Tropical bont tick (Amblyomma variegatum) eradication in the Caribbean. The St. Kitts experience.
The tropical bont tick (TBT) was first identified in St. Kitts in 1978. Initially, infestation was observed on cattle that developed a severe dermatitis. Over a period of seven years, the TBT spread to most areas of the island, affecting cattle, sheep, and goats. The ruminant livestock population declined from, 6,000, 9,000, and 7,000 cattle, sheep, and goats, respectively, in 1984 to an estimated 400, 800, and 1,000, cattle, sheep, and goats in 1990. A project to control the tropical bont tick on St. Kitts was implemented in 1983. This effort was based on the use of plunge dips located in communal grazing areas. In October of 1995, the Caribbean Amblyomma Programme was initiated on St. Kitts to eradicate the TBT from the Caribbean. In 1996, there were 416 animal owners with 2,000, 4,300, and 4,000 cattle, sheep, and goats, respectively. Cases of dermatophilosis, declined from 657 in 1995 to 153 in 1996. During the period 1997 to 1998 treatment with Flumethrin continued. The Department of Agriculture initiated activities for treatment compliance, monitoring, and TBT surveillance. The animal population increased to 3,000, 6,000, and 4,500 cattle, sheep, and goats, respectively, and with 810 animal owners participating. The number of cases of dermatophilosis declined to 42. In 1998, the TBT was confined to three foci. The remainder of the island was declared provisionally tick free.


Mining biochemical information: lessons taught by the ribosome.
The publication of the crystal structures of the ribosome offers an opportunity to retrospectively evaluate the information content of hundreds of qualitative biochemical and biophysical studies of these structures. We assessed the correspondence between more than 2,500 experimental proximity measurements and the distances observed in the ribosomal crystals. Although detailed experimental procedures and protocols are unique in almost each analyzed paper, the data can be grouped into subsets with similar patterns and analyzed in an integrative fashion. We found that, for crosslinking, footprinting, and cleavage data, the corresponding distances observed in crystal structures generally did not exceed the maximum values expected (from the estimated length of the agent and maximal anticipated deviations from the conformations found in crystals). However, the distribution of distances had heavier tails than those typically assumed when building three-dimensional models, and the fraction of incompatible distances was greater than expected. Some of these incompatibilities can be attributed to the experimental methods used. In addition, the accuracy of these procedures appears to be sensitive to the different reactivities, flexibilities, and interactions among the components. These findings demonstrate the necessity of a very careful analysis of data used for structural modeling and consideration of all possible parameters that could potentially influence the quality of measurements. We conclude that experimental proximity measurements can provide useful distance information for structural modeling, but with a broad distribution of inferred distance ranges. We also conclude that development of automated modeling approaches would benefit from better annotations of experimental data for detection and interpretation of their significance.


The relation of endometriosis to menstrual characteristics, smoking, and exercise.
We compared menstrual characteristics and constitutional factors in 268 white women with primary infertility due to endometriosis and in 3,794 white women admitted for delivery at seven collaborating hospitals from 1981 to 1983. Adjusting for confounding factors, including location, age, religion, and education, women with short-cycle lengths (less than or equal to 27 days) and longer flow (greater than or equal to one week) had more than double the risk for endometriosis compared with women with longer cycle lengths and shorter duration of flow. There was a trend for increasing risk for endometriosis to be associated with increasing menstrual pain. Adjusting for these menstrual characteristics, we found decreased risk for endometriosis associated with smoking or exercise that was largely confined to women who began either habit at an early age and were heavier smokers or more strenuous exercisers. We conclude that risk for endometriosis may relate to menstrual factors that predispose to greater pelvic contamination with menstrual products and to constitutional factors that influence endogenous hormonal levels.


Chronic retropharyngeal abscess presenting as obstructive sleep apnea.
Chronic retropharyngeal abscess (RPA) in children is an unusual condition that has rarely been reported in the literature. Pediatric obstructive sleep apnea (OSA) has many etiologies that have been well described, but there have been no reports of a chronic RPA presenting with severe OSA. We describe an infant who presented with severe OSA due to oropharyngeal narrowing by a chronic abscess. An intraoperative magnetic resonance imaging study confirmed the presence of a RPA. Treatment included tracheostomy, surgical drainage, and intravenous followed by oral antibiotics. Physicians evaluating children with recent onset severe OSA after a respiratory infection should include suppurative oropharyngeal pathology in the differential diagnosis. A recent drainage of a head or neck abscess should strengthen that suspicion.


Cognitive dysfunction in individuals with cocaine use disorder: Potential moderating factors and pharmacological treatments.
It is well-documented in the literature that individuals repeatedly exposed to cocaine exhibit cognitive impairment and that cognitive dysfunction is a risk factor for poor treatment outcomes in those with cocaine use disorder (CUD). Specific deficits related to attention, episodic memory, working memory, and executive functioning are the most common deficits noted in this population. Given that cognitive impairment is a risk factor for poor treatment outcomes in those with CUD, identifying possible moderating factors contributing to and/or exacerbating cocaine-related cognitive deficits is of great importance. Some of these factors may include premorbid intellectual functioning, cocaine use patterns, polysubstance use, comorbid emotional symptoms, and sleep dysfunction. It is plausible that by identifying moderating factors impacting cognition, behavioral interventions can then be modified accordingly and/or treatment regimens can be augmented with pharmacological interventions (e.g., cognitive enhancing agents), leading to a reduction in treatment attrition and improved treatment outcomes. The currently available treatments for CUD are mainly behavioral with variable efficacy, and even though there have been great preclinical and clinical research efforts focused on medication development for CUD, there are currently no Food and Drug Administration-approved medications for CUD. A description of some of the several potential moderating factors, along with some pharmacological treatments which have been shown to ameliorate, at least to some extent, cognitive dysfunction in those with CUD are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Lilliputians get into the limelight: novel class of small peptide genes in morphogenesis.
Generally, bioactive small peptides are derived from precursors with signal sequences at their N-terminal ends, which undergo modification and proteolysis through a secretory pathway. By contrast, small peptides encoded in short open reading frames (sORF) lack signaling sequences and therefore are released into the cytoplasm, which may result in their having functions distinct from those of secreted peptides. Several small peptides encoded by sORF are involved in the morphogenesis of multicellular organisms. POLARIS, ROTUNDIFOLIA4, and Enod40 are plant peptides that are involved, respectively, in root formation, leaf shape control, and cortical cell division during nodule formation. Brick1/HSPC300 is an evolutionarily conserved component of the actin reorganization complex. polished rice/tarsal-less and mille-pattes encode related small peptides that are required for epithelial morphogenesis in Drosophila and segmentation in Tribolium. There are only a few known examples of small peptides encoded by sORF, and their molecular functions are still largely obscure. Nevertheless, an increasing number of sORF genes is being identified, and further research should reveal their roles in novel molecular mechanisms underlying developmental events.


A comparative and comprehensive analysis of nonsexual assaults.
The aim of this study was to make a comparative and comprehensive analysis of nonsexual assaults in 488 medico-legal cases presented to Forensic Medicine Outpatient Clinic of Celal Bayar University Hospital (Manisa, Turkey), between 2005 and 2009. There were blunt force injuries (BFI) in 262 cases (53.7%), sharp force injuries (SFI) in 163 cases (33.4%), and firearm-related wounds (FRW) in 63 cases (12.9%). The results showed significant differences in the monthly distribution of assaults, localization of injuries, and severity of injuries depending on the types of assaults. Most of the injuries were localized to the face, head, and neck in BFI and SFI and to the lower limbs in FRW. The results of this study will help researchers to investigate characteristics of victims, offenders, and injuries and types of assaults because of nonsexual violence.


Spatial patterns of the frog Oophaga pumilio in a plantation system are consistent with conspecific attraction.
The conspecific attraction hypothesis predicts that individuals are attracted to conspecifics because conspecifics may be cues to quality habitat and/or colonists may benefit from living in aggregations. Poison frogs (Dendrobatidae) are aposematic, territorial, and visually oriented-three characteristics which make dendrobatids an appropriate model to test for conspecific attraction. In this study, we tested this hypothesis using an extensive mark-recapture dataset of the strawberry poison frog (Oophaga pumilio) from La Selva Biological Station, Costa Rica. Data were collected from replicate populations in a relatively homogenous Theobroma cacao plantation, which provided a unique opportunity to test how conspecifics influence the spatial ecology of migrants in a controlled habitat with homogenous structure. We predicted that (1) individuals entering a population would aggregate with resident adults, (2) migrants would share sites with residents at a greater frequency than expected by chance, and (3) migrant home ranges would have shorter nearest-neighbor distances (NND) to residents than expected by chance. The results were consistent with these three predictions: Relative to random simulations, we observed significant aggregation, home-range overlap, and NND distribution functions in four, five, and six, respectively, of the six migrant-resident groups analyzed. Conspecific attraction may benefit migrant O. pumilio by providing cues to suitable home sites and/or increasing the potential for social interactions with conspecifics; if true, these benefits should outweigh the negative effects of other factors associated with aggregation. The observed aggregation between migrant and resident O. pumilio is consistent with conspecific attraction in dendrobatid frogs, and our study provides rare support from a field setting that conspecific attraction may be a relevant mechanism for models of anuran spatial ecology.


Reactive oxygen species stimulate p44/42 mitogen-activated protein kinase and induce p27(Kip1): role in angiotensin II-mediated hypertrophy of proximal tubular cells.
Angiotensin II (AngII) induces G(1) phase arrest and hypertrophy of cultured renal proximal tubular cells. In previous studies, it was shown that these effects depend on oxygen radical-mediated induction of p27(Kip1), an inhibitor of cyclin-dependent kinases. The present study was undertaken to investigate whether mitogen-activated protein (MAP) kinases serve as signaling intermediates between AngII-induced oxidative stress and induction of p27(Kip1). AngII (10(-7) M) induces a biphasic phosphorylation pattern of p44/42 MAP kinase with an early phosphorylation after 2 min and a later, second phosphorylation peak after prolong incubation (12 h) in cultured proximal tubular cells from two different species (MCT and LLC-PK(1) cells). Total protein expression of MAP kinase was not changed by AngII. These phosphorylation patterns of p44/42 MAP kinase caused activation of the enzyme, as detected by phosphorylated MAP substrate Elk-1 after immuno-precipitation of MAP kinase. Exogenous H(2)O(2) also stimulates a biphasic phosphorylation of p44/42 MAP kinase. The flavoprotein inhibitor diphenylene iodinium, as well as the antioxidant N-acetylcysteine, prevented AngII-induced p44/42 MAP kinase phosphorylation, indicating involvement of reactive oxygen species generated by membrane-bound NAD(P)H oxidase. The MAP kinase kinase inhibitor PD98059 completely inhibits AngII-induced p27(Kip1) expression and (3)[H]leucine incorporation into proteins as a previously established marker of cell hypertrophy. PD98059 did not attenuate AngII-stimulated intracellular synthesis of oxygen radicals. Transient transfection with p44/42 MAP kinase antisense, but not sense, phosphorothioate-modified oligonucleotides also prevented AngII-induced MAP kinase phosphorylation, p27(Kip1) expression, and cell hypertrophy. Furthermore, induction of p27(Kip1) by H(2)O(2) was also abolished in the presence of PD98059. Although AngII induces phosphorylation of the stress-activated p38 MAP kinase, inhibition of this enzyme with SB203580 failed to attenuate induced p27(Kip1) expression and hypertrophy. These data provide evidence that AngII- mediated oxygen stress leads to the phosphorylation of p44/42 MAP kinase in proximal tubular cells. Activation of this enzyme is essential for p27(Kip1) expression, G(1) phase arrest, and hypertrophy of proximal tubular cells. These findings may lead to new concepts concerning interference of the development of proximal tubular hypertrophy, which may eventually turn into a maladaptive process in vivo leading ultimately to tubular atrophy and tubulointerstitial fibrosis.


Successful expansion of hospital-associated clone of vanA-positive vancomycin-resistant Enterococcus faecalis ST9 to an anthropogenically polluted mangrove in Brazil.
Mangrove ecosystems are hotspots of biodiversity, but have been threatened by anthropogenic activities. Vancomycin-resistant enterococci (VRE) are nosocomial bacteria classified as high priority by the World Health Organization (WHO). Herein, we describe the identification and genomic characteristics of a vancomycin-resistant Enterococcus faecalis strain isolated from a highly impacted mangrove ecosystem of the northeastern Brazilian, in 2021. Genomic analysis confirmed the existence of the transposon Tn1546-vanA and clinically relevant antimicrobial resistance genes, such as streptogramins, tetracycline, phenicols, and fluoroquinolones. Virulome analysis identified several genes associated to adherence, immune modulation, biofilm, and exoenzymes production. The UFSEfl strain was assigned to sequence type (ST9), whereas phylogenomic analysis with publicly available genomes from a worldwide confirmed clonal relatedness with a hospital-associated Brazilian clone. Our findings highlight the successful expansion of hospital-associated VRE in a mangrove area and shed light on the need for strengthening genomic surveillance of WHO priority pathogens in these vital ecosystems.


Sexually transmitted infections, sexual risk behavior, and intimate partner violence among African American adolescent females with a male sex partner recently released from incarceration.
Social networks directly and indirectly influence sexually transmitted infections (STIs) risk. The objective was to explore associations between sex with a male recently released from incarceration and sexual risk and intimate partner violence (IPV) among African American adolescent females. Sociodemographic, psychosocial, and sexual behavior data were collected at baseline, 6, and 12 months from African American females, aged 15-21 years, participating in an HIV/STI prevention trial. Among 653 participants with ≥1 follow-up assessments, generalized estimating equations tested associations during follow-up between having a recently released partner and STI acquisition, sexual risk behaviors, and IPV, adjusting for age, treatment assignment, and corresponding baseline measure. Eighty-three (13.6%) participants had a recently released partner at 6 months and 56 (9.3%) at 12 months. Participants with a recently released partner were more likely to have the following: vaginal (adjusted odds ratio [AOR]: 5.48), anal (AOR: 2.43), and oral (AOR: 1.51) sex, a casual partner (AOR: 1.66), sex while high/drunk (AOR: 1.57) or with a high/drunk partner (AOR: 2.27); use condoms inconsistently (AOR: .58); acquire Chlamydia (AOR: 1.80), and experience emotional (AOR: 4.09), physical (AOR: 2.59), or sexual abuse (AOR: 4.10) by a boyfriend. They had a greater number of sex partners, lower partner communication and refusal self-efficacy, were high/drunk during sex more frequently, and used condoms during oral sex less frequently. A recently released sex partner is associated with sexual risk and IPV among African American adolescent females. Prevention programs should inform adolescents about potential risks associated with recently released partners as well as provide adolescents with skills to establish and maintain healthy sexual relationships.


Parents' preferences for enhanced access in the pediatric medical home: a discrete choice experiment.
Efforts to transform primary care through the medical home model may have limited effectiveness if they do not incorporate families' preferences for different primary care services. To assess parents' relative preferences for different categories of enhanced access services in primary care. Internet-based survey that took place with a national online panel from December 8, 2011, to December 22, 2011. Participants included 820 parents of children aged 0 to 17 years. Hispanic and black non-Hispanic parents were each oversampled to 20% of the sample. The survey included a discrete choice experiment with questions that asked parents to choose between hypothetical primary care practices with different levels of enhanced access and other primary care services. We estimated parents' relative preferences for different enhanced access services using travel time to the practice as a trade-off and parents' marginal willingness to travel in minutes for practices with different levels of services. The response rate of parents who participated in the study was 41.2%. Parents were most likely to choose primary care offices that guaranteed same-day sick visits (coefficient, 0.57 [SE, 0.05]; P < .001) followed by those with higher professional continuity (coefficient, 0.36 [SE, 0.03]; P < .001). Parents were also significantly more likely to choose practices with 24-hour telephone advice plus nonurgent email advice (0.08 [0.04]; P < .05), evening hours 4 or more times a week (0.14 [0.04]; P < .001), and at least some hours on weekends. Parents were significantly less likely to choose practices that were closed during some weekday daytime hours or had wait times longer than 4 weeks for preventive care visits. There was very little variation in preferences among parents with different sociodemographic characteristics. Parents' marginal willingness to travel was 14 minutes (95% CI, 11-16 minutes) for guaranteed same-day sick visits and 44 minutes (95% CI, 37-51 minutes) for an office with idealized levels of all services. As primary care practices for children implement aspects of the medical home model, those that emphasize same-day sick care and professional continuity are more likely to meet parents' preferences for enhanced access. Practices should seek to engage families in prioritizing changes in practice services as part of medical home implementation.


Endocrine effects of erythropoietin in cancer patients.
The recent advances in the knowledge of the psychoneuroimmunological pathogenesis of human neoplasms have demonstrated the existence of feed-back mechanisms operating between interleukins and endocrine secretions, which play an important role in the regulation of the immune responses, including the anticancer immunity. In contrast, few studies only have been performed to investigate the possible relation between endocrine activities and hematopoietic growth factors. The present study was performed to analyze the acute endocrine effects of erythropoietin-alpha (EPO) on the main endocrine secretions. The study was carried out in 10 advanced solid tumor patients. EPO was injected subcutaneously at a dose of 10,000 U, and venous blood samples were collected before and 2, 4 and 6 h after EPO administration. No significant changes in mean serum levels of FSH, LH and TSH were seen in response to EPO. Cortisol and DHEAS concentrations increased after EPO injection, whereas those of PRL decreased, but none of these differences was statistically significant. Finally, mean serum levels of both growth hormone (GH) and somatomedin-C (IGF-1) significantly decreased after EPO administration. This preliminary study shows that EPO may inhibit GH secretion from the pituitary gland and IGF-1 production. Since GH would stimulate EPO release, the results of this study may suggest the existence of feedback mechanism operating between GH secretion and EPO production, with inhibitory effect of EPO on GH secretion, and stimulatory action of GH on EPO production. Therefore, this study would describe the first example of hemato-endocrine feedback mechanisms. Moreover, this study, by showing an inhibitory effect of EPO on IGF-1 secretion, would suggest a possible use of EPO in the medical oncology not only for the treatment of cancer related anemia, but also to counteract tumor growth by blocking IGF-1 production, which has been proven to be a growth factor for several tumor histotypes. Obviously, IGF-1 is not the only tumor growth factor, but it could play a fundamental role in the regulation of production and activity of several other tumor growth factors. In any case, this study describes the only acute endocrine effects of EPO. Therefore, further studies, by evaluating the endocrine effects of a chronic treatment with EPO, will be required to establish which may be its effect on IGF-1 endogenous production, and its consequence on survival time.


Are Japanese criteria for obesity useful for screening at risk Japanese? Consideration from anthropometric indices-percentage body fat relationships.
Both childhood and adult obesity are of serious public health concern in Japan. While Japan has diagnostic criteria for both childhood and adult obesity and metabolic syndrome, the appropriateness of the proposed criteria has been questioned. The present study aimed to determine screening ability of anthropometric indices relative to estimated percentage body fat (% BF) and to propose gender- and maturation-specific cut-off points using 1,393 Japanese (552 males and 841 females; 7.6-66.3 years old). Between 20%-50% of individuals with high fat deposits were misclassified using body mass index (BMI), abdominal circumference (AC), abdominal to height ratio (AHtR), and sum of two skinfolds (Sigma2SF). Using the WHO public action point of 23 kg/m2, AC of 80 cm, AHtR of 0.5 for all groups and Sigma2SF of 25 mm for males and 40 mm for females were estimated to be potentially useful cut-off points. The results may indicate a need for further research for appropriate screening cut-off points for Japanese.


Image-guided placement of occipitocervical instrumentation using a reference arc attached to the headholder.
To develop a safe and accurate method of image-guided placement of instrumentation in the upper cervical spine and occiput in which the reference arc is fixed to the headholder. The authors describe a technique for placing screws at the occipital, C1, and C2 levels using 3-dimensional image guidance in which the reference arc is fixed to the headholder. Technical details are discussed as well as modifications to the technique to maximize navigation accuracy and decrease the need for re-registration. One of 2 paired systems, the BrainLAB Vector Vision system (BrainLAB Inc., Westchester, IL) used in conjunction with the Arcadis Orbic Isocentric C-arm (Siemens Medical Solutions, Erlangen, Germany) or the Stealth Treon system (Medtronic, Littleton, MA) paired with the O-arm (Medtronic), was used for image guidance in this study. A total of 18 patients had 82 screws placed at the occipital, C1, or C2 level using this technique. An independent radiologist interpreted postoperative computed tomographic scans of these patients and graded the screws for bony breach. No complications resulted from the use of image guidance or from the placement of instrumentation. Postoperative computed tomography revealed 1 screw with a minimal breach of the outer lamina of C2. Another screw was replaced intraoperatively secondary to a minimal bony breach. No other bony breach occurred. This technique allows safe and accurate placement of instrumentation in the posterior occipitocervical junction using 3-dimensional image guidance in which the reference arc is attached to the headholder.


Statistical power of psychological research: what have we gained in 20 years?
Power was calculated for 6,155 statistical tests in 221 journal articles published in the 1982 volumes of the Journal of Abnormal Psychology, Journal of Consulting and Clinical Psychology, and Journal of Personality and Social Psychology. Power to detect small, medium, and large effects was .17, .57, and .83, respectively. 20 years after Cohen (1962) conducted the first power survey, the power of psychological research is still low. The implications of these results concerning the proliferation of Type I errors in the published literature, the failure of replication studies, and the interpretation of null (negative) results are emphasized. An example is given of the use of power analysis to help interpret null results by setting probable upper bounds on the magnitudes of effects. Limitations of statistical power analyses, suggestions for future research, sources of computational information, and recommendations for improving power are discussed.


Epileptogenic high-frequency oscillations present larger amplitude both in mesial temporal and neocortical regions.
High-frequency oscillations (HFO) are a promising biomarker for the identification of epileptogenic tissue. While HFO rates have been shown to predict seizure outcome, it is not yet clear whether their morphological features might improve this prediction. We validated HFO rates against seizure outcome and delineated the distribution of HFO morphological features. We collected stereo-EEG recordings from 20 patients (231 electrodes; 1,943 contacts). We computed HFO rates (the co-occurrence of ripples and fast ripples) through a validated automated detector during non-rapid eye movement sleep. Applying machine learning, we delineated HFO morphological features within and outside epileptogenic tissue across mesial temporal lobe (MTL) and Neocortex. HFO rates predicted seizure outcome with 85% accuracy, 79% specificity, 100% sensitivity, 100% negative predictive value, and 67% positive predictive value. The analysis of HFO features showed larger amplitude in the epileptogenic tissue, similar morphology for epileptogenic HFO in MTL and Neocortex, and larger amplitude for physiological HFO in MTL. We confirmed HFO rates as a reliable biomarker for epilepsy surgery and characterized the potential clinical relevance of HFO morphological features. Our results support the prospective use of HFO in epilepsy surgery and contribute to the anatomical mapping of HFO morphology.


Multiple sclerosis has a distinct lipid signature in plasma and cerebrospinal fluid.
The diagnosis of multiple sclerosis (MS) has changed over the last decade, but remains a composite of clinical assessment and magnetic resonance imaging to prove dissemination of lesions in time and space. The intrathecal synthesis of immunoglobulin may be a nonspecific marker and there are no plasma biomarkers that are useful in the diagnosis of MS, presenting additional challenges to their early detection. We performed a preliminary untargeted qualitative lipidomics mass spectrometry analysis, comparing cerebrospinal fluid (CSF) and plasma samples from patients with MS, other inflammatory neurological diseases and idiopathic intracranial hypertension. Lipid identification revealed that fatty acids and sphingolipids were the most abundant classes of lipids in the CSF and that glycerolipids and fatty acids were the main class of lipids in the plasma of patients with MS. The area under the curve was 0.995 (0.912-1) and 0.78 (0.583-0.917), respectively. The permutation test indicated that this ion combination was useful for distinguishing MS from other inflammatory diseases (p < 0.001 and 0.055, respectively). This study concluded that the CSF and plasma from patients with MS bear a unique lipid signature that can be useful as a diagnostic biomarker.


Detection and management of latent tuberculosis in liver transplant patients.
The optimal means for detecting and managing liver transplantation (LT) patients with latent tuberculosis (TB) are not well defined. Our study aims were to (1) determine the frequency and risk factors of latent TB in a large cohort of consecutive adult LT candidates and (2) determine the safety and efficacy of isoniazid treatment in LT recipients with latent TB. A review of patients assessed for latent TB by skin testing using purified protein derivative (PPD; January 2004 to September 2008) or with the interferon-γ release assay QuantiFERON-TB Gold (QFT; March 2008 to October 2009) was undertaken. The baseline clinical features and outcomes of subjects with latent TB and subjects without latent TB were compared. Twenty-five of 420 subjects (6.0%) were positive for PPD. In comparison, 11 of 119 subjects (9.2%) had a positive QFT assay, and 15 others (13%) had indeterminate results. Both PPD-positive and QFT-positive subjects were less likely to be Caucasian than subjects without latent TB (p < 0.001). The 3-year survival rate of the 25 LT recipients with latent TB was similar to that of the 296 LT recipients without latent TB (78.7% versus 74.6%, P = 0.58). Fifteen of the 25 latent TB patients received isoniazid at a mean of 0.67 months after LT. Although isoniazid was discontinued in 8 subjects because of possible side effects, none of the 25 latent TB patients developed TB reactivation after transplantation with a mean follow-up of 33 months. In conclusion, both QFT testing and PPD testing demonstrate similar rates of detecting latent TB infection in American LT candidates, but QFT testing also leads to a moderate rate of indeterminate test results. Early isoniazid chemoprophylaxis after LT is poorly tolerated and is frequently discontinued.


Pelvic Radiation-Induced Testicular Damage: An Experimental Study at 1 Gray.
Therapeutic radiation of the pelvic region has been shown to cause damage to testicular germ cells. In this study we aimed to evaluate the effects of a low therapeutic dose of 1 Gy on the induction of cellular and histological damage in early-stage testicular germ cells and the impact of this radiation on offspring sex ratio. Unirradiated and irradiated male rats were mated with unirradiated female rats. Female rats were followed and the sex of the offspring was determined. The male rats were sacrificed at the end of the second week, and the testicular germ cells were subjected to genetic analysis along with cytological and histopathological examination. Sperm DNA was amplified with primers specific to testis-specific Y-linked protein, rat actin beta and testis-specific X-linked genes. The resulting products were separated by capillary electrophoresis. Histopathological changes were investigated by light microscopy along with the TUNEL assay and immunohistochemical staining for caspase-3. There was no significant difference between the two groups for sex ratio and size of offspring. The number of sperm cells bearing X or Y chromosomes' did not differ significantly between these two groups. However, a 1 Gy dose of radiation caused significant cytopathological and histopathological changes in the testicular tissue. In the irradiated group, edematous regions were evident. The number of caspase-3 positive cells in the germinal epithelium of the seminiferous tubules was also significantly higher in the irradiated group. Our results showed that low-dose radiation induced apoptosis and caused significant cyto- and histopathological changes in the testicular tissue. Further research is required to fully elucidate their contribution to apoptosis and if low-dose radiation may potentially lead to long-term effects in the offspring. These results may also lead us to develop a new technique using the caspase-3 staining to monitor the susceptibility to low dose radiation.


Autoinduction of Bacillus subtilis phoPR operon transcription results from enhanced transcription from EsigmaA- and EsigmaE-responsive promoters by phosphorylated PhoP.
The phoPR operon encodes a response regulator, PhoP, and a histidine kinase, PhoR, which activate or repress genes of the Bacillus subtilis Pho regulon in response to an extracellular phosphate deficiency. Induction of phoPR upon phosphate starvation required activity of both PhoP and PhoR, suggesting autoregulation of the operon, a suggestion that is supported here by PhoP footprinting on the phoPR promoter. Primer extension analyses, using RNA from JH642 or isogenic sigE or sigB mutants isolated at different stages of growth and/or under different growth conditions, suggested that expression of the phoPR operon represents the sum of five promoters, each responding to a specific growth phase and environmental controls. The temporal expression of the phoPR promoters was investigated using in vitro transcription assays with RNA polymerase holoenzyme isolated at different stages of Pho induction, from JH642 or isogenic sigE or sigB mutants. In vitro transcription studies using reconstituted EsigmaA, EsigmaB, and EsigmaE holoenzymes identified PA4 and PA3 as EsigmaA promoters and PE2 as an EsigmaE promoter. Phosphorylated PhoP (PhoP approximately P) enhanced transcription from each of these promoters. EsigmaB was sufficient for in vitro transcription of the PB1 promoter. P5 was active only in a sigB mutant strain. These studies are the first to report a role for PhoP approximately P in activation of promoters that also have activity in the absence of Pho regulon induction and an activation role for PhoP approximately P at an EsigmaE promoter. Information concerning PB1 and P5 creates a basis for further exploration of the regulatory coordination or overlap of the PhoPR and SigB regulons during phosphate starvation.


State-dependent electrostatic interactions of S4 arginines with E1 in S2 during Kv7.1 activation.
The voltage-sensing domain of voltage-gated channels is comprised of four transmembrane helices (S1-S4), with conserved positively charged residues in S4 moving across the membrane in response to changes in transmembrane voltage. Although it has been shown that positive charges in S4 interact with negative countercharges in S2 and S3 to facilitate protein maturation, how these electrostatic interactions participate in channel gating remains unclear. We studied a mutation in Kv7.1 (also known as KCNQ1 or KvLQT1) channels associated with long QT syndrome (E1K in S2) and found that reversal of the charge at E1 eliminates macroscopic current without inhibiting protein trafficking to the membrane. Pairing E1R with individual charge reversal mutations of arginines in S4 (R1-R4) can restore current, demonstrating that R1-R4 interact with E1. After mutating E1 to cysteine, we probed E1C with charged methanethiosulfonate (MTS) reagents. MTS reagents could not modify E1C in the absence of KCNE1. With KCNE1, (2-sulfonatoethyl) MTS (MTSES)(-) could modify E1C, but [2-(trimethylammonium)ethyl] MTS (MTSET)(+) could not, confirming the presence of a positively charged environment around E1C that allows approach by MTSES(-) but repels MTSET(+). We could change the local electrostatic environment of E1C by making charge reversal and/or neutralization mutations of R1 and R4, such that MTSET(+) modified these constructs depending on activation states of the voltage sensor. Our results confirm the interaction between E1 and the fourth arginine in S4 (R4) predicted from open-state crystal structures of Kv channels and reveal an E1-R1 interaction in the resting state. Thus, E1 engages in electrostatic interactions with arginines in S4 sequentially during the gating movement of S4. These electrostatic interactions contribute energetically to voltage-dependent gating and are important in setting the limits for S4 movement.


Comparison of the efficiency of peloidotherapy and extracorporeal shock wave therapies in patients diagnosed with lateral epicondylitis: a prospective, randomized, controlled study.
Various treatment methods are used in the management of lateral epicondylitis (LE); however, there is no universally accepted standard treatment approach. The aim of this study is to compare the effects of peloidotherapy and extracorporeal shock wave therapy (ESWT) on pain, functional status, and quality of life in the treatment of LE. The study was designed as a hospital-based, prospective randomized controlled trial. Ninety patients, with a mean age of 47.30±7.95 (range, 18 to 65 years), diagnosed with chronic (3 months) unilateral LE were included in the study. The patients were randomly divided into two groups. The peloidotherapy group received 15 sessions of peloid therapy for 3 weeks, 5 days a week, while the ESWT group received three sessions of ESWT (1.8 bar, 10.0 Hz, 2000 impulses) for 3 weeks, once a week. The patients were evaluated before treatment, at the end of the treatment, and one month after the treatment. The groups were compared in terms of pain, quality of life, functional status, and handgrip strength. At the end of the treatment and one-month follow-up, statistically significant improvements were observed in all parameters. This study is the first randomized trial comparing peloidotherapy to ESWT as an adjunct to exercise therapy in LE. Both ESWT and peloidotherapy, when added to exercise therapy, showed positive short-term effects on pain, quality of life, functional status, and handgrip strength in primary conservative treatment of chronic LE (p<0.001), and no superiority was found between them in terms of efficacy. Peloidotherapy or ESWT may be preferred in the treatment of lateral epicondylitis, depending on the patient's condition. Peloidotherapy appears to be more advantageous due to its lower side effects and painless nature. ClinicalTrials.gov ID: NCT04748406.


UVC inactivation of MS2-phage in drinking water - Modelling and field testing.
UVC disinfection has been recognised by the WHO as an effective disinfection treatment to provide decentralized potable water. Under real conditions there are still unknowns that limit this application including the influence of suspended solids and natural organic matter. This work aims to investigate the influence of two key parameters, suspended solids and natural organic matter, on the efficiency of UVC disinfection of surface water to achieve the drinking water quality requirements established by the WHO for point of use (POU) technologies. Kaolinite (turbidity agent) and humic acids (HA, model of organic matter) were used in a factorial design of experiments (Turbidity from 0 to 5 NTU, and HA from 0 to 3.5 mg/L) to investigate their effect on UVC inactivation of MS2 phage in surface water. A collimated beam (12 W) and a commercial UVC disinfection flow system (16 W) designed to provide drinking water at households were used. The UVC flow system both in the laboratory and in the field was able to achieve the reduction requirements established by WHO (LRV >3.5 for all tested conditions), confirming the good performance of the studied UVC disinfection system. The results found in the lab were used to establish a numerical model that predicts the disinfection rate constant as a function of water turbidity and transmittance at 254 nm (confidence level>95%). The model permitted to elucidate the critical effect of low concentrations of HA in reducing the inactivation rate by 40% for 3.5 mg/L-HA compared with 0, the non-significant detrimental effect of turbidity lower than 5 NTU, and the lack of synergistic effects between both parameters at these levels. The UVC flow system was also tested in the field, in Tzabalho, Chiapas (Mexico), and Antioquia (Colombia), with spiked MS2 into natural surface water. This investigation opens a potential application to monitor the performance of UVC systems with surface water by monitoring transmittance at 254 nm as a tool to control UVC domestic systems to deliver safe drinking water in a household without the need of expensive and laborious biological monitoring tools.


Pharmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V2 receptors.
Some membrane-permeable antagonists restore cell surface expression of misfolded receptors retained in the endoplasmic reticulum (ER) and are therefore termed pharmacochaperones. Whether pharmacochaperones increase protein stability, thereby preventing rapid degradation, or assist folding via direct receptor interactions or interfere with quality control components remains elusive. We now show that the cell surface expression and function (binding of the agonist) of the mainly ER-retained wild-type murine vasopressin V2 receptor GFP fusion protein (mV2R.GFP) is restored by the vasopressin receptor antagonists SR49059 and SR121463B with EC50 values similar to their KD values. This effect was preserved when protein synthesis was abolished. In addition, SR121463B rescued eight mutant human V2Rs (hV2Rs, three are responsible for nephrogenic diabetes insipidus) characterized by amino acid exchanges at the C-terminal end of transmembrane helix TM I and TM VII. In contrast, mutants with amino acid exchanges at the interface of TM II and IV were not rescued by either antagonist. The mechanisms involved in successful rescue of cell surface delivery are explained in a three-dimensional homology model of the antagonist-bound hV2R.


Unraveling the Origin of Long-Lifetime Emission in Low-Dimensional Copper Halides via a Magneto-optical Study.
The origin of the long lifetime of self-trapped exciton emission in low-dimensional copper halides is currently the subject of extensive debate. In this study, we address this issue in a prototypical zero-dimensional copper halide, Cs2(C18)2Cu2I4-DMSO, through magneto-optical studies at low temperatures down to 0.2 K. Our results exclude spin-forbidden dark states and indirect phonon-assisted recombination as the origin of the long photoluminescence lifetime. Instead, we propose that the minimal Franck-Condon factor of the radiative transition from excited states to the ground state is the decisive factor, based on the transition probability analysis. Our findings offer insights into the electronic processes in low-dimensional copper halides and have the potential to advance the application of these distinctive materials in optoelectronics.


[Clinical efficacy and safety of the selective oral neuraminidase inhibitor oseltamivir in treating acute influenza--placebo-controlled double-blind multicenter phase III trial].
We conducted the placebo-controlled double-blind multicenter Phase III trial of newly developed selective oral neuraminidase inhibitor, oseltamivir phosphate (Ro64-0796), in order to evaluate the efficacy and safety, when Ro64-0796 was administered orally to both type A and type B influenzavirus infected patients. Patients were randomly assigned to either Ro64-0796 75 mg twice daily group or matching placebo group for five days. A total of 316 patients (Ro64-0796 group; 154 and placebo group; 162) were recruited, and intent-to-treat infected population, which was defined as the patients that study drug was administered one or more and laboratory-confirmed influenzavirus infection was demonstrated, were 122 and 130, respectively. Ro64-0796 decreased significantly median viral titers after 72 hours (p = 0.0009. Analysis of covariance), indicating the rapid inhibition of virus replication, and duration of illness which was primary variable of efficacy, was reduced statistically significant by one day (23.3 hours) (p = 0.0216, generalized Wilcoxon test). Ro64-0796 treatment also resulted in the reduction of the fever duration and severity of clinical symptoms. Concerning the safety evaluation, the main accompanied symptoms with Ro64-0796 application were gastrointestinal disorders such as bellyache, nausea and vomiting. Most of these events were mild and allowable for the clinical use. There was no abnormal change attributable to Ro64-0796 application in the clinical laboratory tests as well as the physiological tests. Our data suggests that Ro64-0796 is useful in treating the acute influenzavirus infection.


Predictors of lifestyle intervention outcome and dropout: the SLIM study.
To evaluate the effect of a 4.1-year (range 3-6 years) lifestyle intervention according to general public health recommendations on glucose tolerance and dropout in a Dutch population with impaired glucose tolerance (IGT). In the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht, 147 Caucasian IGT subjects were randomized to an intervention group (INT: n=74; 38 male, 36 female) and control group (CON: n=73; 37 male, 36 female). Annually, subjects underwent measurements of body weight, anthropometry, glucose tolerance (oral glucose tolerance test), insulin resistance (homeostasis model assessment-insulin resistance), maximal aerobic capacity (VO(2) max), blood lipids and blood pressure. INT received individual advice regarding a healthy diet and physical activity. INT decreased their saturated fat intake, increased their carbohydrate intake (P<0.05) and VO(2) max (P=0.04) compared with CON. Body weight did not change significantly (P=0.20) between the groups. After an initial decrease, 2-h glucose levels overall increased in INT (+0.11 mmol/l), but significantly less than CON (+1.18 mmol/l; P=0.04). Diabetes incidence was lower in INT versus CON (30 versus 56%, P=0.04). Change in body weight was associated with change in 2-h glucose levels (β=0.399 mmol/l per kg, P=0.02). Dropouts had a lower aerobic fitness and socioeconomic status, and a higher body mass index (BMI) and 2-h glucose compared with non-dropouts. Prolonged feasible changes in diet and physical activity prevent deterioration of glucose tolerance and reduce diabetes risk. Low socioeconomic status, low aerobic fitness and high BMI and 2-h glucose are indicative of dropout to the program.


Paramagnetic solid-state NMR assignment and novel chemical conversion of the aldehyde group to dihydrogen ortho ester and hemiacetal moieties in copper(ii)- and cobalt(ii)-pyridinecarboxaldehyde complexes.
The complex chemical functionalization of aldehyde moieties in Cu(ii)- and Co(ii)-pyridinecarboxaldehyde complexes was studied. X-ray studies demonstrated that the aldehyde group (RCHO) of the four pyridine molecules is converted to dihydrogen ortho ester (RC(OCH3)(OH)2) and hemiacetal (RCH(OH)(OCH3)) moieties in both 4-pyridinecarboxaldehyde copper and cobalt complexes. In contrast, the aldehyde group is retained when the 3-pyridinecarboxaldehyde ligand is complexed with cobalt. In the different copper complexes, similar paramagnetic 1H resonance lines were obtained in the solid state; however, the connectivity with the carbon structure and the 1H vicinities were done with 2D 1H-13C HETCOR, 1H-1H SQ/DQ and proton spin diffusion (PSD) experiments. The strong paramagnetic effect exerted by the cobalt center prevented the observation of 13C NMR signals and chemical information could only be obtained from X-ray experiments. 2D PSD experiments in the solid state were useful for the proton assignments in both Cu(ii) complexes. The combination of X-ray crystallography experiments with DFT calculations together with the experimental results obtained from EPR and solid-state NMR allowed the assignment of NMR signals in pyridinecarboxaldehyde ligands coordinated with copper ions. In cases where the crystallographic information was not available, as in the case of the 3-pyridinecarboxaldehyde Cu(ii) complex, the combination of these techniques allowed not only the assignment of NMR signals but also the study of the functionalization of the substituent group.


A systematic review of the cost-effectiveness of uterotonic agents for the prevention of postpartum hemorrhage.
Several uterotonic options exist for prevention of postpartum hemorrhage (PPH); hence, cost-effectiveness is an important decision-making criterion affecting uterotonic choice. To conduct a systematic review of cost-effectiveness of uterotonics for PPH prevention to support a WHO guideline update. We searched major databases from 1980 to June 2018 and the National Health Services Economic Evaluation (NHS EED) database from inception (1995) to March 2015 for eligible studies. We included comparative economic evaluations, cost-utility analyses, and resource-utilization studies. Two reviewers independently assessed studies and extracted data organized by birth mode and setting. We included 15 studies across all income categories that compared misoprostol versus no uterotonic (five studies) or versus oxytocin (one study), carbetocin versus oxytocin (eight studies), and one study comparing numerous uterotonics. In specific low-resource contexts, we found reasonably good evidence that misoprostol was cost-effective compared with no uterotonic. In the context of cesarean delivery, carbetocin was more cost favorable than oxytocin but certainty of this evidence was low. Evidence on the cost-effectiveness of various uterotonic agents was not generalizable. As the number of competing uterotonics increases, rigorous economic evaluations including contextual factors are needed.


Coherent and dissipative quantum process tensor reconstructions in two-dimensional electronic spectroscopy.
A major goal of time-resolved spectroscopy is to resolve the dynamical processes that follow photoexcitation. This amounts to identifying all the quantum states involved and the rates of population transfer between them. Unfortunately, such quantum state and kinetic reconstructions are ambiguous using one-dimensional methods such as transient absorption even when all the states of the system are fully resolved. Higher-dimensionality methods like two-dimensional spectroscopy lift some of the ambiguity, but unless the spectral features are well-separated, current inversion methods generally fail. Here, we show that, using both coherence and population signals of the nonlinear response, it is indeed possible to accurately extract both static and dynamic information from the 2D spectrum even when features are highly congested. Coherences report on the positions of the vibronic states of the system, providing a useful constraint for extracting the full kinetic scheme. We model time-resolved 2D photon echo spectra using a sum-over-states approach and show in which regimes the Hamiltonian and kinetic schemes may be recovered. Furthermore, we discuss how such algorithms may be applied to experimental data and where some of the underlying assumptions may fail. The ability to systematically extract the maximal information content of multidimensional spectroscopic data is an important step toward utilizing the full power of these techniques and elucidating the structure and dynamics of increasingly complex molecular systems.


Changes in available gonadotropin receptors in the corpus luteum of the rhesus monkey during simulated early pregnancy.
Stimulation of the primate corpus luteum (CL) by endogenous CG in early pregnancy or by exogenous human CG (hCG) in simulated early pregnancy, is transient, despite continued exposure to rising concentrations of CG. The objective of this study was to determine if the transitory response of the CL to CG is related to changes in gonadotropin receptors. Numbers and affinities of available LH/CG binding sites were characterized in the CL of rhesus monkeys (n = 27) during prolonged CG exposure in simulated early pregnancy, and the temporal relationship between changes in receptor parameters and in luteal function was examined. Administration of hCG increased progesterone concentrations above pretreatment levels within 9 h (2.2 +/- 0.8 vs. 7.6 +/- 1.1 ng/ml, mean +/- SE, P less than 0.05); the relative increase (345% of control) in serum progesterone was more profound than that of available hCG binding sites (135%, P greater than 0.05) or luteal weight (128%, P greater than 0.05) over this interval. Receptor affinities for hCG remained comparable to pretreatment values (Kd = 1.1 +/- 0.2 X 10(-10) M) throughout this 9-h period. A significant diminution in available hCG receptors occurred between 9 h (12.7 +/- 2.1 fmol/mg tissue) and 3 days (7.4 +/- 1.5 fmol/mg tissue) of hCG treatment (P less than 0.05). The loss of available CG receptors preceded a significant decline in serum progesterone concentrations. Serum progesterone decreased by 6 days (4.0 +/- 0.6 ng/ml, P less than 0.05) of hCG treatment, as did receptor affinity for hCG (Kd = 4.7 +/- 0.9 X 10(-10) M, P less than 0.05). Numbers and affinities of available receptors for hCG and serum progesterone concentrations fell before any decrease in luteal weight. Binding capacities and receptor affinities for human LH were comparable to those for hCG throughout simulated early pregnancy. In conclusion, the population of available LH/CG receptors in the macaque CL is maintained, or perhaps modestly increased, amidst dramatic stimulation of luteal function during early CG exposure. The subsequent diminution of number and affinity of available LH/CG receptors during prolonged exposure to CG in early pregnancy may compromise CL function and thus participate in the establishment of the transient nature of the luteal response to CG.


Extended-release gabapentin for failed back surgery syndrome: results from a randomized double-blind cross-over study.
Persistent pain after lumbar surgery (failed back surgery syndrome [FBSS]) remains a leading indication for chronic analgesia. However, no analgesics have proven efficacious for this condition. Although trials have evaluated gabapentinoids for chronic low back pain, none of these trials focused solely on FBSS. This randomized, double-blind cross-over trial evaluated the efficacy of gabapentin (1800 mg/day) for FBSS. Eligible patients had a diagnosis of FBBS, an average daily pain score of at least 4 of 10, a neuropathic pain component (indicated by the PainDetect), and reported at least half of their pain radiating in their lower extremity. Participants were randomized to 2, 7-week study periods separated by a 10-day washout. The primary outcome measure was a 0 to 10 numeric rating scale (NRS) of average pain. Secondary measures included the McGill Pain Questionnaire and Patient Global Impression of Change. The treatment effect was analyzed using a mixed effect analysis of covariance with fixed effects for treatment, period, and baseline 7-day mean NRS pain score and a random effect for the participant. The outcome of the model was the mean 7-day NRS score for the last 7 days of each treatment period. Thirty-two participants were randomized and included in the primary analysis; 25 completed both study periods. No difference was detected between treatments on any outcome measure, including the primary (least square mean difference in NRS: -0.01 confidence interval: [-0.22 to 0.20]). Given the escalating rate of complex lumbar surgery, future research to develop novel therapies for this prevalent syndrome is needed.


A real-time 2-D vector Doppler system for clinical experimentation.
A real-time hardware software 2-D vector Doppler system has been realized by means of the FEMMINA platform. The system operates by performing two independent 1-D Doppler estimations on the scan plane of a linear array probe along different directions; the probe is connected to a commercial scanner. The reconstructed velocity is presented in real-time as superposition on the conventional B-mode images. Two different scanning techniques have been implemented, in order to carry out the 2-D Doppler investigation in the area of interest. These techniques allow to use the system both in vivo and in vivo. An extensive set of simulations has been performed in order to establish a gold standard regarding vector Doppler 2-D techniques, and to be able to assess the performance of the 2-D Doppler system by comparing simulated and experimental results. The whole real-time 2-D vector Doppler system is fully certified as hospital equipment, and thus it can be employed to carry out an experimental characterization of the 2-D Doppler technique in the clinical environment.


Lack of a site-specific phosphorylation of Presenilin 1 disrupts microglial gene networks and progenitors during development.
Microglial cells play a key role in brain homeostasis from development to adulthood. Here we show the involvement of a site-specific phosphorylation of Presenilin 1 (PS1) in microglial development. Profiles of microglia-specific transcripts in different temporal stages of development, combined with multiple systematic transcriptomic analysis and quantitative determination of microglia progenitors, indicate that the phosphorylation of PS1 at serine 367 is involved in the temporal dynamics of microglial development, specifically in the developing brain rudiment during embryonic microgliogenesis. We constructed a developing brain-specific microglial network to identify transcription factors linked to PS1 during development. Our data showed that PS1 functional connections appear through interaction hubs at Pu.1, Irf8 and Rela-p65 transcription factors. Finally, we showed that the total number of microglia progenitors was markedly reduced in the developing brain rudiment of embryos lacking PS1 phosphorylation compared to WT. Our work identifies a novel role for PS1 in microglial development.


Mutations in the uncE gene affecting assembly of the c-subunit of the adenosine triphosphatase of Escherichia coli.
The amino acid substitutions in the mutant c-subunits of Escherichia coli F1F0-ATPase coded for by the uncE429, uncE408 and uncE463 alleles affect the incorporation of these proteins into the cell membrane. The DNA sequence of the uncE429 allele differed from normal in that a G leads to A base change occurred at nucleotide 68 of the uncE gene, resulting in glycine being replaced by aspartic acid at position 23 in the c-subunit. The uncE408 and uncE463 mutant DNA sequences were identical and differed from normal in that a C leads to T base change occurred at nucleotide 91 of the uncE gene, resulting in leucine being replaced by phenylalanine at position 31 in the c-subunit. An increased gene dosage of the uncE408 or uncE463 alleles resulted in the incorporation into the membranes of the mutant c-subunits. The results are discussed in terms of the 'Helical Hairpin Hypothesis' of Engelman & Steitz [(1981) Cell 23,411-422].


Potential of microneedle-assisted micro-particle delivery by gene guns: a review.
Gene guns have been used to deliver deoxyribonucleic acid (DNA) loaded micro-particle and breach the muscle tissue to target cells of interest to achieve gene transfection. This article aims to discuss the potential of microneedle (MN) assisted micro-particle delivery from gene guns, with a view to reducing tissue damage. Using a range of sources, the main gene guns for micro-particle delivery are reviewed along with the primary features of their technology, e.g. their design configurations, the material selection of the micro-particle, the driving gas type and pressure. Depending on the gene gun system, the achieved penetration depths in the skin are discussed as a function of the gas pressure, the type of the gene gun system and particle size, velocity and density. The concept of MN-assisted micro-particles delivery which consists of three stages (namely, acceleration, separation and decoration stage) is discussed. In this method, solid MNs are inserted into the skin to penetrate the epidermis/dermis layer and create holes for particle injection. Several designs of MN array are discussed and the insertion mechanism is explored, as it determines the feasibility of the MN-based system for particle transfer. This review suggests that one of the problems of gene guns is that they need high operating pressures, which may result in direct or indirect tissue/cells damage. MNs seem to be a promising method which if combined with the gene guns may reduce the operating pressures for these devices and reduce tissue/cell damages. There is sufficient potential for MN-assisted particle delivery systems.


Ventral cervical versus bilateral lateral approach for extirpation of mandibular and medial retropharyngeal lymph nodes in dogs.
To compare ventral cervical and bilateral lateral incisions for extirpation of mandibular and medial retropharyngeal lymph nodes in dogs. Prospective randomized, crossover controlled cadaver trial. Eight veterinarians with advanced surgical training. Study participants were randomized to perform both techniques on paired cadavers. Time to extirpation of the first and last lymph node, length of incisions, and complications were recorded for both techniques. Participants were asked to rate satisfaction with their ability to identify local anatomy and lymph nodes as well as overall preferred technique by using a 10-point numerical rating scale. The total length of skin incised for the bilateral lateral approach exceeded that of the ventral cervical approach by 52.1 mm (mean, P < .001). The surgical time for removal of all 4 lymph nodes did not differ between the 2 approaches. The bilateral lateral approach was preferred by 62.5% (5/8) of participants for visualization of mandibular lymph nodes, and the ventral cervical approach was preferred by 87.5% (7/8) of participants for visualization of local anatomy. Overall, 62.5% (5/8) preferred the ventral cervical approach and 37.5% (3/8) preferred the bilateral lateral approach. The ventral cervical approach was preferred by participants for its perceived superior visualization of local anatomy and access to lymph nodes for removal. This approach also resulted in an overall shorter incision length. A ventral cervical or bilateral lateral approach allows successful removal of the medial mandibular and retropharyngeal lymph nodes in dogs, and surgical approach may be selected according to individual preference.


Automated Measurement of the Foveal Avascular Zone in Swept-Source Optical Coherence Tomography Angiography Images.
The purpose of this study was to evaluate automated measurement of the foveal avascular zone (FAZ) area using the Kanno-Saitama macro (KSM) software in Image J with swept-source optical coherence tomography angiography (SS-OCTA) images. In this cross-sectional study, one photographer scanned the macular area (3 × 3 mm) of healthy volunteers twice on the same day, at the same time. The FAZ area was measured from the en face image of the superficial retinal layer by two masked examiners, using the KSM and the Advanced Retina Imaging (ARI)-network method in Carl Zeiss online analysis. Intra- and interscan reproducibility and FAZ area were compared among the methods. Forty eyes of 22 healthy volunteers were included in the analysis. The mean ± SD age of the subjects was 34.6 ± 12.4 years. Intra- and interscan intraclass coefficients ranged from 0.997 to 1.000 and 0.989 to 0.995, respectively. The mean FAZ area was 0.264 ± 0.08 mm2 by the KSM, 0.245 ± 0.08 mm2 by the ARI, and 0.281 ± 0.09 mm2 by the manual method. The mean difference between the KSM and manual methods was 0.015 mm2, which was significantly smaller than the mean difference between the ARI and manual methods (0.034 mm2; P < 0.001). Automated determination of the FAZ area is feasible and yields results comparable to those obtained by manual measurement. The FAZ area measured with the KSM program is less user dependent and could potentially contribute to our understanding of the pathophysiology of various retinal diseases, particularly underlying vascular diseases. This study demonstrates a novel automated determination of the FAZ area using the Image J macro program in SS-OCTA images. This program was feasible and yields results comparable to those obtained by manual measurement.


Selective Epitaxy of InP on Si and Rectification in Graphene/InP/Si Hybrid Structure.
The epitaxial integration of highly heterogeneous material systems with silicon (Si) is a central topic in (opto-)electronics owing to device applications. InP could open new avenues for the realization of novel devices such as high-mobility transistors in next-generation CMOS or efficient lasers in Si photonics circuitry. However, the InP/Si heteroepitaxy is highly challenging due to the lattice (∼8%), thermal expansion mismatch (∼84%), and the different lattice symmetries. Here, we demonstrate the growth of InP nanocrystals showing high structural quality and excellent optoelectronic properties on Si. Our CMOS-compatible innovative approach exploits the selective epitaxy of InP nanocrystals on Si nanometric seeds obtained by the opening of lattice-arranged Si nanotips embedded in a SiO2 matrix. A graphene/InP/Si-tip heterostructure was realized on obtained materials, revealing rectifying behavior and promising photodetection. This work presents a significant advance toward the monolithic integration of graphene/III-V based hybrid devices onto the mainstream Si technology platform.


Craniofacial morphology and growth in the rat. Cephalometric analysis of the effects of a low calcium and vitamin D-deficient diet.
The influence of a low calcium and vitamin D-deficient diet on the growth and form of the skull of the growing rat was studied using a cephalometric radiographic technique. First, this technique was used to obtain an intra-individual cephalometric description of the normal growth and form of the skull at different ages during postnatal growth in the rat. It was shown that the methodological error and the biological variation between animals were significantly lower than the registered growth changes, thus demonstrating the suitability of the technique. In the animals fed the low calcium and vitamin D-deficient diet and impaired increase in body weight was found. This diet also caused changes in cranial dimensions, both when the deficient animals were compared with control animals of the same age and with control animals with the same weight. It was concluded that the vitamin D-free and low calcium diet caused a disturbed osteogenesis in growth sites determining the growth and form of the viscerocranium and its relation to the neurocranium.


Evaluation of garlic oil as a contact dissolution agent for gallstones: comparison with monooctanoin.
To find a better contact solvent to dissolve gallstones we studied invitro use of garlic oil and compared it with monooctanoin. In the first stage gall stones obtained from patients after cholecystectomy were subjected to dissolution in different concentrations of garlic oil. Then the rate of dissolution of gall stones in garlic oil was compared to that in monooctanoin in stage II. Efficacy of various concentration of garlic oil and monoocatanoin in dissolving gallstones in artificial gall bladder and common bile duct models were compared in stage III. Garlic oil dissolved the cholesterol gall stones in proportion to the concentration used. The gall stone fragmentation was faster [6 hours V/s 36 hours] and more [88.30% V/s 71.01%] by garlic oil in comparison to monooctanoin in test tubes and even in artificial gallbladder and common bile duct models. Garlic oil is a better contact dissolving agent of gallstones than monooctanoin.


Prospero-related homeobox 1 (Prox1) at the crossroads of diverse pathways during adult neural fate specification.
Over the last decades, adult neurogenesis in the central nervous system (CNS) has emerged as a fundamental process underlying physiology and disease. Recent evidence indicates that the homeobox transcription factor Prox1 is a critical intrinsic regulator of neurogenesis in the embryonic CNS and adult dentate gyrus (DG) of the hippocampus, acting in multiple ways and instructed by extrinsic cues and intrinsic factors. In the embryonic CNS, Prox1 is mechanistically involved in the regulation of proliferation vs. differentiation decisions of neural stem cells (NSCs), promoting cell cycle exit and neuronal differentiation, while inhibiting astrogliogenesis. During the complex differentiation events in adult hippocampal neurogenesis, Prox1 is required for maintenance of intermediate progenitors (IPs), differentiation and maturation of glutamatergic interneurons, as well as specification of DG cell identity over CA3 pyramidal fate. The mechanism by which Prox1 exerts multiple functions involves distinct signaling pathways currently not fully highlighted. In this mini-review, we thoroughly discuss the Prox1-dependent phenotypes and molecular pathways in adult neurogenesis in relation to different upstream signaling cues and cell fate determinants. In addition, we discuss the possibility that Prox1 may act as a cross-talk point between diverse signaling cascades to achieve specific outcomes during adult neurogenesis.


Diuretic response to acute hypoxia in the conscious dog.
Experiments were performed to determine the renal effects of acute hypoxia in conscious normovolemic dogs. Dogs were made hypoxic and also became hypocapnic through increased ventilation. Hypocapnic hypoxia was associated with increased urine flow, arterial blood pressure, cardiac output, PAH and inulin clearance, and electrolyte excretion. Urinary excretion of prostaglandin E2 (PGE2) also increased during hypocapnic hypoxia. To test whether the respiratory alkalosis accompanying hypoxic exposure was important in mediating the observed response, experiments were conducted in which the dogs were hypoxic but remained isocapnic via addition of CO2 to the inspired gas. Urine flow increased and was associated with changes in renal function and hemodynamics similar to those during hypocapnic hypoxia. Experiments were also conducted to determine whether the increased PGE2 release in hypoxia was functionally significant. Dogs were pretreated with meclofenamate and then made hypoxic. Prostaglandin synthesis inhibition did not alter the renal response to hypocapnic hypoxia. Dogs were also treated chronically with propranolol in an attempt to blunt the rise in blood pressure during hypoxia. In dogs with only a small transient increase in blood pressure, the diuresis was blocked. It is concluded that systemic hypoxia results in a mild diuresis in the conscious normovolemic dog. This response occurs independent of changes in arterial pH or renal prostaglandin release. The diuretic effect of hypoxia is probably due to increased renal perfusion pressure and resultant increased filtration.


Managing Genetic Diversity and Extinction Risk for a Rare Plains Bison (Bison bison bison) Population.
Unfenced plains bison are rare and only occur in a small number of locations throughout Canada and the United States. We examined management guidelines for maintenance of genetic health and population persistence for a small and isolated population of plains bison that occupy the interface between a protected national park and private agricultural lands. To address genetic health concerns, we measured genetic diversity relative to other populations and assessed the potential effects of genetic augmentation. We then used individual-based population viability analyses (PVA) to determine the minimum abundance likely to prevent genetic diversity declines. We assessed this minimum relative to a proposed maximum social carrying capacity related to bison use of human agricultural lands. We also used the PVA to assess the probability of population persistence given the limiting factors of predation, hunting, and disease. Our results indicate that genetic augmentation will likely be required to achieve genetic diversity similar to that of other plains bison populations. We also found that a minimum population of 420 bison yields low probability of additional genetic loss while staying within society-based maxima. Population estimates based on aerial surveys indicated that the population has been below this minimum since 2007. Our PVA simulations indicate that current hunting practices will result in undesirable levels of population extinction risk and further declines in genetic variability. Our study demonstrates that PVA can be used to evaluate potential management scenarios as they relate to long-term genetic conservation and population persistence for rare species.


Cystic fibrosis transmembrane conductance regulator is involved in airway epithelial wound repair.
The role of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) in airway epithelial wound repair was investigated using normal human bronchial epithelial (NHBE) cells and a human airway epithelial cell line (Calu-3) of serous gland origin. Measurements of wound repair were performed using continuous impedance sensing to determine the time course for wound closure. Control experiments showed that the increase in impedance corresponding to cell migration into the wound was blocked by treatment with the actin polymerization inhibitor, cytochalasin D. Time lapse imaging revealed that NHBE and Calu-3 cell wound closure was dependent on cell migration, and that movement occurred as a collective sheet of cells. Selective inhibition of CFTR activity with CFTR(inh)-172 or short hairpin RNA silencing of CFTR expression produced a significant delay in wound repair. The CF cell line UNCCF1T also exhibited significantly slower migration than comparable normal airway epithelial cells. Inhibition of CFTR-dependent anion transport by treatment with CFTR(inh)-172 slowed wound closure to the same extent as silencing CFTR protein expression, indicating that ion transport by CFTR plays a critical role in migration. Moreover, morphologic analysis of migrating cells revealed that CFTR inhibition or silencing significantly reduced lamellipodia protrusion. These findings support the conclusion that CFTR participates in airway epithelial wound repair by a mechanism involving anion transport that is coupled to the regulation of lamellipodia protrusion at the leading edge of the cell.


Low-fat, plant-based diet in multiple sclerosis: A randomized controlled trial.
The role that dietary interventions can play in multiple sclerosis (MS) management is of huge interest amongst patients and researchers but data evaluating this is limited. Possible effects of a very-low-fat, plant-based dietary intervention on MS related progression and disease activity as measured by brain imaging and MS related symptoms have not been evaluated in a randomized-controlled trial. Despite use of disease modifying therapies (DMT), poor quality of life (QOL) in MS patients can be a significant problem with fatigue being one of the common disabling symptoms. Effective treatment options for fatigue remain limited. Emerging evidence suggests diet and vascular risk factors including obesity and hyperlipidemia may influence MS disease progression and improve QOL. To evaluate adherence, safety and effects of a very-low-fat, plant-based diet (Diet) on brain MRI, clinical [MS relapses and disability, body mass index (BMI)] and metabolic (blood lipids and insulin) outcomes, QOL [Short Form-36 (SF-36)], and fatigue [Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS)], in relapsing-remitting MS (RRMS). This was a randomized-controlled, assessor-blinded, one-year long study with 61 participants assigned to either Diet (N=32) or wait-listed (Control, N=29) group. The mean age (years) [Control-40.9±8.48; Diet-40.8±8.86] and the mean disease duration (years) [Control -5.3±3.86; Diet-5.33±3.63] were comparable between the two groups. There was a slight difference between the two study groups in the baseline mean expanded disability status scale (EDSS) score [Control-2.22±0.90; Diet-2.72±1.05]. Eight subjects withdrew (Diet, N=6; Control, N=2). Adherence to the study diet based on monthly Food Frequency Questionnaire (FFQ) was excellent with the diet group showing significant difference in the total fat caloric intake compared to the control group [total fat intake/total calories averaged ~15% (Diet) versus ~40% (Control)]. The two groups showed no differences in brain MRI outcomes, number of MS relapses or disability at 12 months. The diet group showed improvements at six months in low-density lipoprotein cholesterol (Δ=-11.99mg/dL; p=0.031), total cholesterol (Δ=-13.18mg/dL; p=0.027) and insulin (Δ=-2.82mg/dL; p=0.0067), mean monthly reductions in BMI (Rate=-1.125kg/m2 per month; p<0.001) and fatigue [FSS (Rate=-0.0639 points/month; p=0.0010); MFIS (Rate=-0.233 points/month; p=0.0011)] during the 12-month period. While a very-low fat, plant-based diet was well adhered to and tolerated, it resulted in no significant improvement on brain MRI, relapse rate or disability as assessed by EDSS scores in subjects with RRMS over one year. The diet group however showed significant improvements in measures of fatigue, BMI and metabolic biomarkers. The study was powered to detect only very large effects on MRI activity so smaller but clinically meaningful effects cannot be excluded. The diet intervention resulted in a beneficial effect on the self-reported outcome of fatigue but these results should be interpreted cautiously as a wait-list control group may not completely control for a placebo effect and there was a baseline imbalance on fatigue scores between the groups. If maintained, the improved lipid profile and BMI could yield long-term vascular health benefits. Longer studies with larger sample sizes are needed to better understand the long-term health benefits of this diet.


The role of nanostructures and hydrophilicity in osseointegration: In-vitro protein-adsorption and blood-interaction studies.
Protein adsorption and blood coagulation play important roles in the early stages of osseointegration and are strongly influenced by surface properties. We present a systematic investigation of the influence of different surface properties on the adsorption of the blood proteins fibrinogen and fibronectin and the degree of early blood coagulation. Experiments on custom-made and commercially available, microroughened hydrophobic titanium (Ti) surfaces (Ti SLA-Hphob ), hydrophilic (Hphil ) microroughened Ti surfaces with nanostructures (Ti SLActive-Hphil NS), and on bimetallic Ti zirconium alloy (TiZr, Roxolid®) samples were performed, to study the biological response in relation to the surface wettability and the presence of nanostructures (NS). Protein adsorption on the different substrates showed a highly significant effect of surface NS. Hydrophilicity alone did not significantly enhance protein adsorption. Overall, the combination of NS and hydrophilicity led to the highest adsorption levels; independent of whether Ti or TiZr were used. Hydrophilicity induced a strong effect on blood coagulation, whereas the effect of NS alone was weak. The combination of both surface characteristics led to early and most pronounced blood-coagulation. Therefore, nanostructured, hydrophilic Ti and TiZr surfaces may perform better in terms of osseointegration due to continuous protein adsorption and the formation of a layer of blood components on the implant surface.


The role of human O(6)-alkylguanine-DNA alkyltransferase in promoting 1,2-dibromoethane-induced genotoxicity in Escherichia coli.
The expression of the DNA repair protein human O(6)-alkylguanine-DNA alkyltransferase (AGT) in Escherichia coli strains GWR109 or TRG8 that lack endogenous AGT greatly increased the toxicity and mutagenicity of 1,2-dibromoethane (DBE). Pretreatment of strain TRG8 expressing human AGT, which is permeable to exogenous drugs, with the AGT inhibitor O(6)-benzylguanine (BG) abolished the lethal and mutagenic effects of DBE, indicating that an active AGT is required for promoting DBE genotoxicity. This was confirmed by the observation that E. coli expressing either the C145A AGT mutant, which is inactive due to loss of the alkyl acceptor site, or mutants Y114E and R128A, which are inactive due to alteration of the DNA binding domain, did not enhance the action of DBE. However, the AGT mutant protein P138M/V139L/P140K, which is active in repairing methylated DNA but is totally resistant to inactivation by BG due to alterations in the active site pocket, was unable to enhance the genotoxicity of DBE. Similarly, other mutants, G156P, Y158H and K165R that are strongly resistant to BG, were much less effective than wild type AGT in mediating the genotoxicity of DBE. Mutant P140A, which is moderately resistant to BG, did increase mutations in response to DBE but was less active than wild type. These results suggest that human AGT is able to interact with a DNA lesion produced by DBE but, instead of repairing it, converts it to a more genotoxic adduct. This interaction is prevented by mutations that modify the active site of AGT to exclude BG.


Ultrasensitive DNA hypermethylation detection using plasma for early detection of NSCLC: a study in Chinese patients with very small nodules.
We had previously developed highly sensitive DNA methylation detection to diagnose lung cancer in patients with pulmonary nodules. To validate this approach and determine clinical utility in Chinese patients with indeterminate pulmonary nodules, we assessed the diagnostic accuracy for early stage lung cancer in plasma samples. Patients with CT-detected small lung nodules (diameter ≤ 3.0 cm) were included. Cases (n = 163) had staged IA or IB non-small cell lung cancer (NSCLC), while controls (n = 83) had non-cancerous lesions. Promoter methylation of eight lung cancer-specific genes (CDO1, TAC1, SOX17, HOXA7, HOXA9, GATA4, GATA5, and PAX5) was detected using nanoparticle-based DNA extraction (MOB) followed by qMSP. Methylation detection for CDO1, TAC1, SOX17, and HOXA7 in plasma was significantly higher in cases compared with the benign group (p < 0.001). The sensitivity and specificity for lung cancer diagnosis using individual gene was 41-69% and 49-82%. A three-gene combination of the best individual genes has sensitivity and specificity of 90% and 71%, with area under the receiver operating curve (AUC) of 0.88, (95% CI 0.84-0.93). Furthermore, three-gene combinations detected even the smallest lung nodules, with the combination of CDO1, SOX17, and HOXA7 having the overall best performance, while the combination of CDO1, TAC1, and SOX17 was best in tumor sizes less than 1.0 cm. Using modified MOB-qMSP, high sensitivity and specificity, for the detection of circulating tumor DNA was obtained for early stage NSCLC. This strategy has great potential to identify patients at high risk and improve the diagnosis of lung cancer at an earlier stage.


Changes in Essential Oil Composition, Polyphenolic Compounds and Antioxidant Capacity of Ajowan (Trachyspermum ammi L.) Populations in Response to Water Deficit.
Ajowan (Trachyspermum ammi L.) is considered a valuable spice plant with a high thymol content. Seed yield, essential oil constituents, polyphenolic composition, and antioxidant capacity of ajowan (Trachyspermum ammi L.) populations were evaluated in three (normal, moderate, and severe) water irrigation regimes. The highest essential oil content (5.55%) was obtained under normal condition in the Yazd population. However, both essential oil and seed yield showed significant reductions as a result of water stress. According to gas chromatography-mass spectrometry (GC-MS) analysis, thymol (61.44%), γ-terpinene (26.96%), and p-cymene (20.32%) were identified as the major components of the oil. The highest (89.01%) and the lowest (37.54%) thymol contents were in Farsmar and Hamadan populations in severe stress condition, respectively. Based on HPLC analysis, chlorogenic (3.75-47.35 mg/100 g), caffeic (13.2-40.10 mg/100 g), and ferulic acid (11.25-40.10 mg/100 g) were identified as the major phenolic acids, while rutin was determined as the major flavonoid (11.741-20.123 mg/100 g). Moreover, total phenolic and flavonoid contents were elevated under drought stress treatment, while antioxidants responded inconsistently to stress based on two model systems. Overall, the Yazd population exhibited a superior response to water stress, as evidenced by its less reduced thymol and oil yield content, while Arak and Khormo had the highest accumulation of polyphenolic compounds.


A synthetic peptide that prevents cAMP regulation in mammalian hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.
Binding of TRIP8b to the cyclic nucleotide binding domain (CNBD) of mammalian hyperpolarization-activated cyclic nucleotide-gated (HCN) channels prevents their regulation by cAMP. Since TRIP8b is expressed exclusively in the brain, we envisage that it can be used for orthogonal control of HCN channels beyond the central nervous system. To this end, we have identified by rational design a 40-aa long peptide (TRIP8bnano) that recapitulates affinity and gating effects of TRIP8b in HCN isoforms (hHCN1, mHCN2, rbHCN4) and in the cardiac current If in rabbit and mouse sinoatrial node cardiomyocytes. Guided by an NMR-derived structural model that identifies the key molecular interactions between TRIP8bnano and the HCN CNBD, we further designed a cell-penetrating peptide (TAT-TRIP8bnano) which successfully prevented β-adrenergic activation of mouse If leaving the stimulation of the L-type calcium current (ICaL) unaffected. TRIP8bnano represents a novel approach to selectively control HCN activation, which yields the promise of a more targeted pharmacology compared to pore blockers.


RAC1 P29S regulates PD-L1 expression in melanoma.
Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5-9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho-protein expression, we identified cyclin B1, PD-L1, Ets-1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion. Using the melanoma patient samples in TCGA, we found PD-L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants. The finding that PD-L1 is upregulated suggests that oncogenic RAC1 P29S may promote suppression of the antitumor immune response. This is a new insight into the biological function of RAC1 P29S mutations with potential clinical implications as PD-L1 is a candidate biomarker for increased benefit from treatment with anti-PD1 or anti-PD-L1 antibodies.


Contemporary sequential segmental approach to congenital heart disease using four-dimensional magnetic resonance imaging with ferumoxytol: an illustrated editorial.
The ferumoxytol-enhanced 4D MR angiography with MUSIC (Multiphase Steady State Imaging with Contrast) technique provides a single data set that captures dynamic cardiovascular anatomy and ventricular function at the same time. Homogeneous opacification of all cardiovascular structures within the imaging volume allows full sequential segmental approach to the congenital heart diseases without any blind spots. The complex systemic and pulmonary venous anatomy is particularly well captured in the MUSIC. Cinematographic display of multiplanar sectional and 3D volume images is helpful in the morphological identification of the cardiac chambers, the assessment of the dynamic nature of the ventricular outflow tracts, and the assessment of the coronary arterial origins and courses.


Automated and nonbiased regional quantification of functional neuroimaging data.
In the quantification of functional neuroimaging data, region-of-interest (ROI) analysis can be used to assess a variety of properties of the activation signal, but taken alone these properties are susceptible to noise and may fail to accurately describe overall regional involvement. Here, the authors present and evaluate an automated method for quantification and localization of functional neuroimaging data that combines multiple properties of the activation signal to generate rank-order lists of regional activation results. The proposed automated quantification method, referred to as neuroimaging results decomposition (NIRD), begins by decomposing an activation map into a hierarchical list of ROIs using a digital atlas. In an intermediate step, the ROIs are rank-ordered according to extent, mean intensity, and total intensity. A final rank-order list (NIRD average rank) is created by sorting the ROIs according to the average of their ranks from the intermediate step. The authors hypothesized that NIRD average rank would have improved regional quantification accuracy compared to all other quantitative metrics, including methods based on properties of statistical clusters. To test their hypothesis, NIRD rankings were directly compared to three common cluster-based methods using simulated fMRI data both with and without realistic head motion. For both the no-motion and motion datasets, an analysis of variance found that significant differences between the quantification methods existed (F = 64.8, p < 0.0001 for no motion; F = 55.2, p < 0.0001 for motion), and a post-hoc test found that NIRD average rank was the most accurate quantification method tested (p < 0.05 for both datasets). Furthermore, all variants of the NIRD method were found to be significantly more accurate than the cluster-based methods in all cases. These results confirm their hypothesis and demonstrate that the proposed NIRD methodology provides improved regional quantification accuracy compared to cluster-based methods.


The Roles of Epidemiologists, Laboratorians, and Public Health Agencies in Preventing Invasive Cronobacter Infection.
Cronobacter can cause severe, invasive infection in very young infants. These bacteria can also colonize or cause insignificant infections in immunocompromised, elderly, and/or hospitalized adults. This editorial review highlights key points addressed in the Frontiers Research Topic on Cronobacter, discusses the clinical presentation and epidemiology of Cronobacter infections, and examines the responses of public health agencies to this problem. Cronobacter is rarely isolated from hospitalized, immunocompromised and/or elderly adults and does not cause significant disease in those patients. Certain species and strains, especially of Cronobacter sakazakii, can cause invasive illness in previously healthy infants <2 months of age. Multilocus sequence type 4 and clonal complex 4 (ST4/MLST 4) C. sakazakii are the predominant cause of Cronobacter meningitis, which occurs only in infants. These infections and this strain type are strongly linked to powdered infant formulas (PIF), which can also be contaminated with other Cronobacter strains. End-product testing is not intended to guarantee the absence of these organisms. WHO has made recommendations that can help decrease but will not eliminate the risk of this infection. To further define the spectrum of Cronobacter-associated disease, all isolates should be genetically typed using every currently available method, typing results should be linked to the associated epidemiologic and clinical data, and these data should be analyzed in a scientifically sound manner. Based on currently available information, more can be done now to prevent cause invasive infection in young infants. This includes encouragement of exclusive breastfeeding and/or use of commercially sterile ready-to-feed formulas in the first 2 months of life.


Entropy and distance of random graphs with application to structural pattern recognition.
The notion of a random graph is formally defined. It deals with both the probabilistic and the structural aspects of relational data. By interpreting an ensemble of attributed graphs as the outcomes of a random graph, we can use its lower order distribution to characterize the ensemble. To reflect the variability of a random graph, Shannon's entropy measure is used. To synthesize an ensemble of attributed graphs into the distribution of a random graph (or a set of distributions), we propose a distance measure between random graphs based on the minimum change of entropy before and after their merging. When the ensemble contains more than one class of pattern graphs, the synthesis process yields distributions corresponding to various classes. This process corresponds to unsupervised learning in pattern classification. Using the maximum likelihood rule and the probability computed for the pattern graph, based on its matching with the random graph distributions of different classes, we can classify the pattern graph to a class.


Two cases of anti-epiligrin cicatricial pemphigoid with and without associated malignancy.
Anti-epiligrin cicatricial pemphigoid (AECP) is a chronic, mucous membrane-dominated, subepithelial blistering disease characterized by circulating anti-basement membrane zone auto-antibodies to laminin 5. Recent studies have shown that people with AECP have an increased relative risk for malignant tumours. In this report we describe two patients with AECP. In both cases, indirect immunofluorescence demonstrated circulating IgG anti-basement membrane auto-antibodies that bound to the dermal side of 1M NaCl split normal skin. Immunoblotting using laminin 5 purified from keratinocyte extract as a substrate showed that the IgG antibodies of patient 1 reacted with the 140-kDa beta3 subunit of laminin 5 and IgG antibodies of patient 2 reacted with the 165-kDa and 145-kDa alpha3 subunits. Patient 1 had prostate carcinoma and his blistering was resistant to therapy. Patient 2 had no detectable malignancy and treatment with doxycycline was successful.


Effects of Pyrolysis on High-Capacity Si-Based Anode of Lithium Ion Battery with High Coulombic Efficiency and Long Cycling Life.
We report a facile pyrolysis process for the fabrication of a porous silicon-based anode for lithium-ion battery. Silicon flakes of 100 nm × 800 nm × 800 nm were mixed with equal weight of sodium carboxymethyl cellulose (CMC) and styrene butadiene rubber (SBR) as the binder and the conductivity enhancement additive, Ketjen Black (KB), at the weight ratio of silicon-binder-KB being 70%:20%:10%, respectively. Pyrolysis was carried out at 700 °C in an inert argon environment for one hour. The process converts the binder to graphitic carbon coatings on silicon and a porous carbon structure. The process led to initial coulombic efficiency (ICE) being improved from 67% before pyrolysis to 75% after pyrolysis with the retention of 2.1 mAh/cm2 areal capacity after 100 discharge-charge cycles at 1 A/g rate. The improved ICE and cycling performance are attributed to graphitic coatings, which protect silicon from irreversible reactions with the electrolyte to form compounds such as lithium-silicon-fluoride (Li2SiF6) and the physical integrity and buffer space provided by the porous carbon structure. By eliminating the adverse effects of KB, the anode made with silicon-to-binder weight ratio of 70%:30% exhibited further improvement of the ICE to approximately 90%. This demonstrated that pyrolysis is a facile and promising one-step process for the fabrication of silicon-based anode with high ICE and long cycling life. This is especially true when the amount and choice of conductivity enhancement additive are optimized.


A promising anticancer drug: a photosensitizer based on the porphyrin skeleton.
Photodynamic therapy (PDT) is a minimally invasive combination of treatments that treat tumors and other diseases by using photosensitizers, light and oxygen to produce cytotoxic reactive oxygen species (ROS) inducing tumor cell apoptosis. Photosensitizers are the key part of PDT for clinical application and experimental research, and most of them are porphyrin compounds at present. Due to their unique affinity for tumor tissues, porphyrins are not only excellent photosensitizers, but also good carriers to transport other active drugs into tumor tissues, which can exert synergistic anticancer effects of PDT and chemotherapy. This article reviews the clinical development of porphyrin photosensitizers and the research status of porphyrin containing bioactive groups. Finally, future perspectives and the current challenges of photosensitizers based on the porphyrin skeleton are discussed.


Visible-light photoelectrodegradation of diuron on WO3 nanostructures.
The degradation of pesticide diuron has been explored by photoelectrocatalysis (PEC) under visible light illumination using two different WO3 nanostructures, obtained by anodization of tungsten. The highest degradation efficiency (73%) was obtained for WO3 nanosheets synthesized in the presence of small amounts of hydrogen peroxide (0.05 M). For that nanostructure, the kinetic coefficient for diuron degradation was 133% higher than that for the other nanostructure (anodized in the presence of fluoride anions). These results have been explained by taking into account the different architecture and dimensions of the two WO3 nanostructures under study.