Relation of the Dietary Approaches to Stop Hypertension Dietary Pattern to Heart Failure Risk and Socioeconomic Status (from the Southern Community Cohort Study).
The Dietary Approaches to Stop Hypertension (DASH) dietary pattern has been associated with a lower risk of incident heart failure (HF); however, previous studies were conducted in mostly middle-income White populations. The association between DASH and incident HF risk in lower income and Black individuals is less well understood. We analyzed 25,300 White and Black adults without a history of HF at enrollment (2002 to 2009) in the Southern Community Cohort Study receiving Centers for Medicare and Medicaid Services. Alignment with DASH was assessed at enrollment using a validated food frequency questionnaire. Incident HF was ascertained from Centers for Medicare and Medicaid Services claims through 2016. The association between DASH diet alignment and incident HF was examined in multivariable-adjusted Cox proportional hazards regression models, including an interaction term testing effect modification by income. The cohort was predominantly middle-aged (median 54 years), Black (68%), female (63%), and low-income (88% <$25,000/year/household). Socioeconomic factors, including education and annual income, were larger contributors to the variance in DASH score than were cardiovascular co-morbidities. The association between DASH dietary alignment and HF risk was not significant overall (hazard ratio [HR] 1.00; 95% confidence interval [CI] 0.96 to 1.04) or in race-sex groups. However, the association between alignment with the DASH diet and HF risk significantly varied by income (interaction p = 0.030), with neutral and inverse associations in lower (<$25,000/year) and higher ($≥25,000) income participants, respectively. In conclusion, income modified the association between healthier dietary patterns and risk of incident HF. In lower income participants, greater alignment with the DASH diet was not associated with lower HF risk.


[Cartilaginous tumors of the cricoid: imaging diagnosis. A case report].
Cartilaginous tumors of the larynx are rare; although chondromas are the most frequent of these tumors. Laryngeal chondrosarcomas are even rarer, in spite of this being the most frequent histological variety of sarcoma (less than 1% of all malignant laryngeal tumors). These tumors are slow-growing, locally aggressive, and tend to recur. They are less aggressive in the larynx than in other sites: cervical or distant metastases are rare (8.5%) and recurrences often can be controlled. The most common presenting symptom is hoarseness with normal indirect laryngoscopy. The complementary studies of choice are computed tomography (CT) and magnetic resonance imaging (MRI). The role of these imaging techniques in the study of laryngeal chondroma and chondrosarcoma was examined. These sporadic tumors may be overlooked, although early identification is necessary for effective treatment.


Chapter 4. A self-theoretical perspective on the use-misuse of alcohol and drugs based on qualitative and narrative data.
This article discusses different self-theoretical perspectives of the self that are of importance in the analysis of the use and misuse of alcohol and psychoactive drugs. The self-theories considered here include cognitive, psychodynamic, transpersonal, and social constructivist perspectives. A multidimensional perspective focusing on the connection between identity structures and analyzing the use/misuse of alcohol and psychoactive drugs is presented. The article argues for a self-theoretical analysis based on narrative data in order to reach an in-depth understanding of the use and misuse of alcohol and psychoactive drugs.


Proteome profiling of mitotic clonal expansion during 3T3-L1 adipocyte differentiation using iTRAQ-2DLC-MS/MS.
Mitotic clonal expansion (MCE) is one of the important events taking place at the early stage during 3T3-L1 adipocyte differentiation. To investigate the mechanism underlying this process, we carried out a temporal proteomic analysis to profile the dynamic changes in MCE. Using 8-plex-iTRAQ-2DLC-MS/MS analysis, 3152 proteins were quantified during the initial 28 h of 3T3-L1 adipogenesis. Functional analysis was performed on 595 proteins with maximum or minimum quantities at 20 h of adipogenic induction that were potentially involved in MCE, which identified PI3K/AKT/mTOR as the most relevant pathway. Among the 595 proteins, PKM2 (Pyruvate kinase M2), a patterned protein identified as a potential target gene of C/EBPβ in our previous work, was selected for further investigation. Network analysis suggested positive correlations among C/EBPβ, PIN1, and PKM2, which may be related with the PI3K-AKT pathway. Knockdown of PKM2 with siRNA inhibited both MCE and adipocyte differentiation of 3T3-L1 cells. Moreover, PKM2 was down-regulated at both the mRNA level and the protein level upon the knockdown of C/EBPβ. And overexpressed PKM2 can partially restore MCE, although it did not restore terminal adipocyte differentiation, which was inhibited by siC/EBPβ. Thus, PKM2, potentially regulated by C/EBPβ, is involved in MCE during adipocyte differentiation. The dynamic proteome changes quantified here provide a promising basis for revealing molecular mechanism regulating adipogenesis.


A smooth polaron-molecule crossover in a Fermi system.
The problem of a single down-spin particle interacting with a Fermi sea of up-spin particles is of current interest in the field of cold atoms. The Hubbard model, appropriate to atoms in an optical lattice potential, is considered in parallel with a gas model. As the strength of an attractive short-range interaction is increased there is a crossover from 'polaron' behaviour, in which the Fermi sea is weakly perturbed, to 'molecule' behaviour in which the down-spin particle is bound to a single up-spin particle. It is shown that this is a smooth crossover, not a sharp transition as claimed by many authors.


Multicenter Observational Study on Factors and Outcomes Associated with Various Methicillin-Resistant Staphylococcus aureus Types in Children with Cystic Fibrosis.
Methicillin-resistant Staphylococcus aureus (MRSA) prevalence continues to increase in patients with cystic fibrosis (CF) in the United States, reaching 26.5% in 2012. Approximately 30% of strains are SCCmec (staphylococcal cassette chromosome mec) IV type, frequently USA300, which in the general population have different genotypic and phenotypic features than SCCmec II type. We hypothesized that risk factors for acquisition and outcomes in patients with CF differed for "health care-associated" (SCCmec II) versus "community-associated" (SCCmec IV) MRSA strains. To determine the role of SCCmec type and Panton-Valentine leukocidin (PVL), MRSA isolates from patients not more than 18 years old at seven CF centers were typed and the association of potential risk factors and subsequent clinical course was assessed, using data provided by the CF Patient Registry. Participants with chronic MRSA (295) had typeable isolates and clinical data; 205 (69.5%) had SCCmec II PVL(-), 39 (13.2%) had SCCmec IV PVL(-), and 51 (17.3%) had SCCmec IV PVL(+) strains. SCCmec IV, compared with SCCmec II, increased during the study period, 1996-2010 (P = 0.03). SCCmec II was associated with Pseudomonas aeruginosa-positive cultures and three or more clinic visits in the 6 months preceding the first positive MRSA culture (adjusted odds ratio, 2.05; 95% confidence interval, 1.13-3.74; P = 0.019). Lung function and anthropometrics remained unchanged in the 6 months after initial MRSA detection compared with the 6 months prior. Although CF care increased for participants in both groups in the 6 months after MRSA detection, inhaled antibiotics were prescribed more frequently in those with SCCmec II strains and increased hospitalizations occurred in those with SCCmec IV PVL(-) strains compared with those with PVL(+) strains (adjusted difference, 34.10%; 95% confidence interval, 7.58-60.61; P = 0.012). Participants in both groups had an increase in CF care in the 2 years after MRSA detection compared with the 2 years prior. Increased exposure to CF clinics and P. aeruginosa may constitute risk factors for acquisition of SCCmec II MRSA strains. Clinical interventions increased 6 months and 2 years after initial MRSA detection regardless of SCCmec type.


Extracellular membrane vesicles as a mechanism of cell-to-cell communication: advantages and disadvantages.
Microvesicles represent a newly identified mechanism of intercellular communication. Two different types of microvesicles have been identified: membrane-derived vesicles (EVs) and exosomes. EVs originate by direct budding from the plasma membrane, while exosomes arise from ectocytosis of multivesicular bodies. Recent attention has focused on the capacity of EVs to alter the phenotype of neighboring cells to make them resemble EV-producing cells. Stem cells are an abundant source of EVs, and the interaction between stem cells and the microenvironment (i.e., stem cell niche) plays a critical role in determining stem cell phenotype. The stem cell niche hypothesis predicts that stem cell number is limited by the availability of niches releasing the necessary signals for self-renewal and survival, and the niche thus provides a mechanism for controlling and limiting stem cell numbers. EVs may play a fundamental role in this context by transferring genetic information between cells. EVs can transfer mRNA and microRNA to target cells, both of which may be involved in the change in target-cell phenotype towards that of EV-producing cells. The exchange of genetic information may be bidirectional, and EV-mediated transfer of genetic information after tissue damage may reprogram stem cells to acquire the phenotypic features of the injured tissue cells. In addition, stem cell-derived EVs may induce the de-differentiation of cells that survive injury by promoting their reentry into the cell cycle and subsequently increasing the possibility of tissue regeneration.


Coarse-graining bacteria colonies for modelling critical solute distributions in picolitre bioreactors for bacterial studies on single-cell level.
Microfluidic single-cell bioreactors have found widespread application to investigate growth and gene expression of microbial model organisms, but yet there are few attempts to systematically characterize different design and cultivation concepts. Quantitative measurements of critical solute concentrations, e.g. limiting nutrients, are not yet feasible within the typical volumes in the range of picolitres. A way to gain new insights about the mass transport within those volumes is by simulation, but the complex geometry resulting from the multitude of cells within a colony leads to time and resource consuming computational challenges. In this work, six different concepts for the model representation of cellular microcolonies within microfluidic monolayer growth chamber devices are compared. The Gini coefficient is proposed as new measure for inhomogeneity within cellular colonies. An example cell colony is represented by a single point source, a cylindrical volume with homogeneous reaction rates with and without adjusted diffusion coefficient, as point sources for each single cell and as rod-shaped, diffusion blocking, three-dimensional cells with varying shapes. Simulated concentration profiles across the chambers depended strongly on the chosen cell representation. The representation with the lowest degree of abstraction, three-dimensional cells, leads to complex geometries and high computational effort, but also gives a conservative and therefore preferable estimate for the cultivation conditions within a given cultivation chamber geometry. Interestingly, the cylindrical volume with adjusted diffusion coefficient gives similar results but requires far less computational effort. Therefore, it is proposed to use the three-dimensional cells for detailed studies and to determine parameters for the cylindrical volume with adjusted diffusion coefficient, which can then be used for experimental design, screening of parameter spaces, and similar applications.


Quantitation of experimental canine infarct size using multipinhole single-photon tomography.
A four-pinhole longitudinal tomographic system, with collimator and software, was developed for a standard-field portable scintillation camera. This system was used with technetium--99m pyrophosphate (Tc-PPi) to quantify the volume of infarcted myocardium in 27 dogs with experimental myocardial infarcts. These were induced by ligation of the left anterior descending (LAD) or the circumflex coronary artery. Tomographic estimations of scintigraphic infarct size agreed well with postmortem findings when the circumflex group (r = 0.87) and LAD group (r = 0.83) were considered separately, but the correlation fell when the groups were pooled (r = 0.73). Whereas multipinhole tomography extends Tc-PPi infarct sizing capability in animals to include posterior and subendocardial infarcts as well as anterior lesions, the tomographic sections contain enough blur artifacts to lower the sizing accuracy of the method. The main advantage of the technique may well be its ability to aid in detection and location of small myocardial infarcts.


Biomaterials for the Treatment of Tendon Injury.
Most tendon injuries are occurring from a gradual wearing and tearing of the tendon tissues from overuse. Such injuries are usually seen in sports, exercising, or daily activities that involve a high mechanical load and weight bearing. However, owing to the lack of both cellularity and blood vessels in tendons, the process of tendon repair is slow and inefficient. Although various conservative (non-surgical) and surgical management options are conducted by the clinicians, a gold standard of these approaches does not exist. In this regard, the treatment of tendon injuries is challenging. Here, we describe the recent advances of biomaterial-based approaches for the treatment of injured tendons. Regenerative medicine is an emerging multidisciplinary research that specializes in the repair of damaged tendon tissues through the delivery of regenerative factors by biomaterials. Although current biomaterial-based treatment strategies have shown their potential for tendon healing, future research and clinical applications should focused on finding the optimum combinations of regenerative factors with ideal biomaterials for the repair of tendons.


Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics.
Diffuse intrinsic pontine glioma (DIPG) and midline high-grade glioma (mHGG) are lethal childhood brain tumors. Spatial genomic heterogeneity has been well-described in adult HGG but has not been comprehensively characterized in pediatric HGG. We performed whole exome sequencing on 38-matched primary, contiguous, and metastatic tumor sites from eight children with DIPG (n = 7) or mHGG (n = 1) collected using a unique MRI-guided autopsy protocol. Validation was performed using Sanger sequencing, Droplet Digital polymerase-chain reaction, immunohistochemistry, and fluorescent in-situ hybridization. Median age at diagnosis was 6.1 years (range: 2.9-23.3 years). Median overall survival was 13.2 months (range: 11.2-32.2 months). Contiguous tumor infiltration and distant metastases were observed in seven and six patients, respectively, including leptomeningeal dissemination in three DIPGs. Histopathological heterogeneity was evident in seven patients, including intra-pontine heterogeneity in two DIPGs, ranging from World Health Organization grade II to IV astrocytoma. We found conservation of heterozygous K27M mutations in H3F3A (n = 4) or HIST1H3B (n = 3) across all primary, contiguous, and metastatic tumor sites in all DIPGs. ACVR1 (n = 2), PIK3CA (n = 2), FGFR1 (n = 2), and MET (n = 1) were also intra-tumorally conserved. ACVR1 was co-mutated with HIST1H3B (n = 2). In contrast, PDGFRA amplification and mutation were spatially heterogeneous, as were mutations in BCOR (n = 1), ATRX (n = 2), and MYC (n = 1). TP53 aberrations (n = 3 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved. Spatial conservation of prognostically-relevant and therapeutically-targetable somatic mutations in DIPG and mHGG contrasts the significant heterogeneity of driver mutations seen in adult HGG and supports uniform implementation of diagnostic biopsy in DIPG and mHGG to classify molecular risk groups and guide therapeutic strategy.


Lung ultrasound in the management of pneumocystis pneumonia: A case series.
Despite the decline in HIV mortality and morbidity, Pneumocystis jirovecii pneumonia (PJP) is still frequently seen, particularly in patients with a low CD4+ cell count. We present a case series where we analyzed the possible role of lung ultrasound (LUS) in the management of PJP in a real-life clinical setting. We describe the ultrasound findings from a consecutive series of six HIV patients hospitalized for PJP, all with a favorable outcome, and evaluated with LUS at admission in our ward and then repeated this once during the hospitalization. Multiple B lines indicating interstitial syndrome were detected at admission in all cases, with a bilateral asymmetric pattern mostly localized in middle and upper lobes. In the follow-up LUS, we noted a substantially improved pattern in all patients, observing a reduction of B lines which correlated with clinical amelioration. One patient at admission and three patients during the follow-up showed lung consolidations with hyperechoic spots inside, that might be typical of the disease. In conclusion, LUS could be a practical and noninvasive imaging tool for supporting diagnosis and treatment response of PJP.


Concentration characteristics of VOCs and acids/bases in the gas phase and water-soluble ions in the particle phase at an electrical industry park during construction and mass production.
The electronics industry is a major business in the Central Taiwan Science Park (CTSP). Particulate samples and 11 water-soluble ionic species in the particulate phase were measured by ionic chromatography (IC). Additionally, acid and base gases were sampled by denuder absorption and analyzed by IC. Volatile organic compounds (VOCs) were collected in stainless-steel canisters four times daily and analyzed via gas chromatography/mass spectrometry. Ozone formation potential (OFP) was measured using maximum increment reactivity. In addition, airborne pollutants during (1) construction and (2) mass production were measured. Particulate matter concentration did not increase significantly near the optoelectronic plant during construction, but it was higher than during mass production. SO(2), HNO(2) and NH(3) were the dominant gases in the denuder absorption system. Nitrate, sulfate, and ammonium ions predominated both in PM(2.5) and PM(10-2.5); but calcium ion concentration was significantly higher in PM(10-2.5) samples during construction. Toluene, propane, isopentane, and n-butane may have come from vehicle exhaust. Construction equipment emitted high concentrations of ethylbenzene, m-xylene, p-xylene, o-xylene, 1,2,4-trimethylbenzene, and toluene. During mass production, methyl ethyl ketone), acetone and ethyl acetate were significantly higher than during construction, although there was continuous rain. The aromatic group constituted >50% of the VOC concentration totals and contributed >70% of OFP.


Novel 180- and 480-base-pair insertions in African and African-American strains of Helicobacter pylori.
Helicobacter pylori is a genetically diverse bacterial species that chronically infects human stomachs and sometimes causes severe gastroduodenal disease. Studies of polymorphic DNA sequences can suggest geographic origins of individual strains. Here, we describe a 180-bp insertion (ins180), which is just after the translation stop of a gene of unknown function, near the promoter of jhp0152-jhp0151 two-component signal transduction genes in strain J99, and absent from this site in strain 26695. This ins180 insertion was found in 9 of 9 Gambian (West African), 9 of 20 (45%) South African, and 9 of 40 (23%) Spanish strains but in only 2 of 20 (10%) North American strains and none of 20 Lithuanian, 20 Indian, and 20 Japanese strains. Four South African isolates that lacked ins180 and that belonged to an unusual outlier group contained a 480-bp insertion at this site (ins480), whereas none of 181 other strains screened contained ins480. In further tests 56% (10 of 18) of strains from African Americans but only 17% (3 of 18) of strains from Caucasian Americans carried ins180 (P < 0.05). Thus, the H. pylori strains of modern African Americans seem to retain traces of African roots, despite the multiple generations since their ancestors were taken from West Africa. Fragmentary ins180-like sequences were found at numerous sites in H. pylori genomes, always between genes. Such sequences might affect regulation of transcription and could facilitate genome rearrangement by homologous recombination. Apparent differences between African-American and Caucasian-American H. pylori gene pools may bear on our understanding of H. pylori transmission and disease outcome.


'WTF is PrEP?': attitudes towards pre-exposure prophylaxis among men who have sex with men and transgender women in New York City.
In the USA, gay and other men who have sex with men and transgender women are disproportionately affected by HIV. Uptake of pre-exposure prophylaxis (PrEP), anti-retroviral therapy to prevent HIV-negative individuals from seroconverting if exposed to HIV, by members of this population remains low, particularly among African-Americans. We conducted two focus groups to assess responses to an online social media campaign focusing on PrEP use in New York City. We designed, produced and disseminated the campaign to address knowledge of PrEP; its physical and psychological side effects; and psychosocial barriers related to PrEP adherence and sex shaming. Focus group participants demonstrated a relatively high knowledge of PrEP, although considerable concern remained about side effects, particularly among Black participants. Participants suggested that stigma against PrEP users was declining as PrEP use became more common, but stigma remained, particularly for those not using condoms. Many focus group participants reported distrust of medical providers and were critical of the commodification of HIV prevention by the pharmaceutical industry. Participants reported that those in romantic relationships confronted unique issues regarding PrEP, namely suspicions of infidelity. Finally, Black participants spoke of the need for more tailored and sensitive representations of Black gay men in future programmes and interventions.


Suprasellar pleomorphic xanthoastrocytoma: A case report.
Pleomorphic xanthoastrocytoma (PXA) is a rare form of astrocytic neoplasm most commonly found in children and young adults. This neoplasm, which is classified as a Grade II tumor by the World Health Organization classification of tumors of the central nervous system, carries a relatively favorable outcome. It is usually found supratentorially in cortical regions of the cerebral hemispheres, and as such, presenting symptoms are similar to other supratentorial cortical neoplasms; with seizures being a common initial symptom. Due to the rarity of this type of neoplasm, PXA arising elsewhere in the brain is often not included in the initial differential diagnosis. This report presents an extremely rare patient with PXA arising in the suprasellar region who presented with progressive peripheral vision loss. Magnetic resonance imaging of the brain demonstrated a heterogeneous suprasellar mass with cystic and enhancing components initially; the most likely differential diagnosis was craniopharyngioma. The patient underwent endoscopic endonasal resection of the tumor. Microscopically, the tumor was consistent with a glial neoplasm with variable morphology. Based on these findings along with further immunohistochemical workup, the patient was diagnosed with a PXA arising in the suprasellar region. At the 1-year follow-up, the patient remained free of recurrence. Although rare PXA originating in other uncommon locations, such as the spinal cord, cerebellum, the ventricular system, and the pineal region have been previously described. Although rare, PXA should be included in the differential diagnosis for solid-cystic tumors arising in the suprasellar region in young adults.


Decision-making in diabetes mellitus type 1.
Decreased treatment adherence in patients with diabetes mellitus type 1 (type 1 DM) may reflect impairments in decision-making and underlying associated deficits in working memory and executive functioning. Other factors, including comorbid major depression, may also interfere with decision-making. The authors sought to review the clinically relevant characteristics of decision-making in type 1 DM by surveying the literature on decision-making by patients with type 1 DM. Deficiencies in decision-making in patients with type 1 DM or their caregivers contribute to treatment nonadherence and poorer metabolic control. Animal models of type 1 DM reveal deficits in hippocampal-dependent memory tasks, which are reversible with insulin. Neurocognitive studies of patients with type 1 DM reveal lowered performance on ability to apply knowledge to solve problems in a new situation and acquired scholarly knowledge, psychomotor efficiency, cognitive flexibility, visual perception, speed of information-processing, and sustained attention. Other factors that might contribute to poor decision-making in patients with type 1 DM, include "hypoglycemia unawareness" and comorbid major depression (given its increased prevalence in type 1 DM). Future studies utilizing novel treatment strategies to help patients with type 1 DM make better decisions about their disease may improve their glycemic control and quality of life, while minimizing the impact of end-organ disease.


Protracted diarrhea in infancy: clinical aspects and ultrastructural analysis of the small intestine.
Protracted diarrhea is a clinical entity characterized by diarrhea lasting greater than 2 weeks, starting before 3 months of age, with severe nutritional aggravation and negative stool culture for enteropathogens. This report deals with the ultrastructural abnormalities found in the intestinal mucosa of children with protracted diarrhea. Forty children (mean age 5.1 months) were studied. They were submitted to the following tests of intestinal function: D-xylose, triglyceride tolerance, small bowel biopsy (light and electron microscope), sigmoidoscopy, and sweat test. D-Xylose absorption and triglyceride tolerance test in these patients were both significantly lower than controls. Ultrastructural analysis of the small bowel of 12 patients showed various degrees of alterations, mainly shortening of the microvilli, increased number of multivesicular bodies, and vacuolation of mitochondria and endoplasmic reticulum. These lesions were totally reversible after clinical and nutritional recovery as could be proven in two children. The most common cause of protracted diarrhea in these patients was secondary carbohydrate intolerance and dietary protein cow's milk and soy bean intolerance, which resulted in colitis or malabsorption as a consequence of intestinal mucosa injury due to acute gastroenteritis.


Monte Carlo simulation of the nonlinear full peak energy responses for gamma-ray scintillation detectors.
A Monte Carlo code has been developed, which predicts the nonlinear full peak energy responses of scintillation detectors to incident gamma-rays. It is illustrated here for the popular scintillation detectors, NaI and BGO. The full energy response can be determined by treating the detector as effectively infinite and assuming that all photons and electrons are fully absorbed within the detector. This assumption means that no geometrical direction or position tracking is required, only the selection of sequential photon interactions based on the appropriate energy-dependent interaction cross-sections. The full energy pulse-height response is determined by the sum of the pulse-height responses from all secondary electrons. Results from infinite NaI and BGO detectors indicate that even though the maximum difference in electron scintillation efficiency is about the same for the two scintillation detectors, the overall effect on the extent of the difference in pulse height is much less for BGO than NaI. This result is due to the larger density and effective atomic number of BGO, which causes significantly fewer Compton scattering events. Compton scattering interactions reduce the incident photon energy without absorption and therefore give more responses at reduced energy where the electron scintillation efficiency is most different.


Ubiquitous distribution of phosphatidylinositol phosphate synthase and archaetidylinositol phosphate synthase in Bacteria and Archaea, which contain inositol phospholipid.
In Eukarya, phosphatidylinositol (PI) is biosynthesized from CDP-diacylglycerol (CDP-DAG) and inositol. In Archaea and Bacteria, on the other hand, we found a novel inositol phospholipid biosynthetic pathway. The precursors, inositol 1-phosphate, CDP-archaeol (CDP-ArOH), and CDP-DAG, form archaetidylinositol phosphate (AIP) and phosphatidylinositol phosphate (PIP) as intermediates. These intermediates are dephosphorylated to synthesize archaetidylinositol (AI) and PI. To date, the activities of the key enzymes (AIP synthase, PIP synthase) have been confirmed in only three genera (two archaeal genera, Methanothermobacter and Pyrococcus, and one bacterial genus, Mycobacterium). In the present study, we demonstrated that this novel biosynthetic pathway is universal in both Archaea and Bacteria, which contain inositol phospholipid, and elucidate the specificity of PIP synthase and AIP synthase for lipid substrates. PIP and AIP synthase activity were confirmed in all recombinant cells transformed with the respective gene constructs for four bacterial species (Streptomyces avermitilis, Propionibacterium acnes, Corynebacterium glutamicum, and Rhodococcus equi) and two archaeal species (Aeropyrum pernix and Sulfolobus solfataricus). Inositol was not incorporated. CDP-ArOH was used as the substrate for PIP synthase in Bacteria, and CDP-DAG was used as the substrate for AIP synthase in Archaea, despite their fundamentally different structures. PI synthase activity was observed in two eukaryotic species, Saccharomyces cerevisiae and Homo sapiens; however, inositol 1-phosphate was not incorporated. In Eukarya, the only pathway converts free inositol and CDP-DAG directly into PI. Phylogenic analysis of PIP synthase, AIP synthase, and PI synthase revealed that they are closely related enzymes.


Magnolol dimer-derived fragments as PPARγ-selective probes.
Partial agonists of the transcription factor PPARγ (peroxisome proliferator-activated receptor γ) have shown potential for the treatment of metabolic and inflammatory conditions and novel activators serve as valuable tool and lead compounds. Based on the natural product magnolol (I) and recent structural information of the ligand-target interaction we have previously developed magnolol dimer (II) which has been shown to have enhanced affinity towards PPARγ and improved selectivity over RXRα (retinoid X receptor α), PPARγ's heterodimerization partner. In this contribution we report the synthesis and evaluation of three fragments of the dimeric lead compound by structural simplifications. Sesqui magnolol A and B (III and IV) were found to exhibit comparable activities to magnolol dimer (II) and selectivity over RXRα persisted. Computational studies suggest a common pharmacophore of the distinctive biphenyl motifs. Truncated magnolol dimer (V) on the other hand does not share this feature and was found to act as an antagonist.


Nurses' advice regarding sterile or clean urinary drainage bags for individuals with a long-term indwelling urinary catheter.
The purpose of this study was to identify, compare, and explore advice nurses give to community-dwelling long-term indwelling catheter users on the use of sterile or clean urinary drainage bags, and to obtain information that would inform the design of a larger-scale international survey. A survey was targeted to nurse members of the International Continence Society (n = 130). Respondents (n = 28; 21.5%) included nurses from Australia, Canada, Belgium, Switzerland, the United Kingdom, and the United States, who specialized in managing incontinence. The project was conducted as a descriptive, exploratory pilot study. Respondents completed an online anonymous survey that was distributed by the International Continence Society. The survey instrument was designed by the investigators and comprised 14 questions with both fixed and open-ended response options. Most respondents in this survey advised indwelling catheter users to reuse their catheter bags (n = 15; 68%). Factors that influenced advice included concerns about the cost of catheter bags, an evaluation of the individual's infection risk, local and national policies, evidence-based guidelines, users' living arrangements, and their ability to clean the bags. Advice on decontamination methods varied; however, the most commonly recommended cleaning agent was water and vinegar, followed by a sterilizing or bleach solution or dishwashing detergent. Nurses play a key role in educating and supporting indwelling catheter users. Results of this study highlight variability in the advice nurses give to community-dwelling long-term indwelling catheter users about sterile or clean urinary drainage bags. This variability requires further investigation and affirms the need for a larger-scale study that draws on a broader sample of nurses.


Adsorbed structures of 4,4'-bipyridine on Cu(111) in acid studied by STM and IR.
The adsorption of 4,4'-bipyridine (BiPy) on Cu(111) has been investigated in 0.1 M HClO4 by cyclic voltammetry, electrochemical scanning tunneling microscopy (STM), and surface-enhanced infrared adsorption spectroscopy (SEIRAS). Cyclic voltammetry showed the double layer region extending from -0.2 to 0.26 V and a pair of redox waves superposing on hydrogen evolution wave at more negative potentials. Diprotonated BiPy, BiPyH2(2+), is adsorbed flat on the Cu(111) (1 x 1) surface and forms a well-ordered monolayer with a (3 x 4) symmetry in the double-layer potential region. At more negative potential, BiPyH2(2+) is reduced to its monocation radical, BiPyH2(*+), and forms another well-ordered structure in which the radicals are stacked in molecular rows with a face-to-face self-dimer as the building unit. The SEIRA spectra of both BiPyH2(2+) and BiPyH2(*+) are dominated by gerade modes which should be IR-inactive for the centrosymmetric species. The breakdown of the selection rule of IR absorption is ascribed to the vibronic coupling associated with charge transfer between BiPyH2(2+) and the surface and between the radicals.


Oncological outcomes of operative treatment of subcutaneous soft-tissue sarcomas of the extremities.
We reviewed the cases of sixty-two patients who had had a subcutaneous sarcoma to determine the effect of tumor and treatment-related variables on the rates of survival and local recurrence. Fifty-nine (95 per cent) of the patients had had an operation at another hospital before being referred to us. Twenty-nine (47 per cent) of the sixty-two tumors were high-grade, forty-two (68 per cent) were small (five centimeters or less), and thirty (48 per cent) were malignant fibrous histiocytomas. We followed a treatment strategy that consisted of repeat excision with the goal of obtaining wide margins. Excluding thirteen patients who had had a palpable local recurrence at the time of presentation, twenty (49 per cent) of forty-one patients who had had a marginal excision at another hospital had microscopic residual tumor on repeat excision. At a median of fifty-six months after the repeat excision, fifty (81 per cent) of the sixty-two patients had been continuously disease-free, one had no evidence of disease, eight had died of the disease, and three had died of other causes. The five-year rate of disease-free survival was 85 per cent (fifty-three of sixty-two patients). There were three local recurrences, all in patients who had had a marginal resection. No recurrences were noted in patients who had had a wide local excision of the tumor or of the previous operative field. Multivariate analysis revealed that a large tumor (greater than five centimeters), a marginal excision, and adjuvant radiation therapy were associated with a worse prognosis. Excellent rates of survival for patients who have a subcutaneous sarcoma, including those who have a large or high-grade tumor and those who have residual tumor following a previous operation, can be obtained with carefully planned operative treatment alone. We recommend operative excision or repeat excision with wide margins because of the high prevalence of residual tumor. Size is the most important tumor-related factor, and the operative margin is the most important treatment-related factor. The additional value of adjuvant radiation therapy remains unproved.


A longitudinal study of hantavirus infection in three sympatric reservoir species in agroecosystems on the Argentine Pampa.
Prevalence of antibody reactive with Sin Nombre hantavirus (SNV) was evaluated from rodents captured over 31 months (March 1988 to September 1990) from six mark-recapture grids on the central Argentine Pampa. The most frequently infected rodents were: Akodon azarae (31/459), Necromys benefactus (8/141), and Oligoryzomys flavescens (10/281), which are known hosts of Pergamino, Maciel, and Lechiguanas hantaviruses, respectively. Relative population density and antibody prevalence varied seasonally and from year to year, population densities were highest in fall and prevalences were highest in spring. A positive association between antibody prevalence and body weight corroborated findings from other studies suggesting that hantaviruses are maintained in reservoir populations by horizontal transmission. In two of three host species, transmission was more frequent among male than among female mice. We found no evidence for a detrimental effect of hantavirus infection on host body weight, growth, longevity, movement, or reproductive preparedness. This analysis, based on cryopreserved specimens, represents the earliest conducted longitudinal, mark-recapture study of the dynamics of infection of autochthonous American hantaviruses in their sigmodontine host populations.


Metabolomic analyses for atherosclerosis, diabetes, and obesity.
Insulin resistance associated with type 2 diabetes mellitus (T2DM), obesity, and atherosclerosis is a global health problem. A portfolio of abnormalities of metabolic and vascular homeostasis accompanies T2DM and obesity, which are believed to conspire to lead to accelerated atherosclerosis and premature death. The complexity of metabolic changes in the diseases presents challenges for a full understanding of the molecular pathways contributing to the development of these diseases. The recent advent of new technologies in this area termed "Metabolomics" may aid in comprehensive metabolic analysis of these diseases. Therefore, metabolomics has been extensively applied to the metabolites of T2DM, obesity, and atherosclerosis not only for the assessment of disease development and prognosis, but also for the biomarker discovery of disease diagnosis. Herein, we summarize the recent applications of metabolomics technology and the generated datasets in the metabolic profiling of these diseases, in particular, the applications of these technologies to these diseases at the cellular, animal models, and human disease levels. In addition, we also extensively discuss the mechanisms linking the metabolic profiling in insulin resistance, T2DM, obesity, and atherosclerosis, with a particular emphasis on potential roles of increased production of reactive oxygen species (ROS) and mitochondria dysfunctions.


Implications of CHA2DS2-VASc Score in Stroke Patients with Atrial Fibrillation: An Analysis of 938 Korean Patients.
The aim of this study was to investigate the stroke mechanisms and associated conditions influencing the decision regarding stroke thromboprophylaxis in patients with atrial fibrillation (AF) plus ischemic stroke, according to the CHA2DS2-VASc score. We evaluated 938 consecutive patients with a diagnosis of AF plus transient ischemic attack/ischemic stroke. Based on the CHA2DS2-VASc scores, patients were stratified as score 0 or 1 (n = 151), score 2 (n = 146), score 3 (n = 213), score 4 (n = 185), or score ≥5 (n = 243). Patients with a higher CHA2DS2-VASc score were more likely to have noncardioembolic stroke mechanism (p = 0.001). Large-artery atherosclerosis causing stenosis >50% was more frequently observed in the high CHA2DS2-VASc group (p < 0.001). Coronary artery disease and the use of antiplatelet agents were more prevalent in the higher group (p < 0.001). A high CHA2DS2-VASc score was associated with a higher frequency of cerebral microbleeds and a higher Fazekas grade for leukoaraiosis (p < 0.001). The HAS-BLED score was correlated with the CHA2DS2-VASc score (γ = 0.650; p < 0.001). A higher CHA2DS2-VASc score is associated with noncardioembolic mechanisms of stroke and with a higher risk of bleeding. Strategies to treat macro/microangiopathy such as use of statin for plaque stabilization, as well as oral anticoagulants with a lower bleeding risk, are needed in these patients.


Metabolism of unsaturated derivatives of valproic acid in rat liver microsomes and destruction of cytochrome P-450.
2-n-Propyl-4-pentenoic acid (delta 4-VPA), an unsaturated metabolite of valproic acid (VPA), and the ethyl ester of delta 4-VPA were tested for their ability to cause NADPH- and time-dependent loss of cytochrome P-450 in hepatic microsomal preparations from phenobarbital-pretreated rats. Ethyl delta 4-VPA gave a large amount of destruction (33 +/- 4% over 30 min), whereas delta 4-VPA was a much less effective inhibitor of the enzyme (8 +/- 2% destruction over 30 min). This difference in degree of enzyme loss correlated well with the respective rates at which the substrates underwent oxidative metabolism of the terminal double bond. It is likely, therefore, that the mechanism of action of these compounds is the same as that for allylisopropylacetamide (AIA) and related monosubstituted olefins, which are converted by cytochrome P-450 to chemically reactive species which bind covalently to the prosthetic heme moiety of the cytochrome and thereby destroy the enzyme. In microsomes, both delta 4-VPA and its ethyl ester were metabolized by cytochrome P-450 to a common cyclic end-product, 3-n-propyl-5-hydroxymethyltetrahydro-2-furanone, although stable isotope labeling experiments with oxygen-18 demonstrated that the pathways followed by the two substrates were mechanistically distinct. These findings, together with data from related metabolic studies on AIA, support the view that the efficiency of the initial double bond oxidation reaction determines the extent of cytochrome P-450 destruction during the metabolism of terminal olefins, rather than any subsequent step.(ABSTRACT TRUNCATED AT 250 WORDS)


Associations of Alzheimer's Disease Neuropathologic Changes with Clinical Presentations of Parkinson's Disease.
Parkinson's disease (PD) and Alzheimer's disease (AD) are the two most prevalent neurodegenerative diseases associated with age. Pathological studies have shown that these two diseases share a certain degree of neuropathological overlap. AD neuropathologic change contributes to cognitive impairment in PD. However, the impact of AD pathology on other clinical phenotypes in PD remains largely unknown. Herein we aimed to assess the impact of co-occurring AD neuropathologic change on the clinical phenotypes of PD. We examined 46 autopsy brains of PD patients and available clinical information to retrospectively assess the effects of comorbid AD pathology on dementia, hallucinations, and dyskinesia commonly seen in advanced PD. AD neuropathology significantly increased the risk of hallucinations and dementia, but not dyskinesia in PD patients. Surprisingly, diffuse Lewy body pathology, but not AD pathology, was associated with the occurrence of dementia and hallucinations. Most importantly, we reported that the severity of neuronal loss in the locus coeruleus (LC), but not the severity of neuronal loss in the substantia nigra (SN), was associated with the occurrence of dyskinesia in advanced PD patients, while neither Lewy body scores in SN nor LC had significant effects. We show for the first time that neuronal loss in LC contributes to dyskinesia. Understanding the relationships between the two distinct pathologies and their relevant clinical phenotypes will be crucial in the development of effective disease-modifying therapies for PD.


Increased incidence of endoscopic erosive esophagitis in solid organ transplant recipients.
Solid organ transplant recipients frequently report gastrointestinal symptoms, especially heartburn or dyspepsia. However, the prevalence of endoscopic erosive esophagitis (EE) and associated risk factors after transplantation are unknown. The aim of this study was to determine whether there was a high incidence of endoscopic findings of EE in solid organ transplant recipients. This retrospective case-control study included 256 of 3,152 solid organ transplant recipients who underwent sequential screening upper endoscopic examinations and an equal number of controls. Forty-four (17.2%) and 16 (6.2%) cases of EE were detected in the solid organ transplant and control groups, respectively (p<0.001). In the multivariate analysis, transplantation was significantly associated with EE (odds ratio [OR], 6.48; 95% confidence interval, 2.74 to 15.35). Factors such as old age (OR, 1.17), the presence of a hiatal hernia (OR, 5.84), an increased duration of immunosuppression (OR, 1.07), and the maintenance administration of mycophenolate mofetil (OR, 4.13) were independently associated with the occurrence of EE in the solid organ transplant recipients. A significant increase in the incidence of endoscopically detected EE was observed in solid organ transplant recipients. This increased incidence was associated with the type and duration of the immunosuppressive therapy.


[Approaches to late prognosis in patients with subacute infectious endocarditis].
To ascertain late prognosis of subacute infectious endocarditis (IE), factors involved in the prognosis, formulate approaches to assessment of late prognosis. A retrospective trial included 98 patients discharged from a hospital with diagnosis "subacute IE", treated without surgery or without endocarditis of the prosthesis. The diagnosis was verified at echocardiography. A mean follow-up 4.8 +/- 3.7 years. Clinical and echo-CG follow-up findings were computer-processed. 5-year lethality was 31%. The patients died of cardiac failure (CF) and acute failure of cerebral circulation (84 and 16%, respectively). Late complications in the survivors were the following: severe CF (18 patients, 32%), moderate CF (18 patients, 32%), recurrent IE (12 patients, 20%). Such factors as IE variant (primary or secondary), affection of the aortic valve, severity of regurgitation, size of the left ventricle, CF progression in the acute phase proved to have a significant influence on late prognosis. The prevalent cause of death in IE is CF. The progression of CF depends on combination of the above factors. High risk group patients should be examined by a cardio-surgeon even in the absence of clinical symptoms of CF.


Thrombosis of portal, superior mesenteric, and splenic veins: a case report.
Patients with venous thrombosis of splanchnic circulation represent a group of high risk with significant morbidity and mortality, if treatment is delayed. We present a patient with thrombosis of portal vein and its tributaries combined with deep venous thrombosis (DVT) of the lower extremities who was successfully treated with conservative management. This patient case highlights the importance of early empiric anti-inflammatory therapy along with systemic anticoagulation to reduce the intestinal inflammation and enteritis and break the vicious circuit resulting in secondary progressive thrombosis of the splanchnic veins, fluid shifts, and functional ileus. Case presentation: A previously healthy 61-years-old female patient with no significant medical history was admitted with progressive upper abdominal pain, nausea and vomiting, low-grade fever, mild signs of ileus, and malaise. Imaging studies revealed portal venous dilation reaching ∼20 mm with near-total obliteration of the lumen by a thrombus. In addition, thrombosis of superior mesenteric and splenic veins with thrombophlebitis was found. Imaging studies also confirmed the presence of DVT of lower extremities including thrombus propagation into the iliac veins. An immediate therapy was started with parenteral antibiotics, anti-inflammatory medications, systemic anticoagulants, and intravenous fluid infusions to restore the circulating volume deficit and treat electrolyte disbalance. With such therapy, the patient's symptoms resolved within a month, and she was discharged from the hospital with full recovery. Heparin infusion was started to reach systemic anticoagulation. With resolution of symptoms, anticoagulation was continued with warfarin. We used non-steroidal anti-inflammatory drugs (NSAIDs) as a component in management of intestinal and systemic inflammation and multifocal thrombosis when the antiphospholipid syndrome was also on the list of differential diagnoses. Conclusion: We present a previously asymptomatic patient with progressive portal venous thrombosis and ascending DVT. Early establishment of diagnosis and initiation of therapy with systemic anticoagulants, anti-inflammatory and antibacterial drugs helped to stop thrombus progression, prevent irreversible intestinal ischemia, and allow for re-canalization of the occluded veins. This case highlights the importance of early interventions to improve the treatment outcome.


MRI safety update 2008: part 2, screening patients for MRI.
This article is the second part of a two-part series on MRI safety. In this article, part 2, the topic of screening patients for MRI procedures is addressed. To prevent incidents and accidents associated with MRI, it is necessary to regularly revisit the safety topics that directly impact patient management especially with respect to the subjects that are "new," those that should be reassessed because of recent changes, topics that deserve emphasis because of controversy or confusion, and information that should be considered in light of new findings.


Diabetes in tuberculosis patients: An emerging public health concern and the determinants and impact on treatment outcome.
Tuberculosis (TB) and diabetes mellitus are still of much public health concern. Screening of TB patients for diabetes will ensure early case detection, better management of diabetes, and better TB treatment outcome. The objective of this study was to determine the prevalence and associated factors of diabetes in TB patients and their impact on treatment outcome of TB. This was a longitudinal follow-up study of registered TB patients under the Revised National Tuberculosis Control Program in all five TB units of Bhopal district. Participants were contacted and the interview was conducted. The blood sugar of all TB patients was checked, and they were followed up to assess the treatment outcome from October 2014 to September 2017. Data were analyzed using SPSS (version 16.0. Chicago, SPSS Inc.). Logistic regression was done to find the factors for diabetes in TB patients. The Chi-square tests were used to find the difference in treatment outcomes and assess the relative risk for poor outcome in diabetic TB patients. Of total 662 TB patients, 82 (12.39%) were diagnosed as diabetic. Age >50 years, males, higher body mass index, pulmonary TB, patients on Category II treatment, and history of smoking were found to be predictors of diabetes in TB patients. The treatment outcome of TB was more unfavorable (defaulter, failure, and death) in diabetic TB patients (16.17%) than in nondiabetic TB patients (5.8%) (risk ratio = 2.78, 1.469-5.284 confidence interval). The high prevalence of diabetes and the unfavorable treatment outcome in diabetic TB patients make screening and management of diabetes at an early-stage crucial for a better outcome in TB patients.


Fast Model-Fitting of Bayesian Variable Selection Regression Using the Iterative Complex Factorization Algorithm.
Bayesian variable selection regression (BVSR) is able to jointly analyze genome-wide genetic datasets, but the slow computation via Markov chain Monte Carlo (MCMC) hampered its wide-spread usage. Here we present a novel iterative method to solve a special class of linear systems, which can increase the speed of the BVSR model-fitting tenfold. The iterative method hinges on the complex factorization of the sum of two matrices and the solution path resides in the complex domain (instead of the real domain). Compared to the Gauss-Seidel method, the complex factorization converges almost instantaneously and its error is several magnitude smaller than that of the Gauss-Seidel method. More importantly, the error is always within the pre-specified precision while the Gauss-Seidel method is not. For large problems with thousands of covariates, the complex factorization is 10-100 times faster than either the Gauss-Seidel method or the direct method via the Cholesky decomposition. In BVSR, one needs to repetitively solve large penalized regression systems whose design matrices only change slightly between adjacent MCMC steps. This slight change in design matrix enables the adaptation of the iterative complex factorization method. The computational innovation will facilitate the wide-spread use of BVSR in reanalyzing genome-wide association datasets.


BAC Recombineering of the Agouti Loci from Spotted Gar and Zebrafish Reveals the Evolutionary Ancestry of Dorsal-Ventral Pigment Asymmetry in Fish.
Dorsoventral pigment patterning, characterized by a light ventrum and a dark dorsum, is one of the most widespread chromatic adaptations in vertebrate body coloration. In mammals, this countershading depends on differential expression of agouti-signaling protein (ASIP), which drives a switch of synthesis of one type of melanin to another within melanocytes. Teleost fish share countershading, but the pattern results from a differential distribution of multiple types of chromatophores, with black-brown melanophores most abundant in the dorsal body and reflective iridophores most abundant in the ventral body. We previously showed that Asip1 (a fish ortholog of mammalian ASIP) plays a role in patterning melanophores. This observation leads to the surprising hypothesis that agouti may control an evolutionarily conserved pigment pattern by regulating different mechanisms in mammals and fish. To test this hypothesis, we compared two ray-finned fishes: the teleost zebrafish and the nonteleost spotted gar (Lepisosteus oculatus). By examining the endogenous pattern of asip1 expression in gar, we demonstrate a dorsoventral-graded distribution of asip1 expression that is highest ventrally, similar to teleosts. Additionally, in the first reported experiments to generate zebrafish transgenic lines carrying a bacterial artificial chromosome (BAC) from spotted gar, we show that both transgenic zebrafish lines embryos replicate the endogenous asip1 expression pattern in adult zebrafish, showing that BAC transgenes from both species contain all of the regulatory elements required for regular asip1 expression within adult ray-finned fishes. These experiments provide evidence that the mechanism leading to an environmentally important pigment pattern was likely in place before the origin of teleosts.


Mechanically activated piezo channels modulate outflow tract valve development through the Yap1 and Klf2-Notch signaling axis.
Mechanical forces are well known for modulating heart valve developmental programs. Yet, it is still unclear how genetic programs and mechanosensation interact during heart valve development. Here, we assessed the mechanosensitive pathways involved during zebrafish outflow tract (OFT) valve development in vivo. Our results show that the hippo effector Yap1, Klf2, and the Notch signaling pathway are all essential for OFT valve morphogenesis in response to mechanical forces, albeit active in different cell layers. Furthermore, we show that Piezo and TRP mechanosensitive channels are important factors modulating these pathways. In addition, live reporters reveal that Piezo controls Klf2 and Notch activity in the endothelium and Yap1 localization in the smooth muscle progenitors to coordinate OFT valve morphogenesis. Together, this work identifies a unique morphogenetic program during OFT valve formation and places Piezo as a central modulator of the cell response to forces in this process.


Self-regulatory ability, fatigue, and the experience of pain: Mechanistic insights from pain-free undergraduates.
Self-regulatory (SR) ability is an important resource for managing pain, but chronic pain patients experience chronic self-regulatory fatigue even when they are not in pain. Pressure pain thresholds (PPT) and pain inhibition are two mechanisms that differentiate people with and without chronic pain. It was hypothesized that trait SR ability would be associated with higher PPT and better pain inhibition and that PPT and pain inhibition would be lower following high versus low SR fatigue. Three studies tested these hypotheses. Study 1 had 240 pain-free undergraduates complete measures of trait SR ability and PPT; 122 also provided data on pain inhibition. Study 2 had 38 of Study 1's participants return for two additional sessions in which they underwent PPT testing under conditions of high or low SR fatigue (within-person, counterbalanced). Study 3 repeated these procedures with pain inhibition as the outcome (n = 39). Results revealed that individual differences in SR ability were not associated with PPT or pain inhibition (all ps > 0.05). Within people, neither PPT (F(1, 36) = 1.57, p = 0.22) nor pain inhibition (F(1, 37) = 1.79, p = 0.19) were significantly different under conditions of low versus high SR fatigue. Results do not support the hypotheses that PPT or pain inhibition associate with individual differences in trait SR ability or transient changes in state SR fatigue in the absence of pain. Instead, the SR deficits in chronic pain patients may arise from the experience of chronic pain.


Outcomes of coronal pulpotomy on permanent first molars in children: a retrospective cohort study.
To investigate the survival probability of permanent first molars (PFMs) after coronal pulpotomy (CP) using two outcome definitions: success-focused and functional survival-focused, and to identify factors influencing tooth survival. A retrospective cohort study reviewing records of children undergoing CP with calcium silicate-based cements (CSCs) on PFMs. Each CP-treated PFM was classified as success, uncertain, failure, or censored. Survival probability was analyzed using Kaplan-Meier estimators. Success-focused definition considered failures and uncertain outcomes as events, while functional survival-focused definition considered only failures as events. Prognostic factors were analyzed using Cox regression analysis. Seventy-seven CP-treated PFMs with a follow-up period of 6-111 months. Using the success-focused definition (two failures and 12 uncertain outcomes as events), survival probabilities were 93.1% (95% CI 84.3-97.1%) at 12 months, 78.7% (95% CI 65.6-87.3%) at 36 months, and 74.9% (95% CI 59.5-89.0%) at 60-111 months. However, with the functional survival-focused definition, survival probabilities were 100% at 12 months and 96.6% (95% CI 86.9-99.1%) at 24-111 months. In multivariable analysis, proximal lesions increased failure risk compared to occlusal lesions (HR 17.17, 95% CI 2.18-135.31, p < 0.01), and resin composite restorations had higher failure risk than stainless steel crowns (HR 13.97, 95% CI 1.49-130.69, p < 0.05). CP using CSCs shows long-term survival potential as an alternative treatment for cariously exposed PFMs in children. Proximal lesions and resin composite restoration could contribute to the lower survival, indicating the need for careful consideration of restoration options and lesion location during treatment planning.


Production of Polyhydroxybutyrate (PHB) and Factors Impacting Its Chemical and Mechanical Characteristics.
Plastic pollution is fueling the grave environmental threats currently facing humans, the animal kingdom, and the planet. The pursuit of renewable resourced biodegradable materials commenced in the 1970s with the need for carbon neutral fully sustainable products driving important progress in recent years. The development of bioplastic materials is highlighted as imperative to the solutions to our global environment challenges and to the restoration of the wellbeing of our planet. Bio-based plastics are becoming increasingly sustainable and are expected to substitute fossil-based plastics. Bioplastics currently include both, nondegradable and biodegradable compositions, depending on factors including the origins of production and post-use management and conditions. Among the most promising materials being developed and evaluated is polyhydroxybutyrate (PHB), a microbial bioprocessed polyester belonging to the polyhydroxyalkanoate (PHA) family. This biocompatible and non-toxic polymer is biosynthesized and accumulated by a number of specialized bacterial strains. The favorable mechanical properties and amenability to biodegradation when exposed to certain active biological environments, earmark PHB as a high potential replacement for petrochemical based polymers such as ubiquitous high density polyethylene (HDPE). To date, high production costs, minimal yields, production technology complexities, and difficulties relating to downstream processing are limiting factors for its progression and expansion in the marketplace. This review examines the chemical, mechanical, thermal, and crystalline characteristics of PHB, as well as various fermentation processing factors which influence the properties of PHB materials.


Association between the Phe206Leu polymorphism of L-selectin and brucellosis.
Brucellosis remains a major zoonosis worldwide; therefore, better understanding of its immunology is a priority for the development of new therapeutic and vaccination strategies. Genetic factors appear to have an important role in the pathogenesis of infectious diseases such as brucellosis. Adhesion molecules, such as members of the selectin family, participate in the interaction between leukocytes and the endothelium, as well as in inflammatory cell recruitment. The impact of L-selectin polymorphisms on brucellosis has not so far been investigated. The aim of this study was to assess an L-selectin Phe206Leu (F206L) polymorphism in patients with active brucellosis, and to analyse its possible relationship with disease progression. A case-control association study was carried out on 619 subjects, including 374 patients with brucellosis and 245 age- and sex-matched healthy controls. Genomic DNA was isolated, and amplification of L-selectin genomic regions was performed by PCR incorporating sequence-specific primers (PCR-SSP) to distinguish the genotypes. The frequencies of the F206L polymorphism were studied. A significant difference in F206L polymorphism was found between patients with brucellosis and controls. The 206Leu allele was more frequent in patients than in healthy individuals (36.6 versus 28 %, P=0.003). In addition, there was an association between the presence of the 206Leu allele and a relapse of brucellosis (odds ratio 6.53, 95 % confidence interval 1.5-28.8, P=0.005). The higher frequency of L-selectin genotypes in patients with brucellosis than in control individuals, as well as the association between the 206Leu allele and the occurrence of brucellosis relapse, suggest that the F206L polymorphism could make individuals more vulnerable to brucellosis.


Effects of Kynurenine Pathway Metabolites on Intracellular NAD Synthesis and Cell Death in Human Primary Astrocytes and Neurons.
The kynurenine pathway (KP) is a major route of L-tryptophan catabolism resulting in the production of the essential pyridine nucleotide nicotinamide adenine dinucleotide, (NAD(+)). Up-regulation of the KP during inflammation leads to the release of a number of biologically active metabolites into the brain. We hypothesised that while some of the extracellular KP metabolites may be beneficial for intracellular NAD(+) synthesis and cell survival at physiological concentrations, they may contribute to neuronal and astroglial dysfunction and cell death at pathophysiological concentrations. In this study, we found that treatment of human primary neurons and astrocytes with 3-hydroxyanthranilic acid (3-HAA), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and picolinic acid (PIC) at concentrations below 100 nM significantly increased intracellular NAD(+) levels compared to non-treated cells. However, a dose dependent decrease in intracellular NAD(+) levels and increased extracellular LDH activity was observed in human astrocytes and neurons treated with 3-HAA, 3-HK, QUIN and PIC at concentrations >100 nM and kynurenine (KYN), at concentrations above 1 μM. Intracellular NAD(+) levels were unchanged in the presence of the neuroprotectant, kynurenic acid (KYNA), and a dose dependent increase in intracellular NAD(+) levels was observed for TRP up to 1 mM. While anthranilic acid (AA) increased intracellular NAD(+) levels at concentration below 10 μM in astrocytes. NAD(+) depletion and cell death was observed in AA treated neurons at concentrations above 500 nM. Therefore, the differing responses of astrocytes and neurons to an increase in KP metabolites should be considered when assessing KP toxicity during neuroinflammation.


Spontaneous renal infarction due to polyarteritis nodosa. A case report.
A case of spontaneous infarction of the kidney due to polyarteritis nodosa of the vasa vasorum of the right main renal artery is reported. The diagnosis was unsuspected until histological examination of a nephrectomy specimen revealed the typical vascular changes in the renal arterial wall.


Vinca alkaloid skin toxicity: antidote and drug disposition studies in the mouse.
A murine (BALB/c) skin toxicity model was used to evaluate various possible antagonists to vinca alkaloid-induced skin ulceration. Reproducible dose-response relationships were developed for vinblastine (VBL) and vindesine (VDS). With vincristine (VCR) only about 70% of mice developed dose-dependent ulceration. On an equal weight basis, VCR proved to be significantly more toxic than either VBL or VDS (P less than .05 by Student's t-test). Effective local intradermal antidotes to VBL, VDS, and VCR included hyaluronidase, normal saline, and calcium leucovorin (P less than .05 by the Student's Newman-Keuls multiple range test). Mild, topical skin heating significantly reduced VCR ulceration. In contrast, diphenhydramine and sodium bicarbonate were ineffective as local antidotes. Topical skin cooling, however, significantly increased vinca-induced skin ulcers for VBL, VDS, and VCR (P less than .05). Hydrocortisone, vitamin A topical cream, and isoproterenol increased skin toxicity. [3H]VBL was given intradermally to follow the drug's pharmacokinetic disposition from the skin and adherent panniculus carnosus muscle. [3H]VBL exhibited two phases of elimination: a rapid early phase [half-life (t 1/2) of approximately equal to 30 min] and a prolonged terminal phase (t 1/2 of approximately equal to 17 hr). The application of heat increased the distributive, early phase by 0.5-2.5 hours and did not enhance the terminal elimination of the drug from skin. Intradermal hyaluronidase significantly reduced the area under the ulceration multiplied by the time curve to one-seventh the control value, the peak [3H]VBL skin concentration to one-half the control value and the terminal [3H]VBL t 1/2 in skin to one-third the control level (P less than .05 by Student's t-test). These results show hyaluronidase to be an effective antidote for vinca-induced skin ulceration. Local glucocorticosteroids and topical cooling are definitely contraindicated in the management of inadvertent vinca alkaloid extravasations.


Aldosterone antagonism and congestive heart failure: a new look at an old therapy.
More than 5 million people in the United States alone have congestive heart failure, and an estimated 40 million have established risks and warrant therapy. Mineralocorticoid antagonists have emerged as a new paradigm for the treatment of congestive heart failure. They have established benefits among patients with chronic symptomatic systolic dysfunction, and recent studies have demonstrated substantial effect on the morbidity and mortality among patients with heart failure after myocardial infarction. The exact biologic mechanism is thus far unknown. Within the last 5 years, efforts have intensified to help define better the biologic mechanisms by which mineralocorticoid receptor antagonisms exert the observed clinical benefit. Elegant human studies have demonstrated some important observations. First, under conditions of increased plasma aldosterone concentrations, the heart will extract aldosterone. Second, aldosterone extraction in the heart stimulates increased collagen turnover culminating in ventricular remodeling. Third, among people with chronic systolic or diastolic heart failure, aldosterone is actually produced and secreted by the heart. Finally, antagonism of the mineralocorticoid receptor will attenuate or abrogate many of these deleterious effects. Combined clinical and detailed mechanistic investigations have established mineralocorticoid receptor antagonism as the new treatment paradigm for congestive heart failure. Recent clinical data have demonstrated that treatment of patients with a combination of mineralocorticoid receptor antagonism (eplerenone) and angiotensin converting enzyme-inhibitor (ACE-I) results in substantial reduction in left ventricular mass. Furthermore, a federally funded initiative to treat more than 6000 patients with diastolic heart failure with spironolactone is in its final phases of planning. It is foreseeable that, along with ACE-I and beta-blockers, mineralocorticoid receptor antagonism will become part of the treatment paradigm for people across the entire spectrum of cardiovascular disease.


Functional recovery of the developing rat ovary after transplantation: contribution of the extrinsic innervation.
These experiments were undertaken to define the neuroendocrine mechanisms underlying the recovery of ovarian function after transplantation to an ectopic site. Both ovaries from 23-day-old rats were transplanted to the region of the neck, next to the jugular vein. Serum gonadotropin and plasma immunoreactive inhibin-alpha levels were determined at several intervals thereafter. Serum estradiol (E2) was measured during the first week posttransplantation. Reinnervation of the ovary by sympathetic and sensory nerves was monitored by immunohistochemistry. Sympathetic nerves were identified as adrenergic by the presence of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, and as peptidergic, by their neuropeptide-Y (NPY) or vasoactive intestinal peptide (VIP) immunoreactivity. Sensory nerves were identified by the presence of substance P (SP) and calcitonin-gene related peptide (CGRP) immunoreactivity. Serum LH and FSH increased, and plasma inhibin levels decreased, within 48 h after transplantation. Serum LH reached maximum levels on day 4, decreasing rapidly thereafter to basal values by day 6. These changes were functionally correlated with the posttransplantation fluctuations in serum E2, which decreased at 48 h, rebounded by day 4, and returned to basal values on day 7. Removal of the transplanted ovaries on day 3 resulted in the disappearance of serum E2 levels on day 4, thus confirming the ovarian graft as the source of E2. In contrast to LH, serum FSH remained significantly elevated for at least 3 weeks after transplantation, then decreased to basal levels after day 21, coinciding with the rise in inhibin secretion. Although a substantial loss of follicles was noted 48 h after transplantation, quantitative examination of the changes on day 4 revealed that approximately 40% of antral follicles were not necrotic. Ovulation and formation of corpora lutea were noted 21 days after transplantation. Reinnervation of the transplanted ovary by TH-, VIP-, NPY-, SP-, and CGRP-containing fibers was first detected 7 days after transplantation. Although VIP reinnervation was sparse and only transiently detected (days 7-21), the density of sympathetic (TH, NPY) and sensory (SP, CGRP) fibers increased 2- to 3-fold between days 7-28, remaining unchanged thereafter. Since apparent completion of this reinnervation coincided with reestablishment of normal levels of both LH and FSH, an additional experiment was performed to determine if the two events were causally related.(ABSTRACT TRUNCATED AT 400 WORDS)


Implant Porosity and the Foreign Body Response.
The biocompatibility of prosthetic mesh is dependent on a number of physicochemical properties that ultimately incite an optimal foreign body response. The magnitude and character of the foreign body response directly affect the clinical success of the hernia repair, with too little scar resulting in bulge or hernia recurrence and too much scar causing mesh wrinkling and pain. Moreover, it is important to consider the effect of a sustained foreign body response and scar remodeling on the combined strength of the mesh-tissue construct over time. Understanding key elements that determine the foreign body response, such as implant porosity, surface area, and filament size, is critical to the performance of surgery. New absorbable materials introduce the additional variable of durability and persistence of the foreign body response after the foreign body itself has dissolved. In this review, we discuss the experimental and clinical literature relating the quality of the foreign body response to the physical attributes of implants in an effort to demystify prosthetic mesh selection.


Manipulating orbital angular momentum of light with tailored in-plane polarization states.
Generally, polarization and phase are considered as two relatively independent parameters of light, and show little interaction when a light propagates in a homogeneous and isotropic medium. Here, we reveal that orbital angular momentum (OAM) of an optical vortex beam can be modulated by specially-tailored locally linear polarization states of light under a tightly-focusing conditon. We perform both theoretical and experimental studies of this interaction between vortex phase and vector polarization, and find that an arbitrary topological charge value of OAM can be achieved in principle through vector polarization modulation, in contrast to the spin-orbital conversion that yields only the ± ћ OAM values through circular polarization. We verify the modulation of optical OAM state with vector beams by observing the orbital rotation of trapped particles.


A lipid nanoparticle platform for mRNA delivery through repurposing of cationic amphiphilic drugs.
Since the recent clinical approval of siRNA-based drugs and COVID-19 mRNA vaccines, the potential of RNA therapeutics for patient healthcare has become widely accepted. Lipid nanoparticles (LNPs) are currently the most advanced nanocarriers for RNA packaging and delivery. Nevertheless, the intracellular delivery efficiency of state-of-the-art LNPs remains relatively low and safety and immunogenicity concerns with synthetic lipid components persist, altogether rationalizing the exploration of alternative LNP compositions. In addition, there is an interest in exploiting LNP technology for simultaneous encapsulation of small molecule drugs and RNA in a single nanocarrier. Here, we describe how well-known tricyclic cationic amphiphilic drugs (CADs) can be repurposed as both structural and functional components of lipid-based NPs for mRNA formulation, further referred to as CADosomes. We demonstrate that selected CADs, such as tricyclic antidepressants and antihistamines, self-assemble with the widely-used helper lipid DOPE to form cationic lipid vesicles for subsequent mRNA complexation and delivery, without the need for prior lipophilic derivatization. Selected CADosomes enabled efficient mRNA delivery in various in vitro cell models, including easy-to-transfect cancer cells (e.g. human cervical carcinoma HeLa cell line) as well as hard-to-transfect primary cells (e.g. primary bovine corneal epithelial cells), outperforming commercially available cationic liposomes and state-of-the-art LNPs. In addition, using the antidepressant nortriptyline as a model compound, we show that CADs can maintain their pharmacological activity upon CADosome incorporation. Furthermore, in vivo proof-of-concept was obtained, demonstrating CADosome-mediated mRNA delivery in the corneal epithelial cells of rabbit eyes, which could pave the way for future applications in ophthalmology. Based on our results, the co-formulation of CADs, helper lipids and mRNA into lipid-based nanocarriers is proposed as a versatile and straightforward approach for the rational development of drug combination therapies.


Gas kinetic flux solver based high-order finite-volume method for simulation of two-dimensional compressible flows.
In this work, a high-order gas kinetic flux solver (GKFS) is developed for simulation of two-dimensional (2D) compressible flows. Different from the conventional gas kinetic scheme, which uses the local integral solution to the Boltzmann equation to reconstruct the numerical fluxes of macroscopic governing equations, the GKFS evaluates the numerical fluxes by the local asymptotic solution to the Boltzmann equation. This local asymptotic solution consists of the equilibrium distribution function and its substantial derivative at the cell interface. To achieve high-order accuracy in the simulation, the substantial derivative is discretized by a difference scheme with second-order accuracy in time and fourth-order accuracy in space, which results in a polynomial of the equilibrium distribution function at different locations and time levels. The Taylor series expansion is then introduced to simplify this polynomial. As a result, a simple high-order accurate local asymptotic solution to the Boltzmann equation is obtained and the numerical fluxes of macroscopic governing equations are given explicitly. A series of numerical examples are presented to validate the accuracy and capability of the developed high-order GKFS. Numerical results demonstrate that the high-order GKFS can achieve the desired accuracy on both the quadrilateral mesh and the triangular mesh and it outperforms the second-order counterpart.


Methanol and formic acid toxicity: biochemical mechanisms.
Metabolism of methanol, methyl ethers, esters and amides give rise to formic acid. This acid is an inhibitor of the mitochondrial cytochrome oxidase causing histotoxic hypoxia. Formic acid is a weaker inhibitor than cyanide and hydrosulphide anions. The body burden of formate in methanol poisoning is high enough to cause acidosis, and other clinical symptoms. Part of the protons can be attributed to formic acid whereas the most significant acid load results from the hypoxic metabolism. The acidosis causes e.g. dilatation of cerebral vessels, facilitation of the entry of calcium ions into cells, loss of lysosomal latency and deranged production of ATP. The latter effect seems to impede parathormone-dependent calcium reabsorption in the kidney tubules. Besides, urinary acidification is affected by formic acid. Its excretion causes continuous recycling of the acid by the tubular cell Cl-/formate exchanger. This sequence of events may partially explain an accumulation of formate in urine. Occupational exposure to vapours of methanol and formic acid can be quantitatively monitored by urinary formic acid determinations. Formic acid toxicity may prove a suitable model for agents causing histotoxic hypoxia.


The Short-run and Long-run Effects of Covid-19 on Energy and the Environment.
Kenneth Gillingham is an Associate Professor of Economics at Yale University, with a primary appointment in the School of Forestry & Environmental Studies. In 2015 to 2016, he served as the Senior Economist for Energy and the Environment at the White House Council of Economic Advisers. His research interests cover energy and environmental economics, industrial organization, technological change, and energy modeling. He held a Fulbright to New Zealand and has worked for Resources for the Future and Pacific Northwest National Laboratory. He received a PhD and two MS degrees from Stanford University and an AB from Dartmouth College. Christopher Knittel is the George P. Shultz Professor of Applied Economics in the Sloan School of Management at the Massachusetts Institute of Technology (MIT). He is also the Director of MIT's Center for Energy and Environmental Policy Research, which serves as the hub for social science research on energy and the environmental since the late 1970s. Professor Knittel is also the Co-Director of the MIT Energy Initiative's Electric Power System Low Carbon Energy Center and a co-director of The E2e Project, a research initiative between MIT, UC Berkeley, and the University of Chicago to undertake rigorous evaluation of energy efficiency investments. Jing Li holds the inaugural William Barton Rogers Career Development Chair of Energy Economics at the MIT Sloan School of Management. From 2017-2018, Jing Li was a Postdoctoral Associate of the MIT Energy Initiative. Jing's research interests lie in energy economics and industrial organization, focusing on development and adoption of new technologies. Her most recent work examines compatibility and investment in electric vehicle recharging networks in the United States and cost pass-through in the E85 retail market. Jing received double BSc degrees in Mathematics and Economics from MIT in 2011 and her PhD in Economics from Harvard in 2017. Marten Ovaere is a Postdoctoral Associate in the School of Forestry & Environmental Studies of Yale University. His research interests lie in energy and environmental economics, with a focus on electricity markets, carbon pricing, and renewable energy. Marten holds a MSc in Economics, a MSc in Energy Engineering, and a PhD in Economics from KU Leuven. Mar Reguant is an Associate Professor in Economics at Northwestern University. She received her PhD from MIT in 2011. Her research uses high-frequency data to study the impact of auction design and environmental regulation on electricity markets and energy-intensive industries. She has numerous awards, including a Sloan Research Fellowship in 2016, the Sabadell Prize for Economic Research in 2017, a Presidential Early Career Award for Scientists and Engineers award in 2019, and the European Association of Environmental and Resource Economists Award for Researchers in Environmental Economics under the Age of Forty in 2019.


Lateral Transorbital Versus Endonasal Transpterygoid Approach to the Lateral Recess of the Sphenoid Sinus-A Comparative Anatomic Study.
The treatment of cerebrospinal fluid leaks of the lateral recess of the sphenoid sinus (LRSS) faces difficulties due to the deep location of the osseous defect. When treated with craniotomies, brain retraction is a concern. The endoscopic endonasal transpterygoid approach (EETA) is a direct and less invasive procedure; however, it may require transection of the vidian nerve (VN). To investigate the feasibility of a lateral transorbital approach (LTOA) as an alternative pathway to the LRSS that avoids VN sacrifice. Six embalmed heads with well-pneumatized LRSS were preselected by inspecting their computed tomography scans. One LTOA and one EETA were performed on 1 side of each specimen. The approaches were compared regarding working distance and neurovascular structures being sacrificed. The working area of the LTOA was also measured. The average working distances were 59.9 (±2.94) mm for the LTOA and 76.4 (±3.99) mm for the EETA (P < .001). The LTOA generated a working area with a diameter of 9 to 14 mm. The EETA demanded the sacrifice of VN and the sphenopalatine artery in all specimens to expose the LRSS. No neurovascular structures were found in the trajectory of the LTOA. The LTOA to the LRSS is feasible, with minimal risk of injuring neurovascular structures. It offers a shorter pathway when compared to the EETA. Although the LTOA provides no options for vascularized flap reconstruction, it allows immediate access to muscle grafts. The LTOA may serve as an alternative to treating cerebrospinal fluid leaks of the LRSS.


Prognostic value of prechemotherapy skin tests in patients with metastatic breast carcinoma.
Two hundred patients with metastatic breast cancer who were treated with combination chemotherapy and nonspecific immunotherapy with BCG or MER were skin tested prior to, and at regular intervals during the administration of chemotherapy with a battery of six antigens (Dermatophytin, Varidase, candida, mumps, PPD, and KLH). Delayed-type hypersensitivity responses to this battery of antigens were analyzed to assess whether they correlated with ability to respond to chemotherapy, length of survival, and a number of other host and tumor characteristics of known prognostic significance. Responsiveness to individual recall antigens or the number of positive skin test responses did not correlate with overall or complete response rates. The correlation did exist with KLH, a primary antigen. A positive response to two or more antigens correlated with a longer survival. Inability to mount a skin test response to any antigen correlated with poor survival. PPD conversions during serial BCG administration did not correlate with a better prognosis. Serial skin testing with a battery of antigens did not correlate with prognosis. Skin test responsiveness to the antigens used in this study did not correlate with the other pretreatment factors of prognostic importance such as tumor burden, absolute lymphocyte count, performance status, prior radiation therapy, menopausal status, and age. Therefore, responsiveness to skin testing with these antigens appears to be an independent prognostic variable and should be incorporated in the planning and analysis of systemic treatment programs in metastatic breast cancer.


Inner medullary hemodynamics in dogs with aortocaval fistula.
To investigate the role of medullary hemodynamics and vasoactive hormones in sodium retention in dogs with aortocaval fistula, we examined papillary plasma flow (PPF), solute content, and renal output of renin, norepinephrine, and prostaglandin E2 (PGE2) in anesthetized normal and fistula dogs. During hydropenia, cardiac output was elevated and systemic vascular resistance reduced in fistula dogs, accompanied by markedly increased renal output of renin, norepinephrine, and PGE2. In fistula dogs the blunted diuretic and natriuretic response to saline loading was not due to impaired myocardial contractility. During hydropenia and after saline loading, glomerular filtration rate (GFR) and renal blood flow were similar in normal and in fistula dogs; however, PPF was significantly lower in fistula dogs, accompanied by significantly greater papillary tissue osmolality and sodium content. These findings indicate that in fistula dogs enhanced medullary sodium reabsorption is associated with decreased PPF and stimulation of the renin-angiotensin and adrenergic nervous system. Furthermore, the reduced PPF obviates medullary solute washout during saline loading, and may contribute to the blunted diuretic and natriuretic response.


Mandatory disclaimers on dietary supplements do not reliably communicate the intended issues.
Some efforts by the government to regulate the promotional statements of pharmaceutical manufacturers have recently been found unconstitutional under the First Amendment, which has been interpreted to protect commercial as well as personal speech. As an alternative means of protecting patients from unreliable marketing claims, courts have proposed that the Food and Drug Administration could add disclaimers to promotional messages that discuss off-label, or unapproved, uses. We conducted a systematic review of studies of the disclaimers currently required for dietary supplements, to assess how well disclaimers inform consumers' health choices. A few small studies reported a modest impact of disclaimers on consumers' attitudes about dietary supplements, but larger and more rigorous studies generally revealed that many consumers were unaware of a disclaimer or reported that it did not affect their perceptions of a product. The available evidence indicates that replacing government restrictions on pharmaceutical marketing with potentially ineffective disclaimers will be an inadequate way of informing patients about the efficacy and safety of drugs, and it risks returning the United States to a previous era when inappropriate marketing claims about prescription drugs proliferated and contributed to the inappropriate use of those products.


Aedes albopictus infection by the native bacterium Elizabethkingia anophelis in Southern Mexico.
To evaluate the presence of Elizabethkingia anophelis infection in Aedes albopictus wild populations of Southern Mexico. Eight sites were selected to collect Aedes albopictus in the Soconusco region, Chiapas, females were analyzed to amplify the Gyrase B gene by PCR, the minimum infection rate of E. anopheliswas calculated and its species was determined by sequencing and phylogeny. The presence of E. anophelis was only observed in Huehuetán with a minimum infection rate of 37.8%. A local strain of E. anophelis was detected for the first time in Ae. albopictus from Chiapas and this bacterium could be considered a candidate for study as a probable control agent or as a vehicle for transgenesis.


Pulse width dependent increase in the pacemaker automatic interval.
From a total of 51 patients equipped with rate and pulse width adjustable pulse generators (Microlith-P 0505, Microthin-PI 0522) implanted over the last 3 years, 10 (19.6%) showed an unexpected drop in pacemaker pulse rate during pulse width programming. For one of the pulse generators used (Microthin-PI 0522), unexpected rate decrease occurred in 7/13 cases (53.8%). For all except one patient, decrease in pacemaker pulse rate corresponded with the total refractory period of the pulse generator ( 320 ms), at a certain pulse width when rate drop first occurred. In seven of the patients the pulse generator automatic interval was extended from 13 ms to 171 ms beyond the refractory period. In two patients it was necessary to replace the pulse generators. Our study strongly proves that this abnormal pacemaker functioning is a result of sensing of the polarization voltage at the pacemaker electrode/tissue interface and/or the T-wave. The polarization voltage is highly dependent on the total pacemaker electrode/tissue interface impedance. Using typical values for pulse generator output and input resistance and output capacitance, Faraday resistance, Helmholtz capacitance and tissue resistance at the electrode/tissue interface it was shown mathematically that in some cases the polarization voltage alone would be of sufficient amplitude and slew rate for pacemaker inhibition. The study demonstrates an urgent need for change in the filter characteristics by making the pulse generators less sensitive in the low frequency region and reducing the polarization voltage by reducing the output circuit capacitance.


Role for Plk1 phosphorylation of Hbo1 in regulation of replication licensing.
In a search for Polo-like kinase 1 (Plk1)-interacting proteins using a yeast two-hybrid system, we have identified histone acetyltransferase binding to the origin recognition complex 1 (Hbo1) as a potential Plk1 target. Here, we show that the interaction between Plk1 and Hbo1 is mitosis-specific and that Plk1 phosphorylates Hbo1 on Ser-57 in vitro and in vivo. During mitosis, Cdk1 phosphorylates Hbo1 on Thr-85/88, creating a docking site for Plk1 to be recruited. Significantly, the overexpression of Hbo1 mutated at the Plk1 phosphorylation site (S57A) leads to cell-cycle arrest in the G1/S phase, inhibition of chromatin loading of the minichromosome maintenance (Mcm) complex, and a reduced DNA replication rate. Similarly, Hbo1 depletion results in decreased DNA replication and a failure of Mcm complex binding to chromatin, both of which can be partially rescued by the ectopic expression of WT Hbo1 but not Hbo1-S57A. These results suggest that Plk1 phosphorylation of Hbo1 may be required for prereplicative complex (pre-RC) formation and DNA replication licensing.


Pediatric obstructive sleep apnea: complications, management, and long-term outcomes.
Obstructive sleep apnea (OSA) in children has emerged not only as a relatively prevalent condition but also as a disease that imposes a large array of morbidities, some of which may have long-term implications, well into adulthood. The major consequences of pediatric OSA involve neurobehavioral, cardiovascular, and endocrine and metabolic systems. The underlying pathophysiological mechanisms of OSA-induced end-organ injury are now being unraveled, and clearly involve oxidative and inflammatory pathways. However, the roles of individual susceptibility (as dictated by single-nucleotide polymorphisms), and of environmental and lifestyle conditions (such as diet, physical, and intellectual activity), may account for a substantial component of the variance in phenotype. Moreover, the clinical prototypic pediatric patient of the early 1990s has been insidiously replaced by a different phenotypic presentation that strikingly resembles that of adults afflicted by the disease. As such, analogous to diabetes, the terms type I and type II pediatric OSA have been proposed. The different manifestations of these two entities and their clinical course and approaches to management are reviewed.


Isolation of a cDNA coding for L-galactono-gamma-lactone dehydrogenase, an enzyme involved in the biosynthesis of ascorbic acid in plants. Purification, characterization, cDNA cloning, and expression in yeast.
L-Galactono-gamma-lactone dehydrogenase (EC 188.8.131.52; GLDase), an enzyme that catalyzes the final step in the biosynthesis of L-ascorbic acid was purified 1693-fold from a mitochondrial extract of cauliflower (Brassica oleracea, var. botrytis) to apparent homogeneity with an overall yield of 1.1%. The purification procedure consisted of anion exchange, hydrophobic interaction, gel filtration, and fast protein liquid chromatography. The enzyme had a molecular mass of 56 kDa estimated by gel filtration chromatography and SDS-polyacrylamide gel electrophoresis and showed a pH optimum for activity between pH 8.0 and 8.5, with an apparent Km of 3.3 mM for L-galactono-gamma-lactone. Based on partial peptide sequence information, polymerase chain reaction fragments were isolated and used to screen a cauliflower cDNA library from which a cDNA encoding GLDase was isolated. The deduced mature GLDase contained 509 amino acid residues with a predicted molecular mass of 57,837 Da. Expression of the cDNA in yeast produced a biologically active protein displaying GLDase activity. Furthermore, we identified a substrate for the enzyme in cauliflower extract, which co-eluted with L-galactono-gamma-lactone by high-performance liquid chromatography, suggesting that this compound is a naturally occurring precursor of L-ascorbic acid biosynthesis in vivo.


Methamphetamine toxicity: treatment with a benzodiazepine versus a butyrophenone.
Patients with methamphetamine toxicity often present to the emergency department (ED) agitated, violent and psychotic. To determine the efficacy of a benzodiazepine versus a butyrophenone for chemical restraint we conducted a prospective, randomized study at a large urban university ED between January 1995 and January 1997. Patients were randomized to receive either lorazepam or droperidol intravenously. A 6-point sedation scale was devised, with 6 representing extreme agitation and 1 deep sleep. Sedation scores were recorded at time 0, 5, 10, 15, 30 and 60 min. Vital signs were recorded at time 0 and at 60 min. If sedation was inadequate, repeat dosages of each drug could be repeated at 30 min. Toxicology screen, ethanol and creatinine phosphokinase levels were obtained. A total of 146 patients were evaluated. Seventy-four patients received lorazepam and 72 received droperidol. Both drugs had similar sedation profiles at 5 min. Patients receiving droperidol had significantly improved sedation scores at times 10, 15, 30 and 60 min than lorazepam (p < 0.001). More repeat doses of lorazepam were given (26) than droperidol (6) at 30 min. Both drugs produced significant reduction in pulse, systolic blood pressure, respiratory rate, and temperature over 60 min. We conclude droperidol produces a more rapid and profound sedation than lorazepam for methamphetamine toxicity. Lorazepam is more likely to require repeat dosing than droperidol.


Changing practice patterns in the management of primary breast cancer: Consensus Development Program.
In the last decade, new knowledge has emerged concerning the efficacy of treatment for breast cancer. For that reason, the National Institutes of Health devoted a consensus conference to this topic. To determine whether the consensus conference had influenced practice patterns, and to evaluate the level of quality of care given to women with breast cancer, the medical records of 573 patients treated in ten hospitals throughout the state of Washington were abstracted and analyzed. Results showed no changes with respect to the consensus conference's recommendations for use of a total mastectomy with axillary dissection or the use of a two-step procedure in which the biopsy is performed first and therapeutic options are discussed before a definitive surgery is undertaken. Analyses of quality of care issues not addressed by the consensus conference revealed that 4 percent of the sample were explicitly staged preoperatively and 29 percent postoperatively and that little changed over time in the use of sentinel laboratory tests. These results also show that consensus recommendations will not necessarily change physicians' behavior even where change is possible, and that quality of care in diagnosis and treatment of breast cancer still needs to be addressed.