Diabetes, sleep apnea, obesity and cardiovascular disease: Why not address them together?
Obesity, sleep apnea, diabetes and cardiovascular diseases are some of the most common diseases encountered by the worldwide population, with high social and economic burdens. Significant emphasis has been placed on obtaining blood pressure, body mass index, and placing importance on screening for signs and symptoms pointing towards cardiovascular disease. Symptoms related to sleep, or screening for sleep apnea has been overlooked by cardiac, diabetic, pulmonary and general medicine clinics despite recommendations for screening by several societies. In recent years, there is mounting data where obesity and obstructive sleep apnea sit at the epicenter and its control can lead to improvement and prevention of diabetes and cardiovascular complications. This editorial raises questions as to why obstructive sleep apnea screening should be included as yet another vital sign during patient initial inpatient or outpatient visit.


What causes mitochondrial DNA deletions in human cells?
Mitochondrial DNA (mtDNA) deletions are a primary cause of mitochondrial disease and are likely to have a central role in the aging of postmitotic tissues. Understanding the mechanism of the formation and subsequent clonal expansion of these mtDNA deletions is an essential first step in trying to prevent their occurrence. We review the previous literature and recent results from our own laboratories, and conclude that mtDNA deletions are most likely to occur during repair of damaged mtDNA rather than during replication. This conclusion has important implications for prevention of mtDNA disease and, potentially, for our understanding of the aging process.


Ethical issues in laryngology: tracheal stenting as palliative care.
To improve understanding of aspects of end-of-life care that may not be intuitive to the otolaryngology community. A comprehensive review of the literature was performed by searching Medline, Embase, and Google Scholar databases. Primary manuscripts' bibliographies were reviewed to identify any nonindexed references. Prospective consultation by means of one-on-one interviews was sought from nonotolaryngology key stakeholders in the areas of hospice nursing care and patient advocacy in order to identify pertinent issues. We identified over 1,000 articles published from 1965 to 2013 on the topic of tracheal stents, as well as over 40,000 on hospice/end-of-life care. Three articles focusing specifically on palliative care and airway stenting were identified, of which three were case reports and none were definitive reviews. There are a number of significant issues and concepts unique to hospice care. These are likely unfamiliar to all except for head and neck oncology-specialized otolaryngologists. An example is that hospice care focuses on quality of life rather than prolongation of life (such as curative surgery). Patients with nonoperable tracheal obstruction from malignancy face an unpleasant demise from suffocation. For those patients, stenting can relieve suffering by restoring airway patency. Airway stenting can be a valid palliative care option, even for terminal patients receiving hospice care, when performed to relieve airway obstruction and improve quality of life. End-of-life ethics is an underdeveloped area of otolaryngology that should be explored.


Lack of miRNA-17 family mediates high glucose-induced PAR-1 upregulation in glomerular mesangial cells.
Upregulation of thrombin receptor protease-activated receptor 1 (PAR-1) is verified to contribute to chronic kidney diseases, including diabetic nephropathy; however, the mechanisms are still unclear. In this study, we investigated the effect of PAR-1 on high glucose-induced proliferation of human glomerular mesangial cells (HMCs), and explored the mechanism of PAR-1 upregulation from alteration of microRNAs. We found that high glucose stimulated proliferation of the mesangial cells whereas PAR-1 inhibition with vorapaxar attenuated the cell proliferation. Moreover, high glucose upregulated PAR-1 in mRNA level and protein expression while did not affect the enzymatic activity of thrombin in HMCs after 48 h culture. Then high glucose induced PAR-1 elevation was likely due to the alteration of the transcription or post-transcriptional processing. It was found that miR-17 family members including miR-17-5p, -20a-5p, and -93-5p were significantly decreased among the eight detected microRNAs only in high glucose-cultured HMCs, but miR-129-5p, miR-181a-5p, and miR-181b-5p were markedly downregulated in both high glucose-cultured HMCs and equivalent osmotic press control compared with normal glucose culture. So miR-20a was selected to confirm the role of miR-17 family on PAR-1 upregulation, finding that miR-20a-5p overexpression reversed the upregulation of PAR-1 in mRNA and protein levels induced by high glucose in HMCs. In summary, our finding indicated that PAR-1 upregulation mediated proliferation of glomerular mesangial cells induced by high glucose, and deficiency of miR-17 family resulted in PAR-1 upregulation.


Practice patterns among U.S. gastroenterologists regarding endoscopic management of Barrett's esophagus.
Endoscopic management of Barrett's esophagus (BE) has evolved over the past decade; however, the practice patterns for managing BE among gastroenterologists remain unclear. To assess practice patterns for management of BE among gastroenterologists working in various practice settings. A random questionnaire-based survey of practicing gastroenterologists in the United States. The questionnaire contained a total of 10 questions pertaining to practice setting, physician demographics, and strategies used for managing BE. Survey of gastroenterologists working in various practice settings. Questionnaire. Practice patterns for endoscopic imaging and management of BE. The response rate was 45% (236/530). The majority (85%) were gastroenterologists in community practice, 72% were aged 41 to 60 years, 80% had >10 years of experience, and 81% had attended postgraduate courses and/or seminars on BE management. A total of 78% did not use the Prague C & M classification, and about a third used advanced endoscopic imaging routinely (37%) or in selected cases (31%). For nondysplastic BE, 86% practiced surveillance, 12% performed ablation, and 3% did no intervention. For BE with low-grade dysplasia, 56% practiced surveillance, 26% performed endoscopic ablation in all low-grade dysplasia cases, and 18% performed endoscopic ablation in only selected patients with low-grade dysplasia. The majority of respondents (58%) referred their patients with high-grade dysplasia to centers with BE expertise, 13% performed endoscopic ablation in all patients with high-grade dysplasia, 25% performed endoscopic ablation in selected cases only, and 3% referred these patients for surgery. The most frequently used endoscopic eradication therapy was radiofrequency ablation (39%) followed by EMR (17%). The sample may be unrepresentative, participation in the study was voluntary, and responses may be skewed toward following the guidelines. Results from this survey show that the majority of practicing gastroenterologists in the United States practice surveillance endoscopy in patients with nondysplastic BE and provide endoscopic therapy for those with high-grade dysplasia. The Prague C & M classification and advanced imaging techniques are used by less than a third of gastroenterologists. Practice patterns did not appear to be affected by respondent age or duration of clinical practice.


Anastomotic Leak in Colorectal Surgery: Predictive Factors and Survival.

Introduction: Anastomotic leak (AL) is a serious complication following colorectal surgery.

Aim: The aim of this study was to identify factors associated with the development of AL and to analyze its impact on survival.

Materials and methods: All consecutive adult colorectal cancer resections performed between 2007 and 2020 with curative intent and anastomosis formation were included from a prospectively maintained database. The primary outcome measure was the rate of AL. The secondary outcome measure was 5-year overall survival (OS).

Results: There were 6837 eligible patients. The rate of AL was 2.2% and 4.0% in patients with colon and rectal cancer, respectively. AL was a significant independent predictor of reduced 5-year OS in patients who underwent curative surgery for rectal cancer (odds ratio 2.293, p = 0.009). Emergency surgery (p = 0.015), surgery at a public hospital (p = 0.002), and an open surgical approach (p = 0.021) were all associated with a significantly higher risk of AL in patients with colon cancer, with higher rates of AL noted in left colectomies as compared to right hemicolectomies (4.4% vs. 1.3%, p < 0.001). In rectal cancer patients, AL was associated with neoadjuvant chemoradiotherapy (p = 0.038) and male gender (p = 0.002). The anastomosis formation technique (hand-sewn vs. stapled) did not impact the rate of AL (p = 0.116 and p = 0.198 with colon and rectal cancer, respectively).

Discussion: Clinicians should be cognizant of the predictive factors for AL and should consider early intervention for at-risk patients.</br&gt.


Development of a wheat single gene FISH map for analyzing homoeologous relationship and chromosomal rearrangements within the Triticeae.
A cytogenetic map of wheat was constructed using FISH with cDNA probes. FISH markers detected homoeology and chromosomal rearrangements of wild relatives, an important source of genes for wheat improvement. To transfer agronomically important genes from wild relatives to bread wheat (Triticum aestivum L., 2n = 6 x = 42, AABBDD) by induced homoeologous recombination, it is important to know the chromosomal relationships of the species involved. Fluorescence in situ hybridization (FISH) can be used to study chromosome structure. The genomes of allohexaploid bread wheat and other species from the Triticeae tribe are colinear to some extent, i.e., composed of homoeoloci at similar positions along the chromosomes, and with genic regions being highly conserved. To develop cytogenetic markers specific for genic regions of wheat homoeologs, we selected more than 60 full-length wheat cDNAs using BLAST against mapped expressed sequence tags and used them as FISH probes. Most probes produced signals on all three homoeologous chromosomes at the expected positions. We developed a wheat physical map with several cDNA markers located on each of the 14 homoeologous chromosome arms. The FISH markers confirmed chromosome rearrangements within wheat genomes and were successfully used to study chromosome structure and homoeology in wild Triticeae species. FISH analysis detected 1 U-6 U chromosome translocation in the genome of Aegilops umbellulata, showed colinearity between chromosome A of Ae. caudata and group-1 wheat chromosomes, and between chromosome arm 7S#3 L of Thinopyrum intermedium and the long arm of the group-7 wheat chromosomes.


The effect of altered tryptophan levels on mood and behavior in normal human males.
The effect of lowering or raising tryptophan levels was studied in normal males using amino acid mixtures that were tryptophan free or tryptophan supplemented. Tryptophan depletion caused a small but significant alteration in food selection in subjects allowed to select from a buffet. Although carbohydrate and total kilocalories selected were unchanged, significantly less protein was chosen. Tryptophan depletion also caused an acute lowering of mood, suggesting that low serotonin (5-HT) may be involved in the etiology of clinical depression in some patients. No effect of altered tryptophan levels was seen in a laboratory test of aggression. However, a study on vervet monkeys indicated that altered tryptophan levels can influence aggression when the animals are at a high level of arousal. High arousal is known to increase the firing rate of 5-HT neurons. In a preliminary study, tryptophan had a therapeutic effect in aggressive schizophrenic patients. The best effect was seen in impulsive patients, which may have been related to high arousal in these subjects. Although carbohydrate is capable of raising brain tryptophan, not all carbohydrate-induced behaviors are mediated by tryptophan. Thus, sucrose was capable of attenuating alcohol intoxication in normal human males without altering blood alcohol concentrations. However, tryptophan had no effect on ethanol intoxication. The challenge for the future is to define the conditions under which alterations in tryptophan levels can influence brain function.


Inhibition of nitric oxide-induced apoptosis by nicotine in oral epithelial cells.
Development of oral cancer is clearly linked to the usage of smokeless tobacco. The molecular mechanisms involved in this process are however not well understood. Toward this goal, we investigated the effect of smokeless tobacco exposure on apoptosis of oral epithelial cells. Exposure of oral epithelial cells to smokeless tobacco extract (STE) induces apoptosis in a dose-dependent manner, until a threshold level of nicotine is achieved upon which apoptosis is inhibited. 1 mM of nicotine is able to inhibit apoptosis significantly induced by STE in these oral cells. Exposure of cells to nicotine alone has no effect on apoptosis, but nicotine inhibits apoptosis induced by other agents present in STE. In this study we show that, the anti-apoptotic action of nicotine is specifically associated with down-regulation of nitric oxide (NO) production. Using specific inducers of NO, we have demonstrated that inhibition of apoptosis by nicotine is through down-regulation of NO production. Further, we observed that nicotine clearly acts as a sink of NO radicals, shown using peroxynitrite generator (SIN-1) in conjunction or absence of radical scavengers. Nicotine thus causes most damage in transformed epithelial cells as depicted by accumulation of nitrotyrosine in a 3-NT ELISA assay. Inhibition of apoptosis is a hallmark in tumor progression and propels development of cancer. It may further result in functional loss of apoptotic effector mechanisms in the transformed cells. Thus, our data clearly indicates that inhibition of NO-induced apoptosis by nicotine may lead to tobacco-induced oral carcinogenesis, and implies careful development of modalities in tobacco cessation programs.


One Fifth of the Nation's Children: Why Are They Poor?
Despite 20 years of concern about poverty, the most recent census figures show that 20 percent of children in the United States live in families with incomes below the poverty line. In understanding why, it is important to recognize the reasons for poverty among children in both two-parent working poor families and single-parent families. Examination of the evidence suggests that family poverty basically reflects the economic and social changes that affect most United States families.


[Phosphodiesterase inhibitors: effectiveness and new applications].
Three different phosphodiesterase 5 (PDE5) inhibitors are currently available for the treatment of erectile dysfunction: sildenafil, vardenafil and tadalafil. The differences between these 3 are limited: tadalafil has a long duration of action, while vardenafil has a rapid onset of action after intake. Various studies have suggested that there is an improvement in the partners' sex lives when men use a PDE5 inhibitor for erectile dysfunction. The introduction of PDE5 inhibitors has renewed the interest in PDE inhibitors in general, for example in the treatment of pulmonary hypertension. In the near future PDE inhibitors may be used for various disorders as chronic obstructive pulmonary disease, benign prostatic hyperplasia, hypertension and coronary heart disease.


Tilt-tuned etalon locking for tunable laser stabilization.
Locking to a fringe of a tilt-tuned etalon provides a simple, inexpensive method for stabilizing tunable lasers. Here, we describe the use of such a system to stabilize an external-cavity quantum cascade laser; the locked laser has an Allan deviation of approximately 1 MHz over a one-second integration period, and has a single-scan tuning range of approximately 0.4 cm(-1). The system is robust, with minimal alignment requirements and automated lock acquisition, and can be easily adapted to different wavelength regions or more stringent stability requirements with minor alterations.


Controversies in diagnosis of pulmonary embolism.
The approach to the diagnosis of acute pulmonary embolism (PE) is under constant revision with advances in technology, noninvasive approaches, and increasing awareness of the risks of ionizing radiation. Optimal approaches in some categories of patients are controversial. Data are insufficient for evidence-based recommendations. Therefore, this survey of investigators in the field was undertaken. Even among experts there were marked differences of opinion regarding the approach to the diagnosis of acute PE. Although CT pulmonary angiography was usually the imaging test of choice, the respondents were keenly aware of the dangers of ionizing radiation. In view of advances in scintigraphic diagnosis since the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) trial, ventilation/perfusion (V/Q) lung scans or perfusion scans alone and single photon emission computed tomography (SPECT) V/Q lung scans are often recommended. The choice depends on the patient's age, gender, and complexity of the findings on the plain chest radiograph.


Urban women's preferences for learning of their mammogram result: a qualitative study.
Research suggests that communication of mammogram results is flawed for many low-income ethnic minority women. This study conducted four focus groups with low-income inner-city minority women (n = 34). The goals of our project were: (1) to elucidate women's experiences learning of their result; (2) to elicit their preferences as to how this communication could be improved; and (3) to gather information to help inform the development of a new tool for communicating mammogram results. Salient themes included dissatisfaction with result communication; difficulty elucidating the meaning of a typical results notification letter; a preference for direct verbal communication of results and for print materials that included pictures, testimonials, and an action plan including a hotline to call with questions; and a strong interest in advance education about the likelihood of having to return for additional follow up. Video and other programs to inform patients before the test about what happens after may improve patient satisfaction and enhance women's understanding of their personal result and follow up plan.


Human Intestinal Enteroids: New Models to Study Gastrointestinal Virus Infections.
Human rotavirus (HRV) and human norovirus (HuNoV) infections are recognized as the most common causes of epidemic and sporadic cases of gastroenteritis worldwide. The study of these two human gastrointestinal viruses is important for understanding basic virus-host interactions and mechanisms of pathogenesis and to establish models to evaluate vaccines and treatments. Despite the introduction of live-attenuated vaccines to prevent life-threatening HRV-induced disease, the burden of HRV illness remains significant in low-income and less-industrialized countries, and small animal models or ex vivo models to study HRV infections efficiently are lacking. Similarly, HuNoVs remained non-cultivatable until recently. With the advent of non-transformed human intestinal enteroid (HIE) cultures, we are now able to culture and study both clinically relevant HRV and HuNoV in a biologically relevant human system. Methods described here will allow investigators to use these new culture techniques to grow HRV and HuNoV and analyze new aspects of virus replication and pathogenesis.


Validity of Inertial Measurement Units to Measure Lower-Limb Kinematics and Pelvic Orientation at Submaximal and Maximal Effort Running Speeds.
Inertial measurement units (IMUs) have been validated for measuring sagittal plane lower-limb kinematics during moderate-speed running, but their accuracy at maximal speeds remains less understood. This study aimed to assess IMU measurement accuracy during high-speed running and maximal effort sprinting on a curved non-motorized treadmill using discrete (Bland-Altman analysis) and continuous (root mean square error [RMSE], normalised RMSE, Pearson correlation, and statistical parametric mapping analysis [SPM]) metrics. The hip, knee, and ankle flexions and the pelvic orientation (tilt, obliquity, and rotation) were captured concurrently from both IMU and optical motion capture systems, as 20 participants ran steadily at 70%, 80%, 90%, and 100% of their maximal effort sprinting speed (5.36 ± 0.55, 6.02 ± 0.60, 6.66 ± 0.71, and 7.09 ± 0.73 m/s, respectively). Bland-Altman analysis indicated a systematic bias within ±1° for the peak pelvic tilt, rotation, and lower-limb kinematics and -3.3° to -4.1° for the pelvic obliquity. The SPM analysis demonstrated a good agreement in the hip and knee flexion angles for most phases of the stride cycle, albeit with significant differences noted around the ipsilateral toe-off. The RMSE ranged from 4.3° (pelvic obliquity at 70% speed) to 7.8° (hip flexion at 100% speed). Correlation coefficients ranged from 0.44 (pelvic tilt at 90%) to 0.99 (hip and knee flexions at all speeds). Running speed minimally but significantly affected the RMSE for the hip and ankle flexions. The present IMU system is effective for measuring lower-limb kinematics during sprinting, but the pelvic orientation estimation was less accurate.


Reproductive synchrony in a recovering bottlenecked sea turtle population.
1. The assessment of species extinction risk has been well established for some time now. Assessing the potential for recovery in endangered species is however much more challenging, because complementary approaches are required to detect reliable signals of positive trends. 2. This study combines genetics, demography and behavioural data at three different time-scales to assess historical and recent population changes and evidence of reproductive synchrony in a small population of olive ridley sea turtle Lepidochelys olivacea. Lepidochelys is considered as the most extraordinary example of reproductive synchrony in reptiles, yet to date, it has only been reported in large populations. 3. Using Bayesian coalescent-based models on microsatellite nuclear DNA variability, we demonstrate that effective population size in olive ridleys nesting in French Guiana has dramatically declined by 99% over the last 20 centuries. This low current population size is further illustrated by the absence of genetic mitochondrial DNA diversity in the present nesting population. Yet, monitoring of nesting sites in French Guiana suggests a possible recovery of the population over the last decade. 4. Satellite telemetry shows that over the first 14 days of their 28-days inter-nesting interval, i.e. when eggs maturation is likely to occur, gravid females disperse over the continental shelf. They then gather together with a striking spatiotemporal consistency close to the nesting site, where they later emerge for their second nesting event. 5. Our results therefore suggest that reproductive synchrony also occurs in small populations. Olive ridleys may ensure this synchrony by adjusting the duration of the second half of their inter-nesting interval prior to landing, possibly through social mediation. 6. Such reproductive synchrony may be related to the maintenance of some species-specific strategy despite former collapse and may contribute to the present population recovery. The gregarious behaviour of reproductive individuals close to shore where human-induced perturbations occur is however a cause for conservation concern for this still poorly known species.


mRNA display selection of a high-affinity, Bcl-X(L)-specific binding peptide.
Bcl-X(L), an antiapoptotic member of the Bcl-2 family, is a mitochondrial protein that inhibits activation of Bax and Bak, which commit the cell to apoptosis, and it therefore represents a potential target for drug discovery. Peptides have potential as therapeutic molecules because they can be designed to engage a larger portion of the target protein with higher specificity. In the present study, we selected 16-mer peptides that interact with Bcl-X(L) from random and degenerate peptide libraries using mRNA display. The selected peptides have sequence similarity with the Bcl-2 family BH3 domains, and one of them has higher affinity (IC(50)=0.9 microM) than Bak BH3 (IC(50)=11.8 microM) for Bcl-X(L) in vitro. We also found that GFP fusions of the selected peptides specifically interact with Bcl-X(L), localize in mitochondria, and induce cell death. Further, a chimeric molecule, in which the BH3 domain of Bak protein was replaced with a selected peptide, retained the ability to bind specifically to Bcl-X(L). These results demonstrate that this selected peptide specifically antagonizes the function of Bcl-X(L) and overcomes the effects of Bcl-X(L) in intact cells. We suggest that mRNA display is a powerful technique to identify peptide inhibitors with high affinity and specificity for disease-related proteins.


The dimensions of maltreatment: introduction.
This special issue includes an introduction and seven papers exploring dimensions of maltreatment including type, severity, chronicity, and substantiation status of referrals to CPS, utilizing a subsample of the LONGSCAN studies. Each paper examines one of the dimensions of maltreatment from various perspectives to determine if different conceptualizations of a dimension, examined in isolation, account for different amounts of variation in child outcomes. A final paper assesses the relationship of the combined maltreatment dimensions, including interactions, on a single sample of maltreated children from the LONGSCAN study. This final paper explores the individual contribution of the "best" conceptualizations of the maltreatment dimensions in relation to each other, and to the 10 child outcomes of interest. Implications of the findings from these papers for future research on dimensions of child maltreatment are discussed in two independent commentaries.


Differences in psychopathology and behavioral characteristics of patients affected by conversion motor disorder and organic dystonia.
Typically, the diagnosis of conversion motor disorder (CMD) is achieved by the exclusion of a wide range of organic illnesses rather than by applying positive criteria. New diagnostic criteria are highly needed in this scenario. The main aim of this study was to explore the use of behavioral features as an inclusion criterion for CMD, taking into account the relationship of the patients with physicians, and comparing the results with those from patients affected by organic dystonia (OD). Patients from the outpatient Movement Disorder Service were assigned to either the CMD or the OD group based on Fahn and Williams criteria. Differences in sociodemographics, disease history, psychopathology, and degree of satisfaction about care received were assessed. Patient-neurologist agreement about the etiological nature of the disorder was also assessed using the k-statistic. A logistic regression analysis estimated the discordance status as a predictor to case/control status. In this study, 31 CMD and 31 OD patients were included. CMD patients showed a longer illness life span, involvement of more body regions, higher comorbidity with anxiety, depression, and borderline personality disorder, as well as higher negative opinions about physicians' delivering of proper care. Contrary to our expectations, CMD disagreement with neurologists about the etiological nature of the disorder was not statistically significant. Additional analysis showed that having at least one personality disorder was statistically associated with the discordance status. This study suggests that CMD patients show higher conflicting behavior toward physicians. Contrary to our expectations, they show awareness of their psychological needs, suggesting a possible lack of recognition of psychological distress in the neurological setting.


[resonant events in membranes having ion channels with two conformational states].
A study was carried out of a mathematical model of ion transport through biological membranes along the channels capable of conformational transitions between two states (R, T) with different conductivities. The model describes changes in time of te membrane potential and surface concentration of channels in one of the states (R). It has been shown that there may exist extinguishing oscillations with the frequency close to f0 on such a system may induce the resonance changes of the membrane potential. The resonance frequency f0 increases with an increase of the amplitude of external influence, this induces hesteresis of the membrane resonance parameters.


Electronic Consultation Between Primary Care Providers and Radiologists.
OBJECTIVE. The purpose of this study was to assess the use of an electronic consultation platform to connect primary care providers and radiologists and provide opportunities for valuable consultation regarding diagnostic imaging in patients, as well as to identify opportunities for targeted education surrounding high-yield radiology topics. MATERIALS AND METHODS. A retrospective review was performed of consultations conducted using the electronic platform from September 2012 to January 2017. Consultations were classified by subspecialty (neuroradiology, thoracic, abdominal, musculoskeletal, or pediatric radiology), question type (workup, surveillance, education, specialist referral query, discharge, or other), anatomy, and pathology. Feedback surveys were completed by primary care providers after each consultation to evaluate timeliness, value, and impact on patient care. RESULTS. A total of 302 consultations were reviewed. Subspecialty breakdown was as follows: abdominal, 94/302 (31%); neuroradiology, 74/302 (25%); musculoskeletal, 61/302 (20%); thoracic, 56/302 (19%); and pediatric, 17/302 (6%). The majority of consultations pertained to patient workup (112/302 [37%]), surveillance of imaging findings (95/302 [31%]), and provider education (48/302 [16%]). Cystic lesions (38/302 [13%]), pain (24/302 [8%]), and bone lesions (21/302 [7%]) were the most queried conditions. Patient management was altered in 167 cases (55%), and unnecessary testing was avoided in 84 (28%). Providers rated the perceived value of the electronic consultation system as excellent in 227 cases (75%). CONCLUSION. The electronic consultation system allowed primary care providers to easily consult with radiologists, was perceived as high value by primary care providers, resulted in altered patient management, and avoided unnecessary imaging tests. We identified follow-up imaging of cystic lesions and imaging workup of pain in patients as opportunities for continuing medical education for primary care providers.


Markers of Microbial Translocation and Immune Activation Predict Cognitive Processing Speed in Heavy-Drinking Men Living with HIV.
HIV infection and alcohol use disorder are associated with deficits in neurocognitive function. Emerging evidence points to pro-inflammatory perturbations of the gut-brain axis as potentially contributing to neurocognitive impairment in the context of HIV and chronic heavy alcohol use. This study examined whether plasma markers of microbial translocation (LPS) from the gastrointestinal tract and related immune activation (sCD14, EndoCAb) were associated with neurocognition in 21 men living with HIV who were virally suppressed on antiretroviral therapy. All participants met federal criteria for heavy drinking and were enrolled in a randomized controlled trial (RCT) of a brief alcohol intervention. This secondary analysis utilized blood samples and cognitive scores (learning, memory, executive function, verbal fluency, and processing speed) obtained at baseline and three-month follow-up of the RCT. In generalized estimating equation models, LPS, sCD14, and EndoCAb individually were significant predictors of processing speed. In a model with all biomarkers, higher LPS and sCD14 both remained significant predictors of lower processing speed. These preliminary findings suggest that inflammation stemming from HIV and/or alcohol could have negative effects on the gut-brain axis, manifested as diminished processing speed. Associations of microbial translocation and immune activation with processing speed in heavy-drinking PLWH warrant further investigation in larger-scale studies.


Serotype Distribution and Antimicrobial Resistance of Shigella Species in Bangui, Central African Republic, from 2002 to 2013.
Shigella is a major cause of severe diarrhea in children less than the age of 5 years in sub-Saharan Africa. The aim of this study was to describe the (sub-)serotype distribution and antimicrobial susceptibility of Shigella serogroups from Centrafrican patients with diarrhea between 2002 and 2013. We collected 443 Shigella isolates in total. The most common serogroups were Shigella flexneri (N = 243, 54.9%), followed by Shigella sonnei (N = 90, 20.3%) and Shigella dysenteriae (N = 72, 16.3%). The high diversity of (sub-)serotypes of S. flexneri and S. dysenteriae may impede the development of an efficient vaccine. Rates of resistance were high for ampicillin, chloramphenicol, tetracycline, and cotrimoxazole but low for many other antimicrobials, confirming recommendations for the use of third-generation cephalosporins (only one organism resistant) and fluoroquinolones (no resistance). However, the detection of one extended-spectrum beta-lactamase-producing Shigella organism highlights the need for continued monitoring of antimicrobial drug susceptibility.


Multidisciplinary clinical guidelines in proactive monitoring, early diagnosis, and effective management of trastuzumab deruxtecan (T-DXd)-induced interstitial lung disease (ILD) in breast cancer patients.
Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate (ADC), has altered the treatment landscape in breast cancer (BC), irrespective of the HR-receptor status. The use of the agent is increasing, despite the finding that exposure to T-DXd increases the risk of interstitial lung disease (ILD), particularly in BC patients. Although T-DXd-related ILD can be potentially severe and life-threatening, most low-grade cases can be treated safely using a multidisciplinary approach comprising early and accurate diagnosis, effective management, close monitoring, and the prompt administration of steroids. Additionally, increasing patients' education on ILD symptoms ensures close attention and enables prompt reporting, enhancing patient outcomes. It is recommended that predictive biomarkers are assessed in patients with risk factors for developing ILD. Currently, diagnostic criteria comprise newly identified pulmonary opacities, the relation of symptom onset to medication initiation, and the exclusion of other causes of ILD. The general condition of patients is weakened during the management of ILD (BC progression and corticosteroid treatment). Consequently, BC chemotherapy might be attenuated. This highlights the importance of preventing (high-grade) ILD, especially since its use is expanded. Identifying high-risk patients, diagnosing, and customizing treatment is, however, challenging and additional information on patient selection is often not fully clarified. In this paper, we provide updated multidisciplinary clinical guidance for patient selection, proactive monitoring, early diagnosis, and effectively management of T-DXd-induced ILD in HER2-positive BC patients. We describe the risk factors for developing ILD, patients' characteristics of ILD, and the histopathological and radiographic characteristics of ILD, including real-world clinical practice reports. These recommendations provide a structured step-by-step approach for managing each suspected BC-related ILD grade.


Serotonin receptor type 1B constitutes a therapeutic target for MDS and CMML.
Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are chronic myeloid clonal neoplasms. To date, the only potentially curative therapy for these disorders remains allogeneic hematopoietic progenitor cell transplantation (HCT), although patient eligibility is limited due to high morbimortality associated with this procedure coupled with advanced age of most patients. Dopamine receptors (DRs) and serotonin receptors type 1 (HTR1s) were identified as cancer stem cell therapeutic targets in acute myeloid leukemia. Given their close pathophysiologic relationship, expression of HTR1s and DRs was interrogated in MDS and CMML. Both receptors were differentially expressed in patient samples compared to healthy donors. Treatment with HTR1B antagonists reduced cell viability. HTR1 antagonists showed a synergistic cytotoxic effect with currently approved hypomethylating agents in AML cells. Our results suggest that HTR1B constitutes a novel therapeutic target for MDS and CMML. Due to its druggability, the clinical development of new regimens based on this target is promising.


Sodium and water retention in experimental glomerulonephritis. The urinary natriuretic material.
A material with a molecular weight comprised between 10,000 and 50,000 has been extracted from the urine of normal and glomerulonephritic (GN) rats submitted to high or normal salt diet. When injected into the renal arteries of normal rats, the material isolated from the urine of normal salt-loaded rats induced a significant natriuresis; on the contrary, the material isolated from GN rats or from normal non-salt-loaded rats induced only a slight natriuresis which did not exceed control values. Injection of natriuretic material in GN rats did not induce any significant natriuresis. The results demonstrate the presence of a natriuretic material in the urine of salt-loaded normal rats; this material is absent in the urine of GN animals; moreover, they demonstrate that the sodium retention by the GN kidney is due to the inability of this organ to respond to the determinants of saline natriuresis such as natriuretic factor(s) as well as non specific changes in blood composition, i.e. blood dilution. Several possibilities could be deduced from these results: a natriuretic material of extrarenal origin could be inactive on the GN kidney which could destroy it; natriuretic material of renal origin could disappear during experimental glomerulonephritis and be absent in the urine of these animals.


Tumor necrosis factor receptor-associated factor 6 (TRAF6) stimulates extracellular signal-regulated kinase (ERK) activity in CD40 signaling along a ras-independent pathway.
CD40 activates nuclear factor kappa B (NF kappa B) and the mitogen-activated protein kinase (MAPK) subfamily, including extracellular signal-regulated kinase (ERK). The CD40 cytoplasmic tail interacts with tumor necrosis factor receptor-associated factor (TRAF)2, TRAF3, TRAF5, and TRAF6. These TRAF proteins, with the exception of TRAF3, are required for NF kappa B activation. Here we report that transient expression of TRAF6 stimulated both ERK and NF kappa B activity in the 293 cell line. Coexpression of the dominant-negative H-Ras did not affect TRAF6-mediated ERK activity, suggesting that TRAF6 may activate ERK along a Ras-independent pathway. The deletion mutant of TRAF6 lacking the NH2-terminal domain acted as a dominant-negative mutant to suppress ERK activation by full-length CD40 and suppress prominently ERK activation by a deletion mutant of CD40 only containing the binding site for TRAF6 in the cytoplasmic tail (CD40 delta 246). Transient expression of the dominant-negative H-Ras significantly suppressed ERK activation by full-length CD40, but marginally suppressed ERK activation by CD40 delta 246, compatible with the possibility that TRAF6 is a major transducer of ERK activation by CD40 delta 246, whose activity is mediated by a Ras-independent pathway. These results suggest that CD40 activates ERK by both a Ras-dependent pathway and a Ras-independent pathway in which TRAF6 could be involved.


[Structure-functional studies of polymyxins. (1)-NMR analysis of polymyxin B and M conformation].
Spatial structures of two polymyxin antibiotics are compared by means of one- and two-dimensional 1H NMR spectroscopy. Cyclic parts of polymyxins B and M contain a system of hydrogen bonds including two beta-turns, however, the analysis of coupling constants 3JHN-C alpha H demonstrated that torsional angles phi of peptide bonds of the residues forming beta-turns in polymyxin M depend on the type of the anion. An increase in lability of the polymyxin M cyclic part in comparison with polymyxin B correlated with the selective cleavage of the peptide bond Dab8-Dab9 of this antibiotic with subtilisin. A similar correlation was found for a short analogue of polymyxin B, a cycloheptapeptide.


Active tuberculosis in HIV-infected injecting drug users from a low-rate tuberculosis area.
This article describes the features of active tuberculosis in HIV-infected injecting drug users (IDUs) from a low-rate tuberculosis area. The cohort was followed in a hospital-based HIV/AIDS registry, and data were extracted from the registry, patient charts, and the Tuberculosis Control Program of the Connecticut Health Department. The setting was an acute care inner-city hospital-based health care system, with a high incidence of AIDS, serving a small-to-medium urban area in Connecticut. The patients were 905 HIV-infected IDUs whose time of HIV diagnosis (TOHD) was between 1984 and 1992. The outcome measures were demographics, clinical characteristics, and morbidity rates of active tuberculosis. Of the 27 IDUs who developed active tuberculosis, none were white, all but one were male, and only one was known to have had a positive purified protein derivative (PPD) reaction prior to TOHD: 59% of cases developed in patients known to be HIV infected, 11% occurred in established AIDS patients, and 67% qualified as extrapulmonary tuberculosis (that is, AIDS defining by pre-1993 definitions). In 22% of cases, both Mycobacterium tuberculosis and M. avium-intracellulare were isolated. Mycobacterium tuberculosis was most commonly isolated from a respiratory specimen (67%). The annual incidence rate has been < or = 1.0% since 1988. The cumulative incidence rate was highest for patients with a positive PPD reaction or a history of tuberculosis (1.4 cases/100 patient years; 52 patients; mean follow-up 4.0 years). The demographics and clinical characteristics of active tuberculosis in our HIV-infected IDUs are similar to those described elsewhere in the United States; the morbidity rates are low and stable. The implications of our findings on tuberculosis control in HIV-infected IDUs may be applicable to health care systems with low tuberculosis rates.


6-Halo-2-pyridone as an efficient organocatalyst for ester aminolysis.
It was found that 6-halo-2-pyridones catalysed ester aminolysis in which not only reactive aryl esters but also relatively less reactive methyl and benzyl esters could be used as a substrate. The reaction could be performed without strictly dry and anaerobic conditions and the 6-chloro-2-pyridone catalyst could be recovered quantitatively after reaction. The method could be applied to dipeptide synthesis from methyl or benzyl esters of amino acids, where a high enantiomeric purity of the products was maintained. The mechanism involving dual activation of ester and amine substrates through hydrogen bonding between catalyst and substrates is proposed where 6-halo-2-pyridones act as a bifunctional Brønsted acid/base catalyst.


Management of Chronic Hepatitis B: Knowledge and Practices of Physicians in Pakistan.
In Pakistan, approximately 4.5 million people are afflicted with chronic hepatitis B (CHB). The compliance with hepatitis B virus (HBV) management guidelines is still unknown. This was the first study from Pakistan in which the knowledge and practices of treating physicians were compared with three standardized guidelines (Asia Pacific Association for the Study of the Liver (APASL) 2012/European Association for the Study of the Liver (EASL) 2012/American Association for the Study of Liver Diseases (AASLD) 2009). A cross-sectional study was conducted during 2014-2015 at four tertiary care teaching hospitals of Karachi, Pakistan. The study participants were internists, gastroenterologist, senior residents who were involved in the management of CHB patients. All participants were offered to fill the study questionnaire. A total of 179 physicians (103 residents, 76 consultants) participated. Mean age of participant was 35 ± 9.3 years. Approximately one-third of them followed AASLD (27.3%) and EASL (24.0%) guidelines. Entecavir, tenofovir or Peg IFN ∞ 2a were considered as first line therapy by 43%, 38.5% and 30.2% respectively. However, 17.9% preferred entecavir with tenofovir for rescue therapy, 25.7% and 23.5% preferred tenofovir or entecavir as both first line and rescue therapy respectively. Serum HBV DNA, alanine transaminase levels were used to monitor during oral antivirals therapy by 45.3%. hepatocellular carcinoma screening was considered for all HBV cases by 51.4% using ultrasound (55.3%) and alfa fetoprotein (52.5%) every 6 months.Overall 40.2% participants had poor knowledge about indication of liver biopsy, treatment initiation and antiviral prophylaxis. Significant association was found between grades of knowledge and gender, age group, designation and specialty (P < 0.05). Younger physicians, consultants (age 25-40 years) and those who were practicing gastroenterology/hepatology were more likely to have higher knowledge scores in compliance with the guidelines as compared to others. Our study highlighted the gaps in knowledge and practices in managing CHB patients according to guidelines. Efforts to improve knowledge, refresher courses and appropriate coordination between gastroenterologists and internal medicine physicians could enable management and follow-up of patients with CHB effectively.


Influences of temporal order in temporal reproduction.
Despite the crucial role of complex temporal sequences, such as speech and music, in our everyday lives, our ability to acquire and reproduce these patterns is prone to various contextual biases. In this study, we examined how the temporal order of auditory sequences affects temporal reproduction. Participants were asked to reproduce accelerating, decelerating or random sequences, each consisting of four intervals, by tapping their fingers. Our results showed that the reproduction and the reproduction variability were influenced by the sequential structure and interval orders. The mean reproduced interval was assimilated by the first interval of the sequence, with the lowest mean for decelerating and the highest for accelerating sequences. Additionally, the central tendency bias was affected by the volatility and the last interval of the sequence, resulting in a stronger central tendency in the random and decelerating sequences than the accelerating sequence. Using Bayesian integration between the ensemble mean of the sequence and individual durations and considering the perceptual uncertainty associated with the sequential structure and position, we were able to accurately predict the behavioral results. The findings highlight the critical role of the temporal order of a sequence in temporal pattern reproduction, with the first interval exerting greater influence on mean reproduction and the volatility and the last interval contributing to the perceptual uncertainty of individual intervals and the central tendency bias.


Influence of severity and level of injury on the occurrence of complications during the subacute and chronic stage of traumatic spinal cord injury: a systematic review.
Secondary health conditions (SHCs) are long-term complications that frequently occur due to traumatic spinal cord injury (tSCI) and can negatively affect quality of life in this patient population. This study provides an overview of the associations between the severity and level of injury and the occurrence of SHCs in tSCI. A systematic search was conducted in PubMed and Embase that retrieved 44 studies on the influence of severity and/or level of injury on the occurrence of SHCs in the subacute and chronic phase of tSCI (from 3 months after trauma). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. In the majority of studies, patients with motor-complete tSCI (American Spinal Injury Association [ASIA] Impairment Scale [AIS] grade A or B) had a significantly increased occurrence of SHCs in comparison to patients with motor-incomplete tSCI (AIS grade C or D), such as respiratory and urogenital complications, musculoskeletal disorders, pressure ulcers, and autonomic dysreflexia. In contrast, an increased prevalence of pain was seen in patients with motor-incomplete injuries. In addition, higher rates of pulmonary infections, spasticity, and autonomic dysreflexia were observed in patients with tetraplegia. Patients with paraplegia more commonly suffered from hypertension, venous thromboembolism, and pain. This review suggests that patients with a motor-complete tSCI have an increased risk of developing SHCs during the subacute and chronic stage of tSCI in comparison with patients with motor-incomplete tSCI. Future studies should examine whether systematic monitoring during rehabilitation and the subacute and chronic phase in patients with motor-complete tSCI could lead to early detection and potential prevention of SHCs in this population.


Genetic and Environmental Influences on Smoking Behavior across Adolescence and Young Adulthood in the Virginia Twin Study of Adolescent Behavioral Development and the Transitions to Substance Abuse Follow-Up.
Little is known regarding the underlying relationship between smoking initiation and current quantity smoked during adolescence into young adulthood. It is possible that the influences of genetic and environmental factors on this relationship vary across sex and age. To investigate this further, the current study applied a common causal contingency model to data from a Virginia-based twin study to determine: (1) if the same genetic and environmental factors are contributing to smoking initiation and current quantity smoked; (2) whether the magnitude of genetic and environmental factor contributions are the same across adolescence and young adulthood; and (3) if qualitative and quantitative differences in the sources of variance between males and females exist. Study results found no qualitative or quantitative sex differences in the relationship between smoking initiation and current quantity smoked, though relative contributions of genetic and environmental factors changed across adolescence and young adulthood. More specifically, smoking initiation and current quantity smoked remain separate constructs until young adulthood, when liabilities are correlated. Smoking initiation is explained by genetic, shared, and unique environmental factors in early adolescence and by genetic and unique environmental factors in young adulthood; while current quantity smoked is explained by shared environmental and unique environmental factors until young adulthood, when genetic and unique environmental factors play a larger role.


Autoantibody Landscape in Patients with Advanced Prostate Cancer.
Autoantibody responses in cancer are of great interest, as they may be concordant with T-cell responses to cancer antigens or predictive of response to cancer immunotherapies. Thus, we sought to characterize the antibody landscape of metastatic castration-resistant prostate cancer (mCRPC). Serum antibody epitope repertoire analysis (SERA) was performed on patient serum to identify tumor-specific neoepitopes. Somatic mutation-specific neoepitopes were investigated by associating serum epitope enrichment scores with whole-genome sequencing results from paired solid tumor metastasis biopsies and germline blood samples. A protein-based immunome-wide association study (PIWAS) was performed to identify significantly enriched epitopes, and candidate serum antibodies enriched in select patients were validated by ELISA profiling. A distinct cohort of patients with melanoma was evaluated to validate the top cancer-specific epitopes. SERA was performed on 1,229 serum samples obtained from 72 men with mCRPC and 1,157 healthy control patients. Twenty-nine of 6,636 somatic mutations (0.44%) were associated with an antibody response specific to the mutated peptide. PIWAS analyses identified motifs in 11 proteins, including NY-ESO-1 and HERVK-113, as immunogenic in mCRPC, and ELISA confirmed serum antibody enrichment in candidate patients. Confirmatory PIWAS, Identifying Motifs Using Next-generation sequencing Experiments (IMUNE), and ELISA analyses performed on serum samples from 106 patients with melanoma similarly revealed enriched cancer-specific antibody responses to NY-ESO-1. We present the first large-scale profiling of autoantibodies in advanced prostate cancer, utilizing a new antibody profiling approach to reveal novel cancer-specific antigens and epitopes. Our study recovers antigens of known importance and identifies novel tumor-specific epitopes of translational interest.


A review of threats to groundwater quality in the anthropocene.
Awareness concerning sustainable groundwater consumption under the context of land use and climate change is gaining traction, raising the bar for adequate understanding of the complexities of natural and anthropogenic processes and how they affect groundwater quality. The heterogeneous characteristics of aquifers have hampered comprehensive source, transport and contaminant identification. As questions remain about the behavior and prediction of well-known groundwater contaminants, new concerns around emerging contaminants are on the increase. This review highlights some of the key contaminants that originate from anthropogenic activities, organized based on land use categories namely agricultural, urban and industrial. It further highlights the extensive overlap, in terms of both provenance as well as contaminant type, between the different land use sectors. A selection of case studies from literature that describe the continued concern of established contaminants, as well as new and emerging compounds, are presented to illustrate the many qualitative threats to global groundwater resources. In some cases, the risk of groundwater contamination lacks adequate gravity, while in others the underlying physical and societal processes are not fully understood and activities may commence without adequately considering potential impacts. In the agricultural context, the historic and current application of fertilizers and plant protectants, use of veterinary pharmaceuticals and hormones, strives to safeguard the growing food demands. In the context of a sprawling urban environment, waste, human pharmaceuticals, and urban pesticide outputs are increasing, with adequate runoff and sanitation infrastructure often lagging. Finally, industrial activities are associated with accidental leaks and spills, while the large-scale storage of industrial byproducts has led to legacy contaminants such as those stemming from raw mineral extraction. With this review paper, we aim to underscore the need for transdisciplinary research, along with transboundary communication, using sound science and adaptive policy and management practice in order to procure sustainable groundwater quality.


In vivo, multimodal imaging of B cell distribution and response to antibody immunotherapy in mice.
B cell depletion immunotherapy has been successfully employed to treat non-Hodgkin's lymphoma. In recent years, increasing attention has been directed towards also using B-cell depletion therapy as a treatment option in autoimmune disorders. However, it appears that the further development of these approaches will depend on a methodology to determine the relation of B-cell depletion to clinical response and how individual patients should be dosed. Thus far, patients have generally been followed by quantification of peripheral blood B cells, but it is not apparent that this measurement accurately reflects systemic B cell dynamics. Cellular imaging of the targeted population in vivo may provide significant insight towards effective therapy and a greater understanding of underlying disease mechanics. Superparamagnetic iron oxide (SPIO) nanoparticles in concert with near infrared (NIR) fluorescent dyes were used to label and track primary C57BL/6 B cells. Following antibody mediated B cell depletion (anti-CD79), NIR-only labeled cells were expeditiously cleared from the circulation and spleen. Interestingly, B cells labeled with both SPIO and NIR were not depleted in the spleen. Whole body fluorescent tracking of B cells enabled noninvasive, longitudinal imaging of both the distribution and subsequent depletion of B lymphocytes in the spleen. Quantification of depletion revealed a greater than 40% decrease in splenic fluorescent signal-to-background ratio in antibody treated versus control mice. These data suggest that in vivo imaging can be used to follow B cell dynamics, but that the labeling method will need to be carefully chosen. SPIO labeling for tracking purposes, generally thought to be benign, appears to interfere with B cell functions and requires further examination.


Thymus-marrow immunocompetence. V. Hydrocortisone-resistant cells and processes in the hemolytic antibody response of mice.
Corticosteroids suppress the humoral antibody response of mice to sheep erythrocytes. This response depends on interactions between thymus-derived helper cells and bone marrow-derived antibody-forming cell precursors (AFC precursors). Previous experiments had shown that spleen cells (a mixture of thymus-derived and marrow-derived cells) were sensitive to corticosteroids while AFC precursors in the bone marrow were resistant. The present experiments showed that the thymus of a mouse given 2.5 mg of hydrocortisone acetate, although containing only about 5% of the number of cells of a normal thymus, was as effective as a normal thymus in cooperating with bone marrow when transferred to irradiated syngeneic mice and stimulated with SRBC. The proliferative response of thymus helper cells to SRBC was also resistant to hydrocortisone. In this context, the majority of thymic cells are in the cortex, are rapidly dividing, are sensitive to corticosteroids and are not iminunocompetent. A small number of thymic cells, probably located in the medulla, are resistant to corticosteroids, but are immunocompetent since they can serve as helper cells. The hydrocortisone-sensitive phase of the splenic response to SRBC was found to be the bone marrow-derived AFC precursor since spleens from hydrocortisone-treated donors had immunocompetence restored by normal bone marrow but not by normal thymus cells.


Induction of autophagy and suppression of type I IFN secretion by CSFV.
Macroautophagy/autophagy plays an essential role in cellular responses to pathogens. However, the precise mechanisms and signaling pathways that modulate cellular autophagy in classical swine fever virus (CSFV)-infected host cells have not been confirmed. In this study, we showed that CSFV infection inhibits the phosphorylation of MTOR (mechanistic target of rapamycin kinase), subsequently leading to autophagy initiation. We also show that MAPK/ERK (mitogen-activated protein kinase) signaling is involved in CSFV-induced autophagy. The CSFV-induced inhibition of AKT/PKB (AKT serine/threonine kinase)-MTOR was observed to be partially responsible for the MTOR inactivation and subsequent autophagy initiation. Moreover, the CAMKK2/CaMKKβ (calcium/calmodulin dependent protein kinase kinase 2)-PRKAA/AMPK (protein kinase AMP-activated catalytic subunit alpha) axis was found to be involved in CSFV-induced autophagy. Meanwhile, CSFV non-structural protein NS5A induced autophagy via the CAMKK2-PRKAA-MTOR signaling pathway but not the AKT-MTOR or MAPK1/ERK2-MAPK3/ERK1-MTOR pathway. Although the AKT-MTOR pathway also plays an important role in the induction of autophagy by CSFV. We also found the interaction between HSP90AB1/HSPCB and NS5A by tandem affinity purification/liquid chromatography-mass spectrometry (LC-MS) and immunoprecipitation. Furthermore, the CSFV-induced [Ca2+]cyto increase potently induced autophagy through CAMKK2 and PRKAA. Moreover, we isolated and identified the BECN1/Beclin 1 protein complexes by tandem affinity purification/LC-MS and immunoprecipitation, the interaction between BECN1 and MAVS was confirmed by immunoprecipitation, laser scanning confocal microscope technology, and GST affinity-isolation experiments. Furthermore, CSFV-mediated autophagy suppressing type I IFN production is related to the interaction between MAVS and BECN1. Finally, the modulation of autophagy induction pathways by different autophagy regulatory factors significantly affected the replication of CSFV.Abbreviations: AKT: AKT serine/threonine kinase; AMPK: Adenosine monophosphate-activated protein kinase; CAMKK2: Calcium/calmodulin dependent protein kinase kinase 2; CSFV: Classical swine fever virus; HRP: Horseradish peroxidase; HSP90AB1: Heat shock protein 90 alpha family class B member 1; IFN: Interferon; ISGs: IFN-stimulated genes; LC-MS: Liquid chromatography-mass spectrometry; MAP1LC3/LC3: Microtubule associated protein 1 light chain 3; MAPK: Mitogen-activated protein kinase; MAVS: Mitochondrial antiviral signaling protein; MOI: Multiplicity of infection; MTOR: Mechanistic target of rapamycin kinase; PBS: Phosphate-buffered saline; PRKAA: Protein kinase AMP-activated catalytic subunit alpha; shRNA: short hairpin RNA.


A fluorescent sensor for spatiotemporally resolved imaging of endocannabinoid dynamics in vivo.
Endocannabinoids (eCBs) are retrograde neuromodulators with important functions in a wide range of physiological processes, but their in vivo dynamics remain largely uncharacterized. Here we developed a genetically encoded eCB sensor called GRABeCB2.0. GRABeCB2.0 consists of a circular-permutated EGFP and the human CB1 cannabinoid receptor, providing cell membrane trafficking, second-resolution kinetics with high specificity for eCBs, and shows a robust fluorescence response at physiological eCB concentrations. Using GRABeCB2.0, we monitored evoked and spontaneous changes in eCB dynamics in cultured neurons and acute brain slices. We observed spontaneous compartmentalized eCB transients in cultured neurons and eCB transients from single axonal boutons in acute brain slices, suggesting constrained, localized eCB signaling. When GRABeCB2.0 was expressed in the mouse brain, we observed foot shock-elicited and running-triggered eCB signaling in the basolateral amygdala and hippocampus, respectively. In a mouse model of epilepsy, we observed a spreading wave of eCB release that followed a Ca2+ wave through the hippocampus. GRABeCB2.0 is a robust probe for eCB release in vivo.


Obesity-associated nonalcoholic fatty liver disease.
Obesity is strongly associated with the prevalence of nonalcoholic fatty liver disease (NAFLD) in adult and pediatric populations. Nutrition, physical activity, and behavioral modifications are critical components of the treatment regimen for all obese patients with NAFLD. Bariatric surgeries that affect or restrict the flow of food through the gastrointestinal tract may improve liver histology in morbidly obese patients with nonalcoholic steatohepatitis (NASH), although randomized clinical trials and quasi-randomized clinical studies are lacking. Early detection of NASH and hepatic fibrosis using noninvasive biochemical and imaging markers that may replace liver biopsy is the current challenge.


Standard bone healing stages occur during delayed bone healing, albeit with a different temporal onset and spatial distribution of callus tissues.
Bone healing is considered as a recapitulation of a developmental program initiated at the time of injury. This study tested the hypothesis that in delayed bone healing the regular cascade of healing events, including remodeling of woven to lamellar bone, would be similar compared to standard healing, although the temporal onset would be delayed. A tibial osteotomy was performed in sheep and stabilized with a rotationally unstable fixator leading to delayed healing. The sheep were sacrificed at 2, 3, 6, 9 weeks and 6 months postoperatively. The temporal and spatial tissue distributions in the calluses and the bone microstructure were examined by histology. Although histological analysis demonstrated temporal and spatial callus tissue distribution differences, delayed healing exhibited the same characteristic stages as those seen during uneventful standard healing. The delayed healing process was characterized by a prolonged presence of hematoma, a different spatial distribution of new bone and delayed and prolonged endochondral bone formation. A change in the spatial distribution of callus formation was seen by week 6 leading to bone formation and resorption of the cortical bone fragments, dependent on the degree to which the cortical bone fragments were dislocated. At 6 months, only 5 out of 8 animals showed complete bony bridging with a continuous periosteum, although lamellar bone and newly formed woven bone were present in the other 3 animals. This study demonstrates that during delayed bone healing all stages of the healing cascade likely take place, even if bony consolidation does not occur. Furthermore, the healing outcome might be related to the periosteum's regenerative capacity leading to bony union or absence of bony bridging.


Comparison of frequency, risk factors, and time course of postoperative delirium in octogenarians after transcatheter aortic valve implantation versus surgical aortic valve replacement.
Postoperative delirium (PD) after transcatheter aortic valve implantation (TAVI) remains to be explored. We sought to (1) determine the incidence of PD in octogenarians who underwent TAVI or surgical aortic valve replacement (SAVR), (2) identify its risk factors, and (3) describe possible differences in the onset and course of PD between treatment groups. A prospective cohort study of consecutive patients aged ≥80 years with severe aortic stenosis who underwent elective TAVI or SAVR (N = 143) was conducted. The incidence of PD was assessed for 5 days using the Confusion Assessment Method (CAM). Risk factors for PD were studied with logistic regression. Patients treated with TAVI were older (p ≤0.001), had lower cognitive scores (p = 0.007), and more co-morbidities (p = 0.003). Despite this, significantly fewer (p = 0.013) patients treated with TAVI (44%) experienced PD compared to patients treated with SAVR (66%). Undergoing SAVR (p = 0.02) and having lower cognitive function (p = 0.03) emerged as risk factors for PD, whereas gender, activities of daily living, frailty, atrial fibrillation, and postoperative use of opioids and anxiolytics did not. Patients treated with TAVI and without PD during the first 2 postoperative days were unlikely to experience PD on subsequent days. The onset of PD after SAVR could occur at any time during the postoperative evaluation. In conclusion, SAVR in octogenarian patients with aortic stenosis might be considered as a predisposing factor for PD. Our data also suggest that the onset of PD was more unpredictable after SAVR.


Optimal Brassinosteroid Levels Are Required for Soybean Growth and Mineral Nutrient Homeostasis.
Brassinosteroids (BRs) are steroid phytohormones that are known to regulate plant growth and nutrient uptake and distribution. However, how BRs regulate nutrient uptake and balance in legume species is not fully understood. Here, we show that optimal BR levels are required for soybean (Glycine max L.) seedling growth, as treatments with both 24-epicastasterone (24-epiCS) and the BR biosynthesis inhibitor propiconazole (PPZ) inhibit root growth, including primary root elongation and lateral root formation and elongation. Specifically, 24-epiCS and PPZ reduced the total phosphorus and potassium levels in the shoot and affected several minor nutrients, such as magnesium, iron, manganese, and molybdenum. A genome-wide transcriptome analysis identified 3774 and 4273 differentially expressed genes in the root tip after brassinolide and PPZ treatments, respectively. The gene ontology (GO) analysis suggested that genes related to "DNA-replication", "microtubule-based movement", and "plant-type cell wall organization" were highly responsive to the brassinolide and PPZ treatments. Furthermore, consistent with the effects on the nutrient concentrations, corresponding mineral transporters were found to be regulated by BR levels, including the GmPHT1s, GmKTs, GmVIT2, GmZIPs, and GmMOT1 genes. Our study demonstrates that optimal BR levels are important for growth and mineral nutrient homeostasis in soybean seedlings.


Long-Range Vibrational Dynamics Are Directed by Watson-Crick Base Pairing in Duplex DNA.
Ultrafast two-dimensional infrared (2D-IR) spectroscopy of a 15-mer A-T DNA duplex in solution has revealed structure-dependent vibrational coupling and energy transfer processes linking bases with the sugar-phosphate backbone. Duplex melting induces significant changes in the positions of off-diagonal peaks linking carbonyl and ring-stretching vibrational modes of the adenine and thymine bases with vibrations of the phosphate group and phosphodiester linkage. These indicate that Watson-Crick hydrogen bonding and helix formation lead to a unique vibrational coupling arrangement of base vibrational modes with those of the phosphate unit. On the basis of observations from time-resolved 2D-IR data, we conclude that rapid energy transfer processes occur between base and backbone, mediated by additional modes located on the deoxyribose moiety within the same nucleotide. These relaxation dynamics are insensitive to duplex melting, showing that efficient intramolecular energy relaxation to the solvent via the phosphate groups is the key to excess energy dissipation in both single- and double-stranded DNA.


A primary care approach to pediatric gastroesophageal reflux.
Gastroesophageal reflux is a common problem that occurs in the pediatric population. Gastroesophageal reflux refers to the retrograde passage of gastric contents into the esophagus. Current thinking implicates transient lower esophageal sphincter relaxations as a major cause for reflux. Infants generally present with symptoms of regurgitation, whereas symptoms of esophagitis are more common in older children. When there are dangerous consequences secondary to gastroesophageal reflux, it is termed gastroesophageal reflux disease (GERD). GERD has been shown to manifest with respiratory symptoms and a pathologic process. A variety of diagnostic procedures are available for the assessment of GERD which include barium swallow, pH probe, scintigraphy, and endoscopy with esophageal biopsy. Medical management of GERD primarily involves prokinetic agents and acid suppression therapy. Surgical therapy, albeit less common, now still has its role in the treatment of GERD.


Strongyloides Stercoralis Infection in Hispanic Veterans Living in Puerto Rico: A Tropical Issue or a Global One?
Strongyloidiasis is a parasitic infection classified by the World Health Organization as a neglected tropical disease. Although predominantly asymptomatic, it can become a life-threatening disease in an immunocompromised host. Epidemiologic studies in the Western Hemisphere are scarce, but even more scarce are descriptions of the natural course of this disease. Our objectives were to identify the different manifestations and outcomes of Strongyloides stercoralis infection in the Hispanic veteran population in Puerto Rico. We also discuss the importance of pursuing a timely diagnosis in high-risk patients migrating from or traveling to endemic areas, regardless of their symptomatic status. This was a single-center, retrospective record review study involving patients diagnosed with S. stercoralis via serology, stool samples, or organ biopsies, from 2008 through 2014. A total of 270 patients tested positive; 210 (77.8%) were asymptomatic. The mean age at diagnosis was 75.4 years old. Symptomatic patients had pulmonary (n = 25), gastrointestinal (n = 21), and dermatologic (n = 5) symptoms; 9 had multiple symptoms. Five had hyperinfection, mostly after treatment with systemic steroids or preexisting immunosuppression. The most common laboratory abnormality was eosinophilia. Reasons for testing were eosinophilia, asthma, diarrhea, screening for parasites, and unexplained skin rash. Our study highlights the importance of being aware of this potentially fatal infection, especially when treating patients traveling from endemic countries. It also highlights the importance of timely screening, diagnosis, and treatment of S. stercoralis infection in order to prevent potentially fatal outcomes, especially when considering immunosuppressive drugs.


Replication origins and a sequence involved in coordinate induction of the immediate-early gene family are conserved in an intergenic region of herpes simplex virus.
We have determined the structure of the 5' portion of herpes simplex virus type 2 (HSF-2) immediate-early (IE) mRNA-3 and have obtained the DNA sequence specifying the N terminus of its encoded polypeptide, Vmw182, its untranslated leader and the intergenic region between IEmRNAs-3 & 4/5. Comparison of the HSV-2 intergenic sequences with the HSV-1 equivalent region identifies several conserved regions: (1) an AT-rich element with core consensus TAATGARAT which is likely to be the 'activator' sequence through which coordinate induction of the IE gene family is mediated. (2) GC-rich and GA-rich tracts, found in a wide variety of eukaryotic promoters, which vary in position and orientation between HSV-2 and HSV-1 and which represent modulators of transcription. (3) TATA homologies present 15-25 base pairs (bp) upstream of mRNA 5' termini. (4) a 137bp direct repeat in HSV-2 which contains sequence almost identical to the HSV-1 replication origin.


Heuristic algorithms for best match graph editing.
Best match graphs (BMGs) are a class of colored digraphs that naturally appear in mathematical phylogenetics as a representation of the pairwise most closely related genes among multiple species. An arc connects a gene x with a gene y from another species (vertex color) Y whenever it is one of the phylogenetically closest relatives of x. BMGs can be approximated with the help of similarity measures between gene sequences, albeit not without errors. Empirical estimates thus will usually violate the theoretical properties of BMGs. The corresponding graph editing problem can be used to guide error correction for best match data. Since the arc set modification problems for BMGs are NP-complete, efficient heuristics are needed if BMGs are to be used for the practical analysis of biological sequence data. Since BMGs have a characterization in terms of consistency of a certain set of rooted triples (binary trees on three vertices) defined on the set of genes, we consider heuristics that operate on triple sets. As an alternative, we show that there is a close connection to a set partitioning problem that leads to a class of top-down recursive algorithms that are similar to Aho's supertree algorithm and give rise to BMG editing algorithms that are consistent in the sense that they leave BMGs invariant. Extensive benchmarking shows that community detection algorithms for the partitioning steps perform best for BMG editing. Noisy BMG data can be corrected with sufficient accuracy and efficiency to make BMGs an attractive alternative to classical phylogenetic methods.


Design and development of novel mitochondrial targeted nanocarriers, DQAsomes for curcumin inhalation.
Curcumin has potent antioxidant and anti-inflammatory properties but poor absorption following oral administration owing to its low aqueous solubility. Development of novel formulations to improve its in vivo efficacy is therefore challenging. In this study, formulation of curcumin-loaded DQAsomes (vesicles formed from the amphiphile, dequalinium) for pulmonary delivery is presented for the first time. The vesicles demonstrated mean hydrodynamic diameters between 170 and 200 nm, with a ζ potential of approximately +50 mV, high drug loading (up to 61%) and encapsulation efficiency (90%), resulting in enhanced curcumin aqueous solubility. Curcumin encapsulation in DQAsomes in the amorphous state was confirmed by X-ray diffraction and differential scanning calorimetry analysis. The existence of hydrogen bonds and cation-π interaction between curcumin and vesicle building blocks, namely dequalinium molecules, were shown in lyophilized DQAsomes using FT-IR analysis. Encapsulation of curcumin in DQAsomes enhanced the antioxidant activity of curcumin compared to free curcumin. DQAsome dispersion was successfully nebulized with the majority of the delivered dose deposited in the second stage of the twin-stage impinger. The vesicles showed potential for mitochondrial targeting. Curcumin-loaded DQAsomes thus represent a promising inhalation formulation with improved stability characteristics and mitochondrial targeting ability, indicating a novel approach for efficient curcumin delivery for effective treatment of acute lung injury and the rationale for future in vivo studies.


[Influence of verapamil and diltiazem on the muscle-relaxing effect of atracurium in vivo].
The interaction between atracurium and the two calcium antagonists verapamil and diltiazem were studied in rabbits. It was observed that intravenous verapamil (0.2 mg/kg) reduced by 25% and 30% respectively, the dose of atracurium required to produce a 50% or 95% of neuromuscular blockade. In contrast, intravenous diltiazem (1 mg/kg) failed to produce significant changes.


[The clinical use of the preparation kordaron in different arrhythmias].
Cordaron (amiodaron, angoron, atlansil, cordinil, trangorax) is a drug produced by the French-Belgian firm "Labaz". Some pharmacological properties of cordaron and in particular its ability to increase the refractory period both of the atrioventricular junction and the abnormal pathway that hampers the circulation of excitation between the atria and ventricles influencing the mechanism of reverse excitation provide favourable conditions for elimination of arrhythmias. In a number of papers of the Soviet and foreign authors there are presented the results of cordaron treatment of patients with various cardiac rhythm disorders which indicate a fairly high antiarrhythmic effectiveness of the drug. Its lethal dose is practically absent. Side effects show up only during a prolonged therapy and disappear after the drug withdrawal.


Metabolic control of oocyte development: linking maternal nutrition and reproductive outcomes.
Obesity, diabetes, and related metabolic disorders are major health issues worldwide. As the epidemic of metabolic disorders continues, the associated medical co-morbidities, including the detrimental impact on reproduction, increase as well. Emerging evidence suggests that the effects of maternal nutrition on reproductive outcomes are likely to be mediated, at least in part, by oocyte metabolism. Well-balanced and timed energy metabolism is critical for optimal development of oocytes. To date, much of our understanding of oocyte metabolism comes from the effects of extrinsic nutrients on oocyte maturation. In contrast, intrinsic regulation of oocyte development by metabolic enzymes, intracellular mediators, and transport systems is less characterized. Specifically, decreased acid transport proteins levels, increased glucose/lipid content and elevated reactive oxygen species in oocytes have been implicated in meiotic defects, organelle dysfunction and epigenetic alteration. Therefore, metabolic disturbances in oocytes may contribute to the diminished reproductive potential experienced by women with metabolic disorders. In-depth research is needed to further explore the underlying mechanisms. This review also discusses several approaches for metabolic analysis. Metabolomic profiling of oocytes, the surrounding granulosa cells, and follicular fluid will uncover the metabolic networks regulating oocyte development, potentially leading to the identification of oocyte quality markers and prevention of reproductive disease and poor outcomes in offspring.


Bacteriorhodopsins with chromophores modified at the beta-ionone site. Formation and light-driven action of the proton pump.
The binding to bacterioopsin of the all-trans isomers of retinal analogues lacking the six-membered ring and differing in length of the conjugated chain, as well as the light-driven action of the proton pump of the resulting bacteriorhodopsin analogues, were studied. The 'opsin shifts' in these modified bacteriorhodopsins are all around 2700 cm-1 and do not depend on the number of double bonds in the chromophore. These experimental results suggest that the 4800 cm-1 'opsin shift' in unmodified bacteriorhodopsin consists of a contribution of about 2700 cm-1 due to the interaction of the protonated Schiff-base with the counterion. The extra 2100 cm-1 shift in bacteriorhodopsin is due to the specific interaction of the cyclohexene ring and the protein. Only the bacteriorhodopsin analogue with the same number of conjugated double bonds in the chromophore as bacteriorhodopsin itself shows light-driven proton pump action.


2-(2-Chloro-8-methyl-quinolin-3-yl)-4-phenyl-1,2-di-hydro-quinazoline.
In the title compound, C24H18ClN3, the di-hydro-quinazoline and methyl-substituted quinoline benzene rings make a dihedral angle of 78.18 (4)° and form dihedral angles of 45.91 (5) and 79.80 (4)°, respectively, with the phenyl ring. The dihedral angle between the phenyl ring of di-hydro-quinazoline and the methyl-substituted benzene ring of quinoline is 78.18 (4)°. The crystal packing can be described as crossed layers parallel to the (011) and (0-11) planes. The structure features N-H⋯N hydrogen bonds and π-π inter-actions [centroid-centroid distance between phenyl rings = 3.7301 (9) Å].


Environmental manipulation to promote stem cell survival in vivo: use of aggregation, oxygen carrier, and BMP-2 co-delivery strategies.
While mesenchymal stem cell (MSC)-based strategies for critically-sized bone defect repair hold promise, poor cell survival in vivo remains a significant barrier to the translation of these therapeutics. One method employed to extend the survival of MSCs is the formation of three-dimensional aggregates, a strategy which modulates the immunomodulatory secretome of the cells, thereby influencing the local inflammatory environment and potentially bone tissue repair. Enrichment of cell-seeded hydrogels with oxygen carriers to counter the hypoxic conditions encountered in vivo or co-delivery of cells with growth factors, are also strategies employed to modulate the cell micro-environment. In this study, we examined the effect of human MSC (hMSC) and rat MSC (rMSC) aggregation on cell survival and bone tissue regeneration within both immunocompromised (nude) and syngeneic (Lewis) rat models. Despite a heightened release of paracrine factors from stem cell aggregates in vitro, the delivery of hMSC or rMSC aggregates in their respective rat models had no beneficial impact on cell survival, construct vascularization, or critically-sized bone defect repair. Co-delivery of oxygen carrier perfluorotributylamine (PFTBA) within the alginate hydrogel delivery vehicle impeded in vivo bone regeneration in both MSC-seeded and acellular constructs. Although rMSC seeding was observed to enhance the osteoinductive potential of bone morphogenetic protein 2 (BMP-2)-containing constructs in vitro, co-delivery of rMSC and BMP-2 to the femoral defect space attenuated bone repair in vivo compared to BMP-2 delivery alone. Overall, despite in vitro evidence to the contrary, the present study observed no beneficial effects of these delivery strategies on cell-based bone tissue repair.


A long-term seal- and cod-liver-oil supplementation in hypercholesterolemic subjects.
In this long-term study, we wanted to explore the effect of dietary supplementation of seal oil (SO) as compared cod-liver oil (CLO) on subjects with moderate hypercholesterolemia. The test parameters included fatty acid composition in serum, blood lipids, platelet aggregation, and the activity of blood monocytes. After a run-in period of 6 mon, 120 clinically healthy hypercholesterolemic (7.0-9.5 mmol/L; 270-366 mg/dL) subjects were randomly selected to consume either 15 mL of SO or CLO daily for 14 mon followed by a 4-mon wash-out period. A third group was not given any dietary supplement (control). Consumption of marine oils (SO and CLO) changed the fatty acid composition of serum significantly. Maximal levels were achieved after 10 mon. No further changes were seen after 14 mon. A wash-out period of 4 mon hardly altered the level of n-3 fatty acids in serum. Addition of SO gave 30% higher level of eicosapentaenoic acid, as compared to CLO. Subjects taking SO or CLO had lower whole-blood platelet aggregation than the control group. Neither SO nor CLO had any effects on the levels of serum total cholesterol, high-density lipoprotein cholesterol, postprandial triacylglycerol, apolipoproteins Al and B100, lipoprotein (a), monocyte function expressed as monocyte-derived tissue factor expression, and tumor necrosis factor.


Rutin, A Natural Inhibitor of IGPD Protein, Partially Inhibits Biofilm Formation in Staphylococcus xylosus ATCC700404 in vitro and in vivo.
Staphylococcus xylosus (S. xylosus) has become an emerging opportunistic pathogen due to its strong biofilm formation ability. Simultaneously, the biofilm of bacteria plays an important role in antibiotic resistance and chronic infection. Here, we confirmed that rutin can effectively inhibit biofilm formation in S. xylosus, of which the inhibition mechanism involves its ability to interact with imidazole glycerol phosphate dehydratase (IGPD), a key enzyme in the process of biofilm formation. We designed experiments to target IGPD and inhibited its activities against S. xylosus. Our results indicated that the activity of IGPD and the amount of histidine decreased significantly under the condition of 0.8 mg/ml rutin. Moreover, the expression of IGPD mRNA (hisB) and IGPD protein was significantly down-regulated. Meanwhile, the results from molecular dynamic simulation and Bio-layer interferometry (BLI) technique showed that rutin could bind to IGPD strongly. Additionally, in vivo studies demonstrated that rutin treatment reduced inflammation and protect mice from acute mastitis caused by S. xylosus. In summary, our findings provide new insights into the treatment of biofilm mediated persistent infections and chronic bacterial infections. It could be helpful to design next generation antibiotics to against resistant bacteria.


[Thoracoscopic Right Upper Lobectomy in a Patient with a Right Aortic Arch:Report of a Case].
It has been reported that the recurrent nerve may not be recognized during mediastinal lymph node dissection in surgery for right upper lobe lung cancer associated with the right aortic arch. In the present case, a 66-year-old man underwent thoracoscopic right upper lobectomy for right upper lobe lung cancer associated with the right aortic arch. The gap between the superior vena cava and descending aortic arch was narrow, and the vagus nerve ran between the superior vena cava and the aorta. The recurrent laryngeal nerve was able to confirm. The vagus nerve ran the hilum of lung back side from arch of azygos vein on the peripheral side. The morphology of the right aortic arch varies from case to case, and if the vagus nerve and recurrent nerve are difficult to identify, the nerve may be hidden by the superior vena cava. If the nerve cannot be recognized, the space between the superior vena cava and the aorta should be dissected and confirmed. In addition, taping the vagus nerve and observing it from the caudal to the cephalic side may be useful for the recurrent nerve that turns to the mediastinum. In this case, magnification of the thoracoscope is extremely useful.


Dynamic model constraints on oxygen-17 depletion in atmospheric O2 after a snowball Earth.
A large perturbation in atmospheric CO2 and O2 or bioproductivity will result in a drastic pulse of (17)O change in atmospheric O2, as seen in the Marinoan Oxygen-17 Depletion (MOSD) event in the immediate aftermath of a global deglaciation 635 Mya. The exact nature of the perturbation, however, is debated. Here we constructed a coupled, four-box, and quick-response biosphere-atmosphere model to examine both the steady state and dynamics of the MOSD event. Our model shows that the ultra-high CO2 concentrations proposed by the "snowball' Earth hypothesis produce a typical MOSD duration of less than 10(6) y and a magnitude of (17)O depletion reaching approximately -35‰. Both numbers are in remarkable agreement with geological constraints from South China and Svalbard. Moderate CO2 and low O2 concentration (e.g., 3,200 parts per million by volume and 0.01 bar, respectively) could produce distinct sulfate (17)O depletion only if postglacial marine bioproductivity was impossibly low. Our dynamic model also suggests that a snowball in which the ocean is isolated from the atmosphere by a continuous ice cover may be distinguished from one in which cracks in the ice permit ocean-atmosphere exchange only if partial pressure of atmospheric O2 is larger than 0.02 bar during the snowball period and records of weathering-derived sulfate are available for the very first few tens of thousands of years after the onset of the meltdown. In any case, a snowball Earth is a precondition for the observed MOSD event.


Initial Experience with the ACS Multi-Link Stent: Serial Angiographic Follow-Up and Comparison with the Palmaz-Schatz Stent in Matched Lesions.
To evaluate the efficacy of the more flexible ACS Multi-Link stent, a prospective angiographic follow-up study was performed. Implantation of the ACS Multi-Link stent was attempted in 70 consecutive patients with 79 coronary lesions from April to November 1995. Clinical success defined as final % diameter stenosis of < 50% without death, bypass surgery or Q-wave myocardial infarction was achieved in 95% of the patients. There was 1 in-hospital death due to acute pulmonary embolism. In-hospital subacute stent occlusion occurred in 2 cases. Follow-up angiograms were obtained in 62 (83%) eligible lesions. The minimal luminal diameter improved from 0.97 +/- 0.41 to 2.72 +/- 0.30 mm, but started to decrease at 1 month (2.38 +/- 0.42 mm), and continued to decrease throughout the 6 months (1.96 +/- 0.41 mm). Angiographic restenosis (stenosis ³ 50%) occurred in 16% of the lesions, a rate smaller though not significantly different from the 25% with the Palmaz-Schatz stent. A revascularization procedure of the target lesion was required in 6% of the patients. Multivariate analysis identified lack of post-dilatation, type of lesion, lesion length and pre-procedural reference diameter to be predictors of angiographic restenosis. In conclusion, the ACS Multi-Link stent can be implanted successfully with a low complication rate and a clinical outcome at least comparable to the Palmaz-Schatz stent.


Biosynthesis of lipid A. Enzymatic incorporation of 3-deoxy-D-mannooctulosonate into a precursor of lipid A in Salmonella typhimurium.
The cell envelope fraction of Salmonella typhimurium contains an enzyme system which catalyzes transfer of 3-deoxyoctulosonate (KDO) from CMP-KDO to an incomplete, KDO-deficient precursor of lipid A. The enzyme system is firmly membrane-bound, but has been solubilized by treatment with nonionic detergent at alkaline pH and partially purified. Both the particulate and partially purified fractions catalyzed formation of a single reaction product containing 2 residues of KDO. Periodate oxidation of the purified product permitted tentative identification of the KDO disaccharide structure as KDO2-4KDO.


RASIM: a novel rotation and scale invariant matching of local image interest points.
This paper presents a novel algorithm for matching image interest points. Potential interest points are identified by searching for local peaks in Difference-of-Gaussian (DoG) images. We refine and assign rotation, scale and location for each keypoint by using the SIFT algorithm . Pseudo log-polar sampling grid is then applied to properly scaled image patches around each keypoint, and a weighted adaptive lifting scheme transform is designed for each ring of the log-polar grid. The designed adaptive transform for a ring in the reference keypoint and the general non-adaptive transform are applied to the corresponding ring in a test keypoint. Similarity measure is calculated by comparing the corresponding transform domain coefficients of the adaptive and non-adaptive transforms. We refer to the proposed versatile system of Rotation And Scale Invariant Matching as RASIM. Our experiments show that the accuracy of RASIM is more than SIFT, which is the most widely used interest point matching algorithm in the literature. RASIM is also more robust to image deformations while its computation time is comparable to SIFT.


Lipid transport function of lipoproteins in blood plasma.
Fatty acid and cholesterol transport in plasma lipoproteins evolved in the context of an open circulatory system in which lipoprotein particles are secreted directly into the blood and have ready access to cells in various tissues. In higher vertebrates with closed capillary beds, hydrolysis of triglycerides at capillary surfaces is required for efficient uptake of their component fatty acids into cells. Likewise, hydrolysis of cellular triglycerides in cells of adipose tissue precedes mobilization of the fatty acids and permits large amounts to be transported in the blood. However, in all Metazoa lipoproteins are secreted primarily from cells adjacent to an open microvascular bed. Uptake of lipoprotein particles as such into cells occurs in invertebrates and vertebrates alike, facilitated by binding to high-affinity receptors on cell surfaces. In vertebrates, a concentration gradient created between cholesterol in cells and lipoproteins by a cholesterol-esterifying enzyme that acts on lipoproteins promotes movement of cholesterol into the plasma compartment. Thus the strategies to transport poorly soluble lipids include enzymatic reactions at cell surfaces and in blood plasma as well as the processes of exocytosis and endocytosis.


In vivo imaging of intracranial human glioma xenografts comparing specific with nonspecific radiolabeled monoclonal antibodies.
Current diagnostic and therapeutic modalities for malignant human gliomas are largely nonspecific. The development of monoclonal antibodies (MA's) with their high degree of specificity may allow precise tumor imaging and selective administration of therapeutic agents. However, the ability of these antibodies to specifically localize tumor tissue in vivo remains speculative. This study compares the localization and imaging properties of two MA's: a specific human glioma-associated extracellular matrix glycoprotein MA, 81C6, and a nonspecific control MA, 45.6, against a human glioma cell line, D-54 MG, intracranially inoculated into athymic rats. Forty-one animals received MA's labeled with iodine-131 (131I) or 125I and underwent imaging with a gamma camera. The images were independently evaluated and compared to tissue radioactivity levels. Radiolabeled antiglioma MA 81C6 specifically localized in intracranial xenografts. The percent of injected dose per gram of tissue for tumor was 1.707 +/- 0.405/gm for 81C6 and 0.118 +/- 0.056/gm for 45.6. All other organs had equivalent levels of specific and nonspecific MA's. For brain, these were 0.004 +/- 0.002/gm and 0.005 +/- 0.005/gm, respectively, and for the other organs, the range was from 0.053 to 0.284/gm. Statistically, 45.6 achieved levels in tumor that were significantly higher than normal brain (p less than 0.05) but significantly less than that achieved with 81C6 (p less than 0.005). With 81C6, the degree of localization was high enough to allow imaging of intracranial tumors at sizes as small as 20 mg. Intracranial tumors were imaged with 45.6 only when they achieved sizes greater than 300 mg. In this imaging study, radiolabeled 81C6, a specific antiglioma MA, proved to be significantly better for imaging small and intermediate-sized tumors than the control MA's. Large tumors were visualized by both MA's, although higher quality scans were obtained earlier and more frequently with specific MA's than with nonspecific immunoglobulin G. These data suggest that specific MA's have a role to play in both the diagnosis and treatment of primary intracranial human tumors.


Blood lead monitoring in a decorative ceramic tiles factory in Singapore.
To illustrate the lead hazard in the ceramics art industry and the importance of blood lead monitoring and suspension of workers with high blood lead levels. Interviews were conducted for workers exposed to the lead hazard from a factory manufacturing decorative ceramic tiles. Serial blood lead levels were taken and measurements of lead-in-air and lead in the bulk samples were conducted. High blood lead levels were observed in four out of 12 workers. Three workers were suspended from further lead exposure and one left the factory. These workers were not aware of the hazards of lead and the importance of good personal hygiene. They were educated on the hazards of lead, the importance of good personal hygiene practices and on the use of the appropriate personal protective equipment. There was an improvement in overall blood lead results in the subsequent months. Lead hazard is present in the ceramics art industry and ingestion is probably an important route of absorption. The monitoring of blood lead levels was useful to identify and follow-up workers with high blood lead levels. Suspension of workers from further lead exposure was effective in decreasing the blood lead levels of the workers.