of NRN1 in endometriotic tissues was examined using immunohistochemistry. In addition, a follow-up study was carried out to monitor the serum level of NRN1 in patients before and after GnRHa treatment. Both mRNA (p = 0.046) and protein (p = 0.0155) levels of NRN1 were significantly lower in endometriotic tissues from patients receiving GnRHa treatment compared to the untreated group. Both epithelial and stromal cells of endometriotic tissues from untreated women with endometriosis exhibited stronger staining of NRN1 but not in those who were treated with GnRHa. The follow-up study showed that the serum level of the NRN1 concentration decreased significantly from 1149 ± 192.3 to 379.2 ± 80.16 pg/mL after GnRHa treatment (p = 0.0098). The expression of NRN1 was significantly lower in women with ovarian endometriosis treated with GnRHa. These results suggest that NRN1 may be a biomarker response to the effect of GnRHa treatment for patients with ovarian endometriosis.


Social inclusion and hepatitis C: exploring new possibilities for prevention.
In Western countries, people who inject drugs experience a disproportionate burden of hepatitis C as a result of effective transmission of the virus via the sharing of used injection equipment. With a hepatitis C prevalence of 60% and higher in many areas, previous and current prevention efforts focusing on the availability of sterile injecting equipment along with education, have had only limited effect on incidence rate. Little attention has been paid to the broader social and political positions that drug use and people who use drugs hold in these societies. Insights from social research provide opportunities to broaden the possibilities for prevention efforts. We will review the social inclusion literature to provide some examples of how hepatitis C prevention may be approached in innovative ways.


Storage lipid accumulation is controlled by photoperiodic signal acting via regulators of growth cessation and dormancy in hybrid aspen.
The signalling pathways that control seasonal modulation of carbon metabolism in perennial plants are poorly understood. Using genetic, metabolic and natural variation approaches, we identify factors mediating photoperiodic control of storage lipid accumulation in the model tree hybrid aspen (Populus tremula × tremuloides). We characterized lipid accumulation in transgenic hybrid aspen with impaired photoperiodic and hormonal responses. Genome-wide association mapping was performed in Swedish aspen (P. tremula) genotypes to determine genetic loci associated with genotype variation in lipid content. Our data show that the storage lipid triacylglycerol (TAG) accumulates in cambial meristem and pith rays of aspen in response to photoperiodic signal controlling growth cessation and dormancy induction. We show that photoperiodic control of TAG accumulation is mediated by the FLOWERING LOCUS T/CONSTANS module, which also controls the induction of growth cessation. Hormonal and chromatin remodelling pathways also contribute to TAG accumulation by photoperiodic signal. Natural variation exists in lipid accumulation that is controlled by input from multiple loci. Our data shed light on how the control of storage metabolism is temporally coordinated with growth cessation and dormancy by photoperiodic signal, and reveals that storage lipid accumulation between seeds and perennating organs of trees may involve distinct regulatory circuits.


The benefits of pass-fail grading on stress, mood, and group cohesion in medical students.
To objectively measure the effect of a pass-fail grading system on stress, mood, group cohesion, and test anxiety in medical students. Beginning with the class of 2006, the Mayo Medical School, Rochester, Minn, changed the grading system for first-year courses from a 5-interval grading system to a pass-fail grading system. Students in the previous class of 2005, who were graded using a 5-interval system during their first year of medical school, were compared with students in the class of 2006. Using a prospective study design, the 2 groups were compared at the end of both the first year and the second year of medical school on the Perceived Stress Scale, Profile of Mood States, Perceived Cohesion Scale, Test Anxiety Inventory, and (after year 2) the United States Medical Licensing Examination Step 1. Data collection occurred in 2002 and 2003 with the class of 2005 and in 2003 and 2004 with the class of 2006. Students graded with the pass-fail system had less perceived stress (median, 15.0 vs 21.0; P-.01) and greater group cohesion (median, 34.5 vs 30.0; P=.02) at the end of their second year of coursework than their 5-interval graded peers. The pass-fail group had better mood (median, 46.5) than the graded group (median, 64.0), but this difference was not statistically significant (P=.07). No significant differences were found between the 2 groups in test-taking anxiety or in United States Medical Licensing Examination Step 1 board scores. Pass-fail grading may reduce stress and increase group cohesion in medical students compared with traditional 5-interval grading.


The complete mitochondrial genome of the rice moth, Corcyra cephalonica.
The complete mitochondrial genome (mitogenome) of the rice moth, Corcyra cephalonica Stainton (Lepidoptera: Pyralidae) was determined as a circular molecular of 15,273 bp in size. The mitogenome composition (37 genes) and gene order are the same as the other lepidopterans. Nucleotide composition of the C. cephalonica mitogenome is highly A+T biased (80.43%) like other insects. Twelve protein-coding genes start with a typical ATN codon, with the exception of coxl gene, which uses CGA as the initial codon. Nine protein-coding genes have the common stop codon TAA, and the nad2, cox1, cox2, and nad4 have single T as the incomplete stop codon. 22 tRNA genes demonstrated cloverleaf secondary structure. The mitogenome has several large intergenic spacer regions, the spacer1 between trnQ gene and nad2 gene, which is common in Lepidoptera. The spacer 3 between trnE and trnF includes microsatellite-like repeat regions (AT)18 and (TTAT)(3). The spacer 4 (16 bp) between trnS2 gene and nad1 gene has a motif ATACTAT; another species, Sesamia inferens encodes ATCATAT at the same position, while other lepidopteran insects encode a similar ATACTAA motif. The spacer 6 is A+T rich region, include motif ATAGA and a 20-bp poly(T) stretch and two microsatellite (AT)(9), (AT)(8) elements.


Macronutrient disposal during controlled overfeeding with glucose, fructose, sucrose, or fat in lean and obese women.
Previous short-term studies (< or =6 h) showed differences in energy expenditure (EE) and macronutrient oxidation in response to overfeeding with different types of dietary carbohydrate. This finding could have implications for obesity. We used 96-h continuous whole-body calorimetry in 8 lean and 5 obese women to assess metabolic disposal (energy dissipation and glycogen or fat storage) of a controlled excess of dietary energy supplied as different carbohydrate sources or as fat. Five dietary treatments were applied in random order: energy balance (control) and overfeeding by 50% of energy requirements with fat (O(fat)) or predominantly with glucose, fructose, or sucrose (O(cho)). Macronutrient oxidation rates were assessed from nonprotein gaseous exchanges. Net macronutrient balances were calculated as cumulative differences between intake and oxidation. Increased EE in response to overfeeding dissipated 7.9% of the energy excess with a variation in EE of <1.7% across overfeeding treatments (NS). EE during the O(fat) treatment significantly exceeded that during the control treatment in the lean but not in the obese women. There were no significant differences between lean and obese women in macronutrient oxidation or balances, so data were pooled. O(cho) induced glycogen storage on day 1 ( approximately 100 g) but thereafter progressively stimulated carbohydrate oxidation so that balance was reached on days 3 and 4. Fat oxidation was proportionately suppressed. Of the excess carbohydrate, 74% was oxidized; there were no significant differences between the various O(cho) treatments. O(fat) stimulated fat oxidation by 18% and suppressed carbohydrate oxidation. On average, 12% of the excess energy was stored as glycogen and 88% as fat; there was no significant difference between overfeeding treatments. There was no significant difference in fat balance during controlled overfeeding with fat, fructose, glucose, or sucrose.


Correlative Analysis of Vertebral Trabecular Bone Microarchitecture and Mechanical Properties: A Combined Ultra-high Field (7 Tesla) MRI and Biomechanical Investigation.
High-resolution imaging and biomechanical investigation of ex-vivo vertebrae. The aim of this study was to assess bone microarchitecture of cadaveric vertebrae using ultra-high field (UHF) 7 Tesla magnetic resonance imaging (MRI) and to determine whether the corresponding microarchitecture parameters were related to bone mineral density (BMD) and bone strength assessed by dual-energy x-ray absorptiometry (DXA) and mechanical compression tests. Limitations of DXA for the assessment of bone fragility and osteoporosis have been recognized and criteria of microarchitecture alteration have been included in the definition of osteoporosis. Although vertebral fracture is the most common osteoporotic fracture, no study has assessed directly vertebral trabecular bone microarchitecture. BMD of 24 vertebrae (L2, L3, L4) from eight cadavers was investigated using DXA. The bone volume fraction (BVF), trabecular thickness (Tb.Th), and trabecular spacing (Tb.Sp) of each vertebra were quantified using UHF MRI. Measurements were performed by two operators to characterize the inter-rater reliability. The whole set of specimens underwent mechanical compression tests to failure and the corresponding failure stress was calculated. The inter-rater reliability for bone microarchitecture parameters was good with intraclass correlation coefficients ranging from 0.82 to 0.94. Failure load and stress were significantly correlated with BVF, Tb.Sp, and BMD (P < 0.05). Tb.Th was only correlated with the failure stress (P < 0.05). Multiple regression analysis demonstrated that the combination of BVF and BMD improved the prediction of the failure stress from an adjusted R = 0.384 for BMD alone to an adjusted R = 0.414. We demonstrated for the first time that the vertebral bone microarchitecture assessed with UHF MRI was significantly correlated with biomechanical parameters. Our data suggest that the multimodal assessment of BMD and trabecular bone microarchitecture with UHF MRI provides additional information on the risk of vertebral bone fracture and might be of interest for the future investigation of selected osteoporotic patients. N /A.


Is prnt a pseudogene? Identification of ram Prt in testis and ejaculated spermatozoa.
A hallmark of prion diseases or transmissible spongiform encephalopaties is the conversion of the cellular prion protein (PrP(C)), expressed by the prion gene (prnp), into an abnormally folded isoform (PrP(Sc)) with amyloid-like features that causes scrapie in sheep among other diseases. prnp together with prnd (which encodes a prion-like protein designated as Doppel), and prnt (that encodes the prion protein testis specific--Prt) with sprn (shadow of prion protein gene, that encodes Shadoo or Sho) genes, constitute the "prion gene complex". Whereas a role for prnd in the proper functioning of male reproductive system has been confirmed, the function of prnt, a recently discovered prion family gene, comprises a conundrum leading to the assumption that ruminant prnt is a pseudogene with no protein expression. The main objective of the present study was to identify Prt localization in the ram reproductive system and simultaneously to elucidate if ovine prnt gene is transcribed into protein-coding RNA. Moreover, as Prt is a prnp-related protein, the amyloid propensity was also tested for ovine and caprine Prt. Recombinant Prt was used to immunize BALB/c mice, and the anti-Prt polyclonal antibody (APPA) immune response was evaluated by ELISA and Western Blot. When tested by indirect immunofluorescence, APPA showed high avidity to the ram sperm head apical ridge subdomain, before and after induced capacitation, but did not show the same behavior against goat spermatozoa, suggesting high antibody specificity against ovine-Prt. Prt was also found in the testis when assayed by immunohistochemistry during ram spermatogenesis, where spermatogonia, spermatocytes, spermatids and spermatozoa, stained positive. These observations strongly suggest ovine prnt to be a translated protein-coding gene, pointing to a role for Prt protein in the ram reproductive physiology. Besides, caprine Prt appears to exhibit a higher amyloid propensity than ovine Prt, mostly associated with its phenylalanine residue.


Home visiting programmes for the prevention of child maltreatment: cost-effectiveness of 33 programmes.
There is a body of published research on the effectiveness of home visiting for the prevention of child maltreatment, but little in the peer reviewed literature on cost-effectiveness or value to society. The authors sought to determine the cost-effectiveness of alternative home visiting programmes to inform policy. All trials reporting child maltreatment outcomes were identified through systematic review. Information on programme effectiveness and components were taken from identified studies, to which 2010 Australian unit costs were applied. Lifetime cost offsets associated with maltreatment were derived from a recent Australian study. Cost-effectiveness results were estimated as programme cost per case of maltreatment prevented and net benefit estimated by incorporating downstream cost savings. Sensitivity analyses were conducted. 33 home visiting programmes were evaluated and cost-effectiveness estimates derived for the 25 programmes not dominated. The incremental cost of home visiting compared to usual care ranged from A$1800 to A$30 000 (US$1800-US$30 000) per family. Cost-effectiveness estimates ranged from A$22 000 per case of maltreatment prevented to several million. Seven of the 22 programmes (32%) of at least adequate quality were cost saving when including lifetime cost offsets. There is great variation in the cost-effectiveness of home visiting programmes for the prevention of maltreatment. The most cost-effective programmes use professional home visitors in a multi-disciplinary team, target high risk populations and include more than just home visiting. Home visiting programmes must be carefully selected and well targeted if net social benefits are to be realised.


Efficacy of Group Cognitive-behavioral Therapy in Maintenance Treatment and Relapse Prevention for Bipolar Adolescents.
Despite conducting wide-ranging of pharmacotherapy for bipolar adolescents, many of them are showing a deficit in functioning with high relapse rate. The aim of the current study was to develop a manual and investigate the efficacy of group cognitive-behavioral therapy (G-CBT) for female bipolar adolescents. During the first qualitative phase of a mixed-methods study, a manual of G-CBT was developed. Then, 32 female bipolar adolescents aged 12-19 years old, receiving usual maintenance medications (UMM), were selected. Participants were randomized to the control (UMM) and intervention group (5, 2 h weekly sessions based on G-CBT manual with UMM). The parents in intervention group participated in three parallel sessions. All participants filled the following questionnaires before 1, 3, and 6 months after the initiation of the study: Young Mania Rating Scale, Children Depression Inventory and Global Assessment of Functioning. The results were analyzed using SPSS 21 software. The concurrent qualitative phase was analyzed through thematic analysis. The results showed no significant differences in all questionnaires' scores through intervention and follow-up sessions (P > 0.05). However, using cutoff point of CDI, G-CBT was effective for intervention group (relapse rate: 25% vs. 44.4%). Two themes were extracted from the second qualitative phase: emotion recognition and emotion regulation, especially in anger control. The results showed that the addition of G-CBT to UMM leads to decrease in the depressive scores but has no effect on manic symptoms and relapse rate.


Thermophilic anaerobic digestion of sewage sludge with high solids content.
The treatment performance of thermophilic anaerobic digestion (AD) of sewage sludge with high solids content was investigated with two laboratory-scale thermophilic anaerobic reactors (R1 and R2) with a feeding of pre-centrifuged sewage sludge. Reactor R1 was fed with sludge of 3.7% total solids (TS). The volatile solids (VS) removal ratio and methane yield in the stable state were 54.9% and 0.29 NL CH(4)/g VS(added), respectively. For reactor R2, when the TS content of fed sludge was 7.4%, the VS removal ratio and methane yield in the stable state were 73.2% and 0.38 NL CH(4)/g VS(added), respectively. When the TS content was increased to 9.5%, the VS removal ratio and methane yield slightly decreased to 69.3% and 0.32 NL CH(4)/g VS(added), respectively, but the reactor was stably operated. An increase of ammonia concentration was observed, but it was in the safe range without severe inhibition on the methane production. The result indicated that thermophilic AD could support sewage sludge with high TS content (9.5%) without abrupt deterioration of the treatment performance. The high-solids AD process is an economical method for centralized sewage sludge treatment with lower transport cost.


Knowledge of norovirus prevention and control among infection preventionists.
A Web-based survey was administered to infection preventionists (IPs) (N = 941) to characterize awareness and knowledge of norovirus (NoV). Only 44% of respondents correctly identified NoV as one of the 3 most common foodborne pathogens in the United States, and 5% correctly identified the 3 most common settings for NoV outbreaks. Several gaps in IPs' knowledge of NoV were identified; specifically, IPs could benefit from learning more about the natural history of NoV, modes of transmission, and cleaning and disinfection processes.


A life course approach to patterns and trends in modern Latin American sexual behavior.
This article explores trends in sexual behavior in Latin America, envisaged from a life-course perspective, taking into account social differences. It is focused on three main issues: the timing of early sexual and reproductive events, sexual activity during adulthood, and measurement of homosexuality-bisexuality. It draws on general population data from nonspecific surveys, as surveys dealing specifically with sexual behavior are scarce in Latin American countries. A traditional feature in these societies is the huge amount of social inequality, which translates directly into social differences in sexual experience, especially among women. Despite the decline in fertility, an early start of unions and of reproductive experience remains typical of groups with lower education. Another aspect is the diversity of national patterns and gender systems, very far from the image of cultural homogeneity generally associated with this region. Data show a low prevalence of homosexuality/bisexuality, which can be a result of underreporting. The paper eventually stresses the necessity of carrying out more sexual behavior surveys of the general population in the region.


Phase extraction from a single fringe pattern based on guidance of an extreme map.
A method for automatic phase extraction from a single fringe pattern based on the guidance of an extreme map is introduced. The method uses an adaptive weighted filter to reduce noise and enhance contrast and to locate the fringe extremes. Wrapped phase values are calculated by use of an arccosine function obtained from the extreme map. With this method, wrapped phase values can be efficiently demodulated from a single fringe pattern without the need for assigning fringe order or interpolating fractional fringe order. The validity of the method is demonstrated by use of closed-fringe patterns generated by digital speckle interferometry.


Timely monitoring of Asian Migratory locust habitats in the Amudarya delta, Uzbekistan using time series of satellite remote sensing vegetation index.
The Asian Migratory locust (Locusta migratoria migratoria L.) is a pest that continuously threatens crops in the Amudarya River delta near the Aral Sea in Uzbekistan, Central Asia. Its development coincides with the growing period of its main food plant, a tall reed grass (Phragmites australis), which represents the predominant vegetation in the delta and which cover vast areas of the former Aral Sea, which is desiccating since the 1960s. Current locust survey methods and control practices would tremendously benefit from accurate and timely spatially explicit information on the potential locust habitat distribution. To that aim, satellite observation from the MODIS Terra/Aqua satellites and in-situ observations were combined to monitor potential locust habitats according to their corresponding risk of infestations along the growing season. A Random Forest (RF) algorithm was applied for classifying time series of MODIS enhanced vegetation index (EVI) from 2003 to 2014 at an 8-day interval. Based on an independent ground truth data set, classification accuracies of reeds posing a medium or high risk of locust infestation exceeded 89% on average. For the 12-year period covered in this study, an average of 7504 km2 (28% of the observed area) was flagged as potential locust habitat and 5% represents a permanent high risk of locust infestation. Results are instrumental for predicting potential locust outbreaks and developing well-targeted management plans. The method offers positive perspectives for locust management and treatment of infested sites because it is able to deliver risk maps in near real time, with an accuracy of 80% in April-May which coincides with both locust hatching and the first control surveys. Such maps could help in rapid decision-making regarding control interventions against the initial locust congregations, and thus the efficiency of survey teams and the chemical treatments could be increased, thus potentially reducing environmental pollution while avoiding areas where treatments are most likely to cause environmental degradation.


Sporadic Burkitt lymphomas of children and adolescents in Chinese: a clinicopathological study of 43 cases.
To investigate the clinical and pathologic features as well as the MYC translocations of childhood Burkitt lymphoma (BL) from China. Fourty-three cases of childhood BL were retrospectively investigated in morphology, immunophenotype, genotype, treatments and survival analysis. Clinically, there was a marked male predominance in sex distribution (M: F=9.75:1); abdomen was the most frequent extranodal sites of involvement (46.5%), followed by jaws and facial bones (16.3%). Two third of the patients were in stageI ~ II. Morphologically, 69.76% of the cases showed classical histologic features, while 30.24% of them showed greater nuclear pleomorphism in size and shape. Five cases (11.6%) were positive for EBER1/2. Thirty-one of the 40 cases (77.5%) had the aberration of IGH/MYC translocation while 7 (17.5%) had non-IGH/MYC translocation. Thirty patients (69.7%) received operation and/or chemotherapy while 13 patients (30.3%) received no treatment. Twenty-seven patients (62.8%) died of the tumor, 16 alive, with the average survival time 4.9 and 48.7 months respectively. High IPI, advanced clinical stage, increased serum level of LDH and no chemotherapy received as well as tumor size≥10 cm were related to the lower survival rates of the tumor. Several differences were showed in this group of BL, including a much higher ratio of male patients, more cases in stageII, clinically inconsistent treatment and a very poor outcome. The virtual slide(s) for this article can be found here http://www.diagnosticpathology.diagnomx.eu/vs/1552295877710135.


Novel, objective, multivariate biomarkers composed of plasma amino acid profiles for the diagnosis and assessment of inflammatory bowel disease.
Inflammatory bowel disease (IBD) is a chronic intestinal disorder that is associated with a limited number of clinical biomarkers. In order to facilitate the diagnosis of IBD and assess its disease activity, we investigated the potential of novel multivariate indexes using statistical modeling of plasma amino acid concentrations (aminogram). We measured fasting plasma aminograms in 387 IBD patients (Crohn's disease (CD), n = 165; ulcerative colitis (UC), n = 222) and 210 healthy controls. Based on Fisher linear classifiers, multivariate indexes were developed from the aminogram in discovery samples (CD, n = 102; UC, n = 102; age and sex-matched healthy controls, n = 102) and internally validated. The indexes were used to discriminate between CD or UC patients and healthy controls, as well as between patients with active disease and those in remission. We assessed index performances using the area under the curve of the receiver operating characteristic (ROC AUC). We observed significant alterations to the plasma aminogram, including histidine and tryptophan. The multivariate indexes established from plasma aminograms were able to distinguish CD or UC patients from healthy controls with ROC AUCs of 0.940 (95% confidence interval (CI): 0.898-0.983) and 0.894 (95%CI: 0.853-0.935), respectively in validation samples (CD, n = 63; UC, n = 120; healthy controls, n = 108). In addition, other indexes appeared to be a measure of disease activity. These indexes distinguished active CD or UC patients from each remission patients with ROC AUCs of 0.894 (95%CI: 0.853-0.935) and 0.849 (95%CI: 0.770-0.928), and correlated with clinical disease activity indexes for CD (r(s) = 0.592, 95%CI: 0.385-0.742, p<0.001) or UC (r(s) = 0.598, 95%CI: 0.452-0.713, p<0.001), respectively. In this study, we demonstrated that established multivariate indexes composed of plasma amino acid profiles can serve as novel, non-invasive, objective biomarkers for the diagnosis and monitoring of IBD, providing us with new insights into the pathophysiology of the disease.


Large-area highly crystalline WSe2 atomic layers for ultrafast pulsed lasers.
Large-area and highly crystalline transition metal dichalcogenides (TMDs) films possess superior saturable absorption compared to the TMDs nanosheet counterparts, which make them more suitable as excellent saturable absorbers (SA) for ultrafast laser technology. Thus far, the nonlinear optical properties of large-scale WSe2 and its applications in ultrafast photonics have not yet been fully investigated. In this work, the saturable absorption of chemical vapor deposition (CVD) grown WSe2 films with large-scale and high quality are studied and the use of WSe2 films as a broadband SA for passively mode-locked fiber lasers at both 1.5 and 2 μm ranges is demonstrated. To enhance the light-material interaction, large-area WSe2 film is tightly transferred onto the side wall of a microfiber to form a hybrid structure, which realizes strong evanescent wave interaction between light and WSe2 film. The integrated microfiber-WSe2 device shows a large modulation depth of 54.5%. Using the large-area WSe2 as a mode-locker, stable soliton mode-locked pulse generation is achieved and the pulse durations of 477 fs (at 1.5 μm) and 1.18 ps (at 2.0 μm) are demonstrated, which suggests that the large-area and highly crystalline WSe2 films afford an excellent broadband SA for ultrafast photonic applications.


Estimating African American admixture proportions by use of population-specific alleles.
We analyzed the European genetic contribution to 10 populations of African descent in the United States (Maywood, Illinois; Detroit; New York; Philadelphia; Pittsburgh; Baltimore; Charleston, South Carolina; New Orleans; and Houston) and in Jamaica, using nine autosomal DNA markers. These markers either are population-specific or show frequency differences >45% between the parental populations and are thus especially informative for admixture. European genetic ancestry ranged from 6.8% (Jamaica) to 22.5% (New Orleans). The unique utility of these markers is reflected in the low variance associated with these admixture estimates (SEM 1.3%-2.7%). We also estimated the male and female European contribution to African Americans, on the basis of informative mtDNA (haplogroups H and L) and Y Alu polymorphic markers. Results indicate a sex-biased gene flow from Europeans, the male contribution being substantially greater than the female contribution. mtDNA haplogroups analysis shows no evidence of a significant maternal Amerindian contribution to any of the 10 populations. We detected significant nonrandom association between two markers located 22 cM apart (FY-null and AT3), most likely due to admixture linkage disequilibrium created in the interbreeding of the two parental populations. The strength of this association and the substantial genetic distance between FY and AT3 emphasize the importance of admixed populations as a useful resource for mapping traits with different prevalence in two parental populations.


Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: a clinical study.
To explore the clinical significance of seven diabetes-related serum microRNAs (miR-9, miR-29a, miR-30d, miR34a, miR-124a, miR146a and miR375) during the pathogenesis of type 2 diabetes (T2D), 56 subjects were recruited to this study: 18 cases of newly diagnosed T2D (n-T2D) patients, 19 cases of pre-diabetes individuals (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) and 19 cases of T2D-susceptible individuals with normal glucose tolerance (s-NGT). Serum miRNAs were determined by real-time RT-PCR. Expression levels of single miRNAs and the expression signatures of miRNAs as a panel were analysed among the three groups. In n-T2D, all 7 miRNAs were significantly up-regulated compared with s-NGT and five were significantly up-regulated compared with pre-diabetes, while miRNA expression was not significantly different between s-NGT and pre-diabetes. By Canonical discriminant analysis, 70.6% of n-T2D subjects (12/17) were recognized by canonical discriminant function, while s-NGT and pre-diabetes subjects could not be discriminated from each other. Similar results were found in Hierarchical Clustering analysis based on the expression levels of all seven miRNAs. In different statistical analysis, miR-34a always showed the most significant differences. We conclude that the expression levels of seven diabetes-related miRNAs in serum were significantly elevated in n-T2D compared with pre-diabetes and/or s-NGT, and the latter two groups featured similar expression patterns of these miRNAs, suggesting that during the pathogenesis of T2D, the peripheral diabetes-related miRNAs have not changed significantly from s-NGT at pre-diabetic stage.


Explaining the persistent influence of facial cues in social decision-making.
Impressions of trustworthiness based on facial cues influence many consequential decisions, in spite of their (generally) poor accuracy. Here, we test whether reliance on facial cues can be better explained by (a) the belief that facial cues are more valid than other cues or by (b) the quick and primary processing of faces, which makes relying on facial cues relatively effortless. Six studies (N = 2,732 with 73,182 trust decisions) test the two accounts by comparing the effects of facial cues and economic payoffs on trust decisions. People believe that facial cues are less valid than economic payoffs (Study 1) but relying on facial cues takes less time than relying on economic payoffs (Study 2). Critically, introducing facial cues causes people to discount payoff information, but introducing payoff information does not reduce the effect of facial cues (Studies 3a-c). Finally, when making intuitive (vs. reflective) trust decisions, people rely less on payoff information, but they do not rely less on facial cues (Study 4). Together, these findings suggest that persistent reliance on facial trustworthiness is better explained by the intuitive accessibility of facial cues, rather than beliefs that facial cues are particularly valid. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Clinical and epidemiological performance of WHO Ebola case definitions: a systematic review and meta-analysis.
Ebola virus disease case definition is a crucial surveillance tool to detect suspected cases for referral and as a screening tool for clinicians to support admission and laboratory testing decisions at Ebola health facilities. We aimed to assess the performance of the WHO Ebola virus disease case definitions and other screening scores. In this systematic review and meta-analysis, we searched PubMed, Scopus, Embase, and Web of Science for studies published in English between June 13, 1978, and Jan 14, 2020. We included studies that estimated the sensitivity and specificity of WHO Ebola virus disease case definitions, clinical and epidemiological characteristics (symptoms at admission and contact history), and predictive risk scores against the reference standard (laboratory-confirmed Ebola virus disease). Summary estimates of sensitivity and specificity were calculated using bivariate and hierarchical summary receiver operating characteristic (when four or more studies provided data) or random-effects meta-analysis (fewer than four studies provided data). We identified 2493 publications, of which 14 studies from four countries (Sierra Leone, Guinea, Liberia, and Angola) were included in the analysis. 12 021 people with suspected disease were included, of whom 4874 were confirmed as positive for Ebola virus infection. Six studies explored the performance of WHO case definitions in non-paediatric populations, and in all of these studies, suspected and probable cases were combined and could not be disaggregated for analysis. The pooled sensitivity of the WHO Ebola virus disease case definitions from these studies was 81·5% (95% CI 74·1-87·2) and pooled specificity was 35·7% (28·5-43·6). History of contact or epidemiological link was a key predictor for the WHO case definitions (seven studies) and for risk scores (six studies). The most sensitive symptom was intense fatigue (79·0% [95% CI 74·4-83·0]), assessed in seven studies, and the least sensitive symptom was pain behind the eyes (1·0% [0·0-7·0]), assessed in three studies. The performance of fever as a symptom varied depending on the cutoff used to define fever. WHO Ebola virus disease case definitions perform suboptimally to identify cases at both community level and during triage at Ebola health facilities. Inclusion of intense fatigue as a key symptom and contact history could improve the performance of case definitions, but implementation of these changes will require effective collaboration with, and trust of, affected communities. Médecins sans Frontières.


TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia.
Stromal cells can have a significant impact on the carcinogenic process in adjacent epithelia. The role of transforming growth factor-beta (TGF-beta) signaling in such epithelial-mesenchymal interactions was determined by conditional inactivation of the TGF-beta type II receptor gene in mouse fibroblasts (Tgfbr2fspKO). The loss of TGF-beta responsiveness in fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach, both associated with an increased abundance of stromal cells. Activation of paracrine hepatocyte growth factor (HGF) signaling was identified as one possible mechanism for stimulation of epithelial proliferation. Thus, TGF-beta signaling in fibroblasts modulates the growth and oncogenic potential of adjacent epithelia in selected tissues.


Breathing systems for use in anaesthesia. Evaluation using a physical lung model and classification.
A lung model which measures effective alveolar ventilation is described and used to evaluate different breathing systems during simulated spontaneous ventilation. The model measures VD/VT ratios in relation to fresh gas flow and the characteristic shape of the resulting curve characterizes the particular breathing system. The various curves reflect the functional performance and, therefore, the flow requirements of the systems which have been reclassified accordingly. The classification described is based upon the structural arrangements which determine the flow patterns within the particular systems. The breathing systems compared during spontaneous ventilation were a circle "C" absorber system, the circle "C" without the absorber, the Mapleson A, B, C and D systems and a series of "enclosed" and modified Mapleson A systems and the modified Mapleson D or Bain system.


Congruent genetic structure in the lichen-forming fungus Lobaria pulmonaria and its green-algal photobiont.
The extent of codispersal of symbionts is one of the key factors shaping genetic structures of symbiotic organisms. Concordant patterns of genetic structure are expected in vertically transmitted symbioses, whereas horizontal transmission generally uncouples genetic structures unless the partners are coadapted. Here, we compared the genetic structures of mutualists, the lichen-forming fungus Lobaria pulmonaria and its primary green-algal photobiont, Dictyochloropsis reticulata. We performed analysis of molecular variance and variogram analysis to compare genetic structures between symbiosis partners. We simulated the expected number of multilocus-genotype recurrences to reveal whether the distribution of multilocus genotypes of either species was concordant with panmixia. Simulations and tests of linkage disequilibrium provided compelling evidence for the codispersal of mutualists. To test whether genotype associations between symbionts were consistent with randomness, as expected under horizontal transmission, we simulated the recurrence of fungal-algal multilocus genotype associations expected by chance. Our data showed nonrandom associations of fungal and algal genotypes. Either vertical transmission or horizontal transmission coupled with coadaptation between symbiont genotypes may have created these nonrandom associations. This study is among the first to show codispersal and highly congruent genetic structures in the partners of a lichen mutualism.


Precursors of insight in event-related brain potentials.
Event-related potentials (ERPs) were investigated to find precursors of insightful behavior. Participants had to process successive pairs in strings of digits to obtain a final response in each trial. Within the sequence of five responses required in each trial, the last two responses mirrored the two preceding ones. This hidden regularity, allowing for shortcutting each trial from five to two responses, was discovered by 6 out of 26 participants. Both groups, solvers and nonsolvers, implicitly learned the regularity, reflected by faster responses to the repeated, predictable responses, but this differential effect was larger in solvers, whereas nonsolvers became unspecifically faster with all responses. Several ERP components were larger in solvers than in nonsolvers from the outset: slow positive wave, frontocentral P3a, anterior N1 to those digits that triggered the critical repeating responses, and P3b to the digit that evoked the immediately repeating response. Being already present in the first block, these effects were early precursors of insightful behavior. This early occurrence suggests that participants who will gain insight may be distinguished beforehand by their individual characteristics.


EGFR-targeted liposomal nanohybrid cerasomes: theranostic function and immune checkpoint inhibition in a mouse model of colorectal cancer.
Epidermal growth factor receptor (EGFR) is a major target for the treatment of colorectal cancers (CRCs), and programmed death ligand-1 (PD-L1) is an attractive target for CRC immunotherapy. Herein, we report the synthesis of porphyrin-containing liposomal nanohybrid cerasomes decorated with cetuximab, an anti-EGFR antibody, and conjugated with IRDye800CW and MRI contrast DOTA-Gd, to enable in vivo tumor detection and photodynamic therapy (PDT). Moreover, PD-L1 was added for adjuvant therapy. The antitumor efficacy of PDT combined with PD-L1 immunotherapy was assessed. EGFR-targeted nanoparticles showed the targeted imaging of tumors. EGFR-targeted PDT combined with PD-L1 immunotherapy was more effective against tumor growth than simultaneous albeit nontargeted nanoparticle delivery with laser irradiation plus PD-L1 immunotherapy. Thus, EGFR-targeted nanoparticles exhibited significant potential toward dual-modality imaging-guided precise PDT, combined with immunotherapy.


Bone stress injury of the ankle in professional ballet dancers seen on MRI.
Ballet dancers have been shown to have a relatively high incidence of stress fractures of the foot and ankle. It was our objective to examine MR imaging patterns of bone marrow edema (BME) in the ankles of high performance professional ballet dancers, to evaluate clinical relevance. MR Imaging was performed on 12 ankles of 11 active professional ballet dancers (6 female, 5 male; mean age 24 years, range 19 to 32). Individuals were imaged on a 0.2 T or 1.5 T MRI units. Images were evaluated by two musculoskeletal radiologists and one orthopaedic surgeon in consensus for location and pattern of bone marrow edema. In order to control for recognized sources of bone marrow edema, images were also reviewed for presence of osseous, ligamentous, tendinous and cartilage injuries. Statistical analysis was performed to assess the strength of the correlation between bone marrow edema and ankle pain. Bone marrow edema was seen only in the talus, and was a common finding, observed in nine of the twelve ankles imaged (75%) and was associated with pain in all cases. On fluid-sensitive sequences, bone marrow edema was ill-defined and centered in the talar neck or body, although in three cases it extended to the talar dome. No apparent gender predilection was noted. No occult stress fracture could be diagnosed. A moderately strong correlation (phi = 0.77, p= 0.0054) was found between edema and pain in the study population. Bone marrow edema seems to be a specific MRI finding in the talus of professional ballet dancers, likely related to biomechanical stress reactions, due to their frequently performed unique maneuvers. Clinically, this condition may indicate a sign of a bone stress injury of the ankle.


Peptide modulators of Src activity in G1 regulate entry into S phase and proliferation of NIH 3T3 cells.
Cascades of kinases and phosphatases are regulated by selective protein-protein interactions that are essential for signal transduction. Peptide modulators of these interactions have been used to dissect the function of individual components of the signaling cascade, without relying on either the over- or underexpression of proteins. Previously, we identified RACK1 as an endogenous substrate, binding partner and inhibitor of Src tyrosine kinases. Here, we utilized cell-permeable peptides that selectively disrupt or enhance the interaction of RACK1 and Src to further examine the function of RACK1. Our results provide direct physiologic evidence that RACK1 regulates growth of NIH3T3 cells by suppressing the activity of Src and other cell cycle regulators in G1, and delaying entry into S phase. They also demonstrate the potential for using peptide modulators of Src activity as a tool for regulating cell growth, and for designing new strategies for cancer therapy that target specific protein-protein interactions.


Fungus infections after liver transplantation.
The problem of fungus infections after liver transplantation was studied. In 100 consecutive recipients of orthotopic liver homografts there were 10 and 8 examples, respectively, of localized and disseminated infections caused by Candida species. Candidemia was demonstrated in 8 of these 18 patients. One patient who had a localized Candida infection also had disseminated cryptococcosis. An additional 31 patients were infested in that Candida could be cultured from sites where it is not normally found, such as the blood (8 examples), urine (8), ascitic fluid (8), and wounds (22). This exorbitant incidence of monilial infections and infestations was associated with a high frequency of complications involving the homograft as well as the hosts' gastrointestinal tract during the post-transplantation period. The yeasts found in blood, urine, ascitic fluid and elsewhere were thought to have originated from the gut. Ten of the 100 patients had aspergillosis which was localized in 7 instances and disseminated in 3. The lung was the most frequently affected organ. The fungus infections played a contributory role in the downhill course of our patients but in the event of death more fundamental and more frequent causes of failure were technical complications involving the homografts, difficulties in controlling rejection with reasonable immunosuppressive doses and bacterial sepsis. Suggestions have been made for the better control of fungal infections in liver recipients.


Visual Tracking with Multiview Trajectory Prediction.
Recent progresses in visual tracking have greatly improved the tracking performance. However, challenges such as occlusion and view change remain obstacles in real world deployment. A natural solution to these challenges is to use multiple cameras with multiview inputs, though existing systems are mostly limited to specific targets (e.g. human), static cameras, and/or require camera calibration. To break through these limitations, we propose a generic multiview tracking (GMT) framework that allows camera movement, while requiring neither specific object model nor camera calibration. A key innovation in our framework is a cross-camera trajectory prediction network (TPN), which implicitly and dynamically encodes camera geometric relations, and hence addresses missing target issues such as occlusion. Moreover, during tracking, we assemble information across different cameras to dynamically update a novel collaborative correlation filter (CCF), which is shared among cameras to achieve robustness against view change. The two components are integrated into a correlation filter tracking framework, where features are trained offline using existing single view tracking datasets. For evaluation, we first contribute a new generic multiview tracking dataset (GMTD) with careful annotations, and then run experiments on the GMTD and CAMPUS datasets. The proposed GMT algorithm shows clear advantages in terms of robustness over state-of-the-art ones.


Identification of five clusters of comorbidities in a longitudinal Japanese chronic obstructive pulmonary disease cohort.
Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from various comorbidities. Recently, cluster analysis has been proposed to examine the phenotypic heterogeneity in COPD. In order to comprehensively understand the comorbidities of COPD in Japan, we conducted multicenter, longitudinal cohort study, called the Keio COPD Comorbidity Research (K-CCR). In this cohort, comorbid diagnoses were established by both objective examination and review of clinical records, in addition to self-report. We aimed to investigate the clustering of nineteen clinically relevant comorbidities and the meaningful outcomes of the clusters over a two-year follow-up period. The present study analyzed data from COPD patients whose data of comorbidities were completed (n = 311). Cluster analysis was performed using Ward's minimum-variance method. Five comorbidity clusters were identified: less comorbidity; malignancy; metabolic and cardiovascular; gastroesophageal reflux disease (GERD) and psychological; and underweight and anemic. FEV1 did not differ among the clusters. GERD and psychological cluster had worse COPD assessment test (CAT) and Saint George's respiratory questionnaire (SGRQ) at baseline compared to the other clusters (CAT: p = 0.0003 and SGRQ: p = 0.00046). The rate of change in these scores did not differ within 2 years. The underweight and anemic cluster included subjects with lower baseline ratio of predicted diffusing capacity (DLco/VA) compared to the malignancy cluster (p = 0.036). Five clusters of comorbidities were identified in Japanese COPD patients. The clinical characteristics and health-related quality of life were different among these clusters during a follow-up of two years.


Transcriptome analysis of embryonic domains in Norway spruce reveals potential regulators of suspensor cell death.
The terminal differentiation and elimination of the embryo-suspensor is the earliest manifestation of programmed cell death (PCD) during plant ontogenesis. Molecular regulation of suspensor PCD remains poorly understood. Norway spruce (Picea abies) embryos provide a powerful model for studying embryo development because of their large size, sequenced genome, and the possibility to obtain a large number of embryos at a specific developmental stage through somatic embryogenesis. Here, we have carried out global gene expression analysis of the Norway spruce embryo-suspensor versus embryonal mass (a gymnosperm analogue of embryo proper) using RNA sequencing. We have identified that suspensors have enhanced expression of the NAC domain-containing transcription factors, XND1 and ANAC075, previously shown to be involved in the initiation of developmental PCD in Arabidiopsis. The analysis has also revealed enhanced expression of Norway spruce homologues of the known executioners of both developmental and stress-induced cell deaths, such as metacaspase 9 (MC9), cysteine endopeptidase-1 (CEP1) and ribonuclease 3 (RNS3). Interestingly, a spruce homologue of bax inhibitor-1 (PaBI-1, for Picea abies BI-1), an evolutionarily conserved cell death suppressor, was likewise up-regulated in the embryo-suspensor. Since Arabidopsis BI-1 so far has been implicated only in the endoplasmic reticulum (ER)-stress induced cell death, we investigated its role in embryogenesis and suspensor PCD using RNA interference (RNAi). We have found that PaBI-1-deficient lines formed a large number of abnormal embryos with suppressed suspensor elongation and disturbed polarity. Cytochemical staining of suspensor cells has revealed that PaBI-1 deficiency suppresses vacuolar cell death and induces necrotic type of cell death previously shown to compromise embryo development. This study demonstrates that a large number of cell-death components are conserved between angiosperms and gymnosperms and establishes a new role for BI-1 in the progression of vacuolar cell death.


Cortical network resonance and motor activity in humans.
Large areas of the human motor cortex are devoted to the control of the contralateral hand and forearm. Just how activities scattered across these motor areas may be brought together in the execution of a given movement remains unclear. There is increasing evidence, largely from animal studies, suggesting that sensory integration involves the synchronization of activity between spatially distributed cortical sites. Here we review recent evidence that cortical activity becomes oscillatory and synchronized between spatially distributed sites during performance of a movement in humans. Cortico-cortical synchronization may occur with a precision in the millisecond range, is essentially limited to those cortical elements active in a given task, and changes in both its distribution and frequency in a task-related manner. Synchronization at specific frequencies may therefore link disparate cortical activities into the functional ensembles underlying voluntary movement in humans.


Archaeal MBF1 binds to 30S and 70S ribosomes via its helix-turn-helix domain.
MBF1 (multi-protein bridging factor 1) is a protein containing a conserved HTH (helix-turn-helix) domain in both eukaryotes and archaea. Eukaryotic MBF1 has been reported to function as a transcriptional co-activator that physically bridges transcription regulators with the core transcription initiation machinery of RNA polymerase II. In addition, MBF1 has been found to be associated with polyadenylated mRNA in yeast as well as in mammalian cells. aMBF1 (archaeal MBF1) is very well conserved among most archaeal lineages; however, its function has so far remained elusive. To address this, we have conducted a molecular characterization of this aMBF1. Affinity purification of interacting proteins indicates that aMBF1 binds to ribosomal subunits. On sucrose density gradients, aMBF1 co-fractionates with free 30S ribosomal subunits as well as with 70S ribosomes engaged in translation. Binding of aMBF1 to ribosomes does not inhibit translation. Using NMR spectroscopy, we show that aMBF1 contains a long intrinsically disordered linker connecting the predicted N-terminal zinc-ribbon domain with the C-terminal HTH domain. The HTH domain, which is conserved in all archaeal and eukaryotic MBF1 homologues, is directly involved in the association of aMBF1 with ribosomes. The disordered linker of the ribosome-bound aMBF1 provides the N-terminal domain with high flexibility in the aMBF1-ribosome complex. Overall, our findings suggest a role for aMBF1 in the archaeal translation process.


Magneto-electric nanoparticles to enable field-controlled high-specificity drug delivery to eradicate ovarian cancer cells.
The nanotechnology capable of high-specificity targeted delivery of anti-neoplastic drugs would be a significant breakthrough in Cancer in general and Ovarian Cancer in particular. We addressed this challenge through a new physical concept that exploited (i) the difference in the membrane electric properties between the tumor and healthy cells and (ii) the capability of magneto-electric nanoparticles (MENs) to serve as nanosized converters of remote magnetic field energy into the MENs' intrinsic electric field energy. This capability allows to remotely control the membrane electric fields and consequently trigger high-specificity drug uptake through creation of localized nano-electroporation sites. In in-vitro studies on human ovarian carcinoma cell (SKOV-3) and healthy cell (HOMEC) lines, we applied a 30-Oe d.c. field to trigger high-specificity uptake of paclitaxel loaded on 30-nm CoFe₂O₄ @BaTiO₃ MENs. The drug penetrated through the membrane and completely eradicated the tumor within 24 hours without affecting the normal cells.


Intracavity optical trapping of microscopic particles in a ring-cavity fiber laser.
Standard optical tweezers rely on optical forces arising when a focused laser beam interacts with a microscopic particle: scattering forces, pushing the particle along the beam direction, and gradient forces, attracting it towards the high-intensity focal spot. Importantly, the incoming laser beam is not affected by the particle position because the particle is outside the laser cavity. Here, we demonstrate that intracavity nonlinear feedback forces emerge when the particle is placed inside the optical cavity, resulting in orders-of-magnitude higher confinement along the three axes per unit laser intensity on the sample. This scheme allows trapping at very low numerical apertures and reduces the laser intensity to which the particle is exposed by two orders of magnitude compared to a standard 3D optical tweezers. These results are highly relevant for many applications requiring manipulation of samples that are subject to photodamage, such as in biophysics and nanosciences.


Synergistic effect of apoptosis and necroptosis inhibitors in cisplatin-induced nephrotoxicity.
Necroptosis is a nonapoptotic cell death pathway. We aim to study the effect of necrostatin-1 (a specific necroptosis inhibitor) in cisplatin-induced injury. We analyzed the effect of the combined use of inhibitors of apoptosis (z-vad) and necroptosis (necrostatin-1) in acute kidney injury by cisplatin in human proximal tubule cells. Our results showed moderate effectiveness in cytoprotection after treatment with z-vad. But the concomitant use of inhibitors (z-vad and necrostatin-1) presented synergistic and additive protection. The present study analyzed the caspase-3 activity and we observed a significant decrease in the group treated with z-vad and cisplatin. However we did not observe changes in the group treated with both inhibitors (z-vad and necrostatin-1) and cisplatin. Thus, demonstrating that necroptosis is a caspase-independent mechanism. We also analyzed the effect of necrostatin-1 in vivo model. C57BL/6 mice were treated with cisplatin and/or inhibitors. The concomitant use of inhibitors (z-vad and necrostatin-1) recovered renal function and decreased levels of urinary Ngal. Additionally, we analyzed the expression of RIP-1, a specific marker for necroptosis. In animals treated with cisplatin and z-VAD levels of RIP-1 were higher. This result reinforces that necroptosis occurs only in conditions where apoptosis was blocked. However, the use of both inhibitors (z-vad and necrostatin-1) provided additional protection. In conclusion, our study has a significant potential to show in vitro and in vivo protection obtained by necrostatin-1. Therefore, our results suggest that necroptosis may be an important mechanism of cell death after kidney injury.


IRF8 mutations and human dendritic-cell immunodeficiency.
The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained. We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease. We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells. These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.).


Free lunches and student involvement.
Dental students have precious little free time, so the challenge of promoting involvement in discussion about issues that affect their future becomes one of many priorities. The staple in schools has been the free lunch with an invited speaker, and that has not worked well. At the University of Southern California (USC) dental school we experimented with making time and opportunity for students to engage multiple outside parties on a single topic, initial licensure. This case describes a much more engaged study response.


Bone mass and muscle strength in young female soccer players.
In this cross-sectional study, bone mass and muscle strength of the thigh were investigated in 51 female soccer players, age 16.3 +/- 0. 3 years, who had been playing soccer for 8.1 +/- 2.1 years and were at the time of the study in soccer training for 5.0 +/- 1.7 hours/week. They were compared with 41 nonactive females, age 16.2 +/- 1.3 years. The groups were matched according to age, weight, and height. Areal bone mineral density (BMD) was measured of the total body, head, lumbar spine, femoral neck, Ward's triangle, and the greater trochanter using dual energy X-ray absorptiometry (DXA). Isokinetic muscle strength of the quadriceps and hamstrings muscles was measured using an isokinetic dynamometer. Compared with the nonactives, the soccer players had significantly higher BMD of the total body (2.7%), lumbar spine (6.1%), the dominant and nondominant hip (all sites). The largest differences were found in the greater trochanter on both sides (dominant, 16.5%, nondominant, 14.8%). The soccer players had significantly higher concentric and eccentric peak torque of the thigh muscles. In the soccer group, there was only a positive association between thigh muscle strength and BMD of the adjacent hip, and in the nonactive group there were several positive associations between muscle strength and BMD. However, when adjusting for the variation in weight and height all these associations became nonsignificant. Using multiple linear regression, the type of activity (soccer player, nonactive) independently predicted BMD of all dominant hip sites (beta = 0.32-0.48, P < 0.01). No other variable was found to independently predict BMD of any site. In the younger subjects (</=16 years) only BMD of the greater trochanter was significantly higher in the soccer players. In the older subjects (>16 years) the soccer players had significantly higher BMD in all measured sites except for the nonweight-bearing head. The differences in muscle strength between soccer players and nonactives were already seen in the young age group. In conclusion, girls who train and play soccer in adolescence have a higher bone mass in the hip and lumbar spine, and a higher muscle strength of the thigh compared with nonactive controls, indicating a site-specific skeletal response of weight-bearing and impact-loadng acting on the skeleton. The differences in bone mass were already apparent in early adolescence, but became more pronounced in late adolescence, probably explained by a longer exposure to soccer training with time. Our results also indicate that muscle strength in itself might not be of decisive importance for bone mass in the hip of adolescent females.


Developmental change in fetal response to repeated low-intensity sound.
The aim of this study was to investigate developmental changes in heart rate response to repeated low-intensity (85 dB) sound stimulation in fetuses between 32 and 37 weeks of gestation. We measured amplitude changes in heart rate as our index of fetal response. At 35 to 37 weeks of gestation, the majority of fetuses showed a deceleratory response at the first trial. Amplitude decreased with further trials using the same stimulus before recovering when exposed to another type of stimulation. In contrast, responses in fetuses at 32 to 34 weeks of gestation were variable across trials and there was no recovery with exposure to another type of stimulation. Our results suggest that fetal habituation of cardiac response changes with developmental age.


Determinants of change in patella cartilage volume in healthy subjects.
To examine whether the amount of patella cartilage in healthy, middle-aged subjects is stable or changes over time, and what factors may influence the changes. Eighty-five subjects (28 men and 57 women, mean age 55.5 yrs) had magnetic resonance imaging of their dominant knee at baseline and 2 years later. Patella and tibial cartilage volume was measured at baseline and followup. Risk factors assessed at baseline were tested for their association with change in patella cartilage volume over time. Mean annual percentage loss of patella cartilage was 2.1 (95% confidence interval: 1.1-3.2; p < 0.001). Age, gender, body mass index, and initial cartilage volume did not affect rate of change of patellar cartilage volume. There was a weak association between change in patellar cartilage volume and change in lateral tibial cartilage volume (R = 0.23, p = 0.03) but not medial tibial cartilage volume (R = 0.09, p = 0.43). In healthy subjects, a significant amount of patella cartilage is lost annually. The poor correlation between patella and tibial cartilage loss suggests that pathogenetic mechanisms for osteoarthritis in the patellofemoral and tibiofemoral joint may differ. Further work will be required to determine whether the rate of patella cartilage loss in healthy subjects is steady or phasic, and to determine which factors can be modified to reduce cartilage loss.


Association of beta2-adrenergic receptor and insulin receptor substrate-1 polymorphisms with obesity in a Northern Indian population.
Imbalance in hormonal levels, regulated by host genetic factors, are known to be a major cause of obesity. Therefore, we aimed to evaluate association of genetic polymorphisms of beta(2)-adrenergic receptor (beta(2)-AR) and insulin receptor substrate-1 (IRS-1) with hormonal levels in northern Indian obese. A total of 111 obese and 89 age matched non-obese subjects were studied after taking detailed clinical profile. Hormonal assays in serum/plasma for different hormones were done using IRMA and RIA kits. Genetic analysis of beta(2)-AR (-47 and -20, T to C) and IRS-1 (Arg972Gly) was done using PCR-RFLP. Statistical analysis was performed by SPSS (version 11.5) software. All continuous variables were expressed as mean +/- SD and tested by ANOVA test. Comparisons of categorical variables were assessed using X(2) tests or Fisher's exact test. P-value <0.05 was considered as significant. Analysis showed that obese subjects had significantly higher value of blood pressure (systolic), WHR, leptin insulin and glucagon and lower value of GH. In beta(2)-AR (-47) T/C and IRS-1 Gly972Arg gene polymorphisms we did not found significant differences in genotype or allele frequencies. Moreover, none of the studied hormonal or metabolic parameters showed any association with the gene polymorphisms. Study reveals no significant association of beta(2)-AR (-47 and -20, T to C) and IRS-1 Gly 972 Arg polymorphisms with obesity in northern Indians.


Pyrvinium pamoate changes alternative splicing of the serotonin receptor 2C by influencing its RNA structure.
The serotonin receptor 2C plays a central role in mood and appetite control. It undergoes pre-mRNA editing as well as alternative splicing. The RNA editing suggests that the pre-mRNA forms a stable secondary structure in vivo. To identify substances that promote alternative exons inclusion, we set up a high-throughput screen and identified pyrvinium pamoate as a drug-promoting exon inclusion without editing. Circular dichroism spectroscopy indicates that pyrvinium pamoate binds directly to the pre-mRNA and changes its structure. SHAPE (selective 2'-hydroxyl acylation analysed by primer extension) assays show that part of the regulated 5'-splice site forms intramolecular base pairs that are removed by this structural change, which likely allows splice site recognition and exon inclusion. Genome-wide analyses show that pyrvinium pamoate regulates >300 alternative exons that form secondary structures enriched in A-U base pairs. Our data demonstrate that alternative splicing of structured pre-mRNAs can be regulated by small molecules that directly bind to the RNA, which is reminiscent to an RNA riboswitch.


The Impact of Medicaid Expansion on Diabetes Management.
Diabetes is a chronic health condition contributing to a substantial burden of disease. According to the Robert Wood Johnson Foundation, 10.9 million people were newly insured by Medicaid between 2013 and 2016. Considering this coverage expansion, the Affordable Care Act (ACA) could significantly affect people with diabetes in their management of the disease. This study evaluates the impact of the Medicaid expansion under the ACA on diabetes management. This study includes 22,335 individuals with diagnosed diabetes from the 2011 to 2016 Behavioral Risk Factor Surveillance System. It uses a difference-in-differences approach to evaluate the impact of the Medicaid expansion on self-reported access to health care, self-reported diabetes management, and self-reported health status. Additionally, it performs a triple-differences analysis to compare the impact between Medicaid expansion and nonexpansion states considering diabetes rates of the states. Significant improvements in Medicaid expansion states as compared with non-Medicaid expansion states were evident in self-reported access to health care (0.09 score; P = 0.023), diabetes management (1.91 score; P = 0.001), and health status (0.10 score; P = 0.026). Among states with large populations with diabetes, states that expanded Medicaid reported substantial improvements in these areas in comparison with those that did not expand. The Medicaid expansion has significant positive effects on self-reported diabetes management. While states with large diabetes populations that expanded Medicaid have experienced substantial improvements in self-reported diabetes management, non-Medicaid expansion states with high diabetes rates may be facing health inequalities. The findings provide policy implications for the diabetes care community and policy makers.


Clarithromycin as monotherapy for eradication of Helicobacter pylori: a randomized, double-blind trial.
Current regimens to eradicate Helicobacter pylori usually consist of metronidazole plus a bismuth compound, as well as a third agent such as tetracycline. Such regimens are not ideal because organisms may be metronidazole-resistant, side-effects occur, and compliance is often poor. This randomized, double-blind study was designed to assess the ability of clarithromycin, a new macrolide antimicrobial, as monotherapy to eradicate H. pylori. Thirty-seven healthy volunteers who were H. pylori positive by 13C-urea breath test plus histology and/or culture completed 14 days of oral therapy with clarithromycin in one of three dosages. Eradication, defined as all three tests negative at 4-6 wk after the end of therapy, was achieved in 2/13 (15%) with clarithromycin 500 mg bid, 4/11 (36%) with 1000 mg bid, and 7/13 (54%) with 500 mg qid. Isolates of H. pylori were resistant to clarithromycin prior to therapy in 12% of subjects, and became resistant during therapy in 21% of subjects. Taste perversion, the most common side effect, resulted in one subject terminating therapy. Whereas clarithromycin is a promising antimicrobial in the eradication of H. pylori, it is not sufficient to be used as monotherapy.


Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita.
The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human CLCN1 gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing CLCN1 mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions.


Mechanical support in dilated cardiomyopathy: signs of early left ventricular recovery.
Recent reports have documented left ventricular recovery in patients with dilated cardiomyopathy off-loaded long term with a left ventricular assist device. We sought to document the natural history of left ventricular recovery. We implanted the TCI left ventricular assist device without the intention to perform transplantation in 2 patients with dilated cardiomyopathy who had been rejected for transplantation. Both were in New York Heart Association functional class IV and had renal failure. One was a diabetic. We studied left ventricular function with detailed echocardiography at 4, 6, and 8 weeks postoperatively. With the left ventricular assist device turned off, we observed a progressive increase in myocardial contractility beginning as early as 4 weeks after implantation and improving progressively. Histologic examination showed resolution of myocytolysis in both patients. Left ventricular recovery begins earlier than was previously suspected. Mechanical bridge to myocardial recovery is a potential approach to therapy for such patients.


Dose-effect relationship between drinking water fluoride levels and damage to liver and kidney functions in children.
Although a dose-effect relationship between water fluoride levels and damage to liver and kidney functions in animals has been reported, it was not demonstrated in humans. To evaluate the effects of drinking water fluoride levels on the liver and kidney functions in children with and without dental fluorosis, we identified 210 children who were divided into seven groups with 30 each based on different drinking water fluoride levels in the same residential area. We found that the fluoride levels in serum and urine of these children increased as the levels of drinking water fluoride increased. There were no significant differences in the levels of total protein (TP), albumin (ALB), aspartate transamine (AST), and alanine transamine (ALT) in serum among these groups. However, the activities of serum lactic dehydrogenase (LDH), urine N-acetyl-beta-glucosaminidase (NAG), and urine gamma-glutamyl transpeptidase (gamma-GT) in children with dental fluorosis and having water fluoride of 2.15-2.96 mg/L and in children having water fluoride of 3.15-5.69 mg/L regardless of dental fluorosis were significantly higher than children exposed to water fluoride of 0.61-0.87 mg/L in a dose-response manner. In contrast to children with dental fluorosis and having water fluoride of 2.15-2.96 and 3.10-5.69 mg/L, serum LDH activity of children without dental fluorosis but exposed to the same levels of water fluoride as those with dental fluorosis were also markedly lower, but the activities of NAG and gamma-GT in their urine were not. Therefore, our results suggest that drinking water fluoride levels over 2.0mg/L can cause damage to liver and kidney functions in children and that the dental fluorosis was independent of damage to the liver but not the kidney. Further studies on the mechanisms and significance underlying damage to the liver without dental fluorosis in the exposed children are warranted.


Intimate partner violence and HIV risk factors among African-American and African-Caribbean women in clinic-based settings.
Despite progress against intimate partner violence (IPV) and HIV/AIDS in the past two decades, both epidemics remain major public health problems, particularly among women of color. The objective of this study was to assess the relationship between recent IPV and HIV risk factors (sexual and drug risk behaviors, sexually transmitted infections [STIs], condom use, and negotiation) among women of African descent. We conducted a comparative case-control study in women's health clinics in Baltimore, MD, USA and St. Thomas and St. Croix, US Virgin Islands (USVI). Women aged 18-55 years who experienced physical and/or sexual IPV in the past two years (Baltimore, n=107; USVI, n=235) were compared to women who never experienced any form of abuse (Baltimore, n=207; USVI, n=119). Logistic regression identified correlates of recent IPV by site. In both sites, having a partner with concurrent sex partners was independently associated with a history of recent IPV (Baltimore, AOR: 3.91, 95% CI: 1.79-8.55 and USVI, AOR: 2.25, 95% CI: 1.11-4.56). In Baltimore, factors independently associated with recent IPV were lifetime casual sex partners (AOR: 1.99, 95% CI: 1.11-3.57), exchange sex partners (AOR: 5.26, 95% CI: 1.92-14.42), infrequent condom use during vaginal sex (AOR: 0.24, 95% CI: 0.08-0.72), and infrequent condom use during anal sex (AOR: 0.29, 95% CI: 0.09-0.93). In contrast, in the USVI, having a concurrent sex partner (AOR: 3.33, 95% CI: 1.46-7.60), frequent condom use during vaginal sex (AOR: 1.97, 95% CI: 1.06-3.65), frequent condom use during anal sex (AOR: 6.29, 95% CI: 1.57-25.23), drug use (AOR: 3.16, 95% CI: 1.00-10.06), and a past-year STI (AOR: 2.68, 95% CI: 1.25-5.72) were associated with recent IPV history. The divergent results by site warrant further investigation into the potential influence of culture, norms, and intentions on the relationships examined. Nonetheless, study findings support a critical need to continue the development and implementation of culturally tailored screening for IPV within HIV prevention and treatment programs.


Successful conservative management of iatrogenic femoral arterial trauma.
We have developed a protocol for nonoperative management of pseudoaneurysms and arteriovenous fistulas secondary to cardiac catheterization. Hemodynamically stable patients were placed at bed rest and underwent serial physical examination, hematocrit, and duplex ultrasonography for a minimum of three days prior to discharge and subsequently as outpatients. Sixteen initially stable patients out of 56 with femoral artery catheter trauma managed over a four-year period underwent deliberate conservative management. Their lesions included six arteriovenous fistulas, seven pseudoaneurysms, and three patients with both complications. All but one of the pseudoaneurysms resolved spontaneously within four weeks regardless of initial size or associated arteriovenous fistula. One patient receiving anticoagulant therapy required surgery for bleeding after a three-day period of observation of a pseudoaneurysm. Six of the nine arteriovenous fistulas also resolved within the initial period of observation. The remaining three have been followed for four to 20 months and have remained asymptomatic. Nonoperative therapy of catheter-related femoral artery trauma is both safe and effective. Conservative management avoids potential wound complications associated with dissection through surrounding hematoma as well as the additional hospitalization required for postoperative care. We recommend a period of observation for all hemodynamically stable patients with catheter-induced pseudoaneurysms and arteriovenous fistulas of the femoral vessels, with surgery reserved for hemorrhage, expanding masses, or compromised cardiac output.


[An adult case of probable Bassen-Kornzweig syndrome, presenting resting tremor].
We report a 53-year-old woman with probable Bassen-Kornzweig syndrome. Her parents were a consanguineous marriage. At two years of age, she developed night blindness. During her childhood she had severe diarrhea that disappeared in adulthood. At 26 years of age, she was diagnosed as having retinitis pigmentosa and her visual acuity became worse thereafter. She noted tremor in the right hand at 37 years of age, gait ataxia at 42, and developed tremor in the bilateral lower extremities at 48. On admission, bilateral visual disturbance, resting and postural tremor, moderately poor coordination, mild distal dominant sensory impairment, an absence of tendon reflex in all four extremities, moderate to severe gait ataxia, and positive Romberg sign were found. Muscle rigidity and akinesia were not observed. Intelligence and muscle power were normal and pathological reflexes were absent. Acanthocytes were found in blood. Serum chemistry showed remarkable decreases in total cholesterol (54 mg/dl, normal 180-220), triglyceride (0 mg/dl, normal 30-150), beta-lipoprotein (3 mg/dl, normal 190-500), apoA-1 protein (66 mg/dl, normal 105-184), apoA-2 protein (11 mg/dl, normal 26-46), apoB protein (0 mg/dl, normal 38-104), apoC-2 protein (1.1 mg/dl, normal 1.2-6.4), vitamin A (297 ng/ml, normal 431-1,041), and vitamin E (0.19 ng/dl, normal 0.75-1.41). While, a marked increase in PIVKA II (703 mAU/ml, normal<40) due to a decrease in vitamin K was found. She was thus diagnosed as having Bassen-Kornzweig syndrome or hypo-betalipoproteinemia. Although brain MRI was normal, single-photon emission CT (SPECT) showed mildly decreased perfusion in the left parietal cortex and right striatum. Motor nerve conduction velocities were normal, but sensory nerve action potentials were not evoked in all four extremities. Surface EMG recorded on the right radial extensor and flexor carpi muscles at rest showed a 4.5 Hz tremor. Vitamin replacement therapy with vitamin A (10,000 IU/day), E (200 mg/day), and K (10 mg/day) was initiated. Several days after treatment, amplitude of resting tremor ameliorated mildly. Clonazepam was administered (0.5 mg/day) for further treatment. After one-month of treatment, vitamin A (656 ng/ml) and E (0.39 mg/dl) levels were elevated and PIVKA II level (29 mAU/ml) decreased. Only a mild right hand tremor remained, but sensory impairment and gait ataxia were not changed. The cause of Bassen-Kornzweig syndrome is a deletion of the microsomal triglyceride transfer protein (MTP) gene. While, familial hypo-betalipoproteinemia, due to a mutation of apolipoprotein B gene, is known to show the same phenotype. Because of the patient's refusal of genetic examination, which disease she has cannot be conclusively determined. Intention tremor was reported in Bassen-Kornzweig syndrome. However, her 4.5 Hz tremor was also present at rest, which resembled resting tremor in Parkinson's disease. Pathophysiology of Bassen-Kornzweig syndrome is known to be due to hypo-vitaminosis. Decreased [18F]-dopa uptake in striatum of patients with long-term hypo-vitamin E has been reported in PET study. Mild hypoperfusion was found in the striatum of the present cases: indicating that her tremor was associated with striatonigral damage. Thus, careful observation of extrapyramidal signs is necessary in abeta- or hypo-betalipoproteinemia.


Chimeric Filoviruses for Identification and Characterization of Monoclonal Antibodies.
Recent experiments suggest that some glycoprotein (GP)-specific monoclonal antibodies (MAbs) can protect experimental animals against the filovirus Ebola virus (EBOV). There is a need for isolation of MAbs capable of neutralizing multiple filoviruses. Antibody neutralization assays for filoviruses frequently use surrogate systems such as the rhabdovirus vesicular stomatitis Indiana virus (VSV), lentiviruses or gammaretroviruses with their envelope proteins replaced with EBOV GP or pseudotyped with EBOV GP. It is optimal for both screening and in-depth characterization of newly identified neutralizing MAbs to generate recombinant filoviruses that express a reporter fluorescent protein in order to more easily monitor and quantify the infection. Our study showed that unlike neutralization-sensitive chimeric VSV, authentic filoviruses are highly resistant to neutralization by MAbs. We used reverse genetics techniques to replace EBOV GP with its counterpart from the heterologous filoviruses Bundibugyo virus (BDBV), Sudan virus, and even Marburg virus and Lloviu virus, which belong to the heterologous genera in the filovirus family. This work resulted in generation of multiple chimeric filoviruses, demonstrating the ability of filoviruses to tolerate swapping of the envelope protein. The sensitivity of chimeric filoviruses to neutralizing MAbs was similar to that of authentic biologically derived filoviruses with the same GP. Moreover, disabling the expression of the secreted GP (sGP) resulted in an increased susceptibility of an engineered virus to the BDBV52 MAb isolated from a BDBV survivor, suggesting a role for sGP in evasion of antibody neutralization in the context of a human filovirus infection. The study demonstrated that chimeric rhabdoviruses in which G protein is replaced with filovirus GP, widely used as surrogate targets for characterization of filovirus neutralizing antibodies, do not accurately predict the ability of antibodies to neutralize authentic filoviruses, which appeared to be resistant to neutralization. However, a recombinant EBOV expressing a fluorescent protein tolerated swapping of GP with counterparts from heterologous filoviruses, allowing high-throughput screening of B cell lines to isolate MAbs of any filovirus specificity. Human MAb BDBV52, which was isolated from a survivor of BDBV infection, was capable of partially neutralizing a chimeric EBOV carrying BDBV GP in which expression of sGP was disabled. In contrast, the parental virus expressing sGP was resistant to the MAb. Thus, the ability of filoviruses to tolerate swapping of GP can be used for identification of neutralizing MAbs specific to any filovirus and for the characterization of MAb specificity and mechanism of action.


Localization of Helicobacter pylori urease and heat shock protein in human gastric biopsies.
Helicobacter pylori is a spiral, gram-negative bacterium which causes chronic gastritis and plays a critical role in peptic ulcer disease, gastric carcinoma, and gastric lymphoma. H. pylori expresses significant urease activity which is an essential virulence factor. Since a significant fraction of urease activity is located on the surface of the bacterium, the urease molecule is a logical choice as an antigen for a vaccine; currently recombinant urease apoenzyme is being tested as a vaccine in phase II clinical trials. We have recently demonstrated that urease and HspB (a homolog of the GroEL heat shock protein) become associated with the surface of H. pylori in vitro in a novel manner: these cytoplasmic proteins are released by bacterial autolysis and become adsorbed to the surface of intact bacteria, reflecting the unique characteristics of the outer membrane. To determine if similar mechanisms are operative in vivo, we determined the ultrastructural locations of urease and HspB within bacteria present in human gastric biopsies. Our results demonstrate that both urease and HspB are located within the cytoplasm of all bacteria examined in human gastric biopsies. Interestingly, a significant proportion of the bacteria examined also possessed variable amounts of surface-associated urease and HspB antigen (from 5 to 50% of the total antigenic material), indicating that in vivo, H. pylori has surface characteristics which enable it to adsorb cytoplasmic proteins. This is consistent with our altruistic autolysis model in which H. pylori uses genetically programmed bacterial autolysis to release urease and other cytoplasmic proteins which are subsequently adsorbed onto the surface of neighboring viable bacteria. These observations have important implications regarding pathogenesis and development of vaccines for H. pylori.