Proprioception 2.0: novel functions for muscle spindles.
Muscle spindles are encapsulated mechanosensory receptors within skeletal muscle tissue that inform the central nervous system about the contractile status of each muscle. This information is required for any coordinated movement and for stable posture. This review summarizes recent findings regarding novel functions for proprioceptive feedback information, muscle spindle disease and the molecular basis of mechanoreception. Muscle spindle function is not limited to regulating motor control but is also required for appropriate realignment of fractured bones, successful regeneration of spinal cord axons after injury and spinal alignment. Several proteins responsible for or modulating mechanotransduction in proprioceptive sensory neurons have been identified, including the Piezo2 channel as a candidate for the principal mechanotransduction channel. Many neuromuscular diseases are known to be accompanied by an impaired function of muscle spindles, resulting in a decline of motor performance and coordination in the patients. Our knowledge regarding the molecular basis of muscle spindle function is still incomplete. However, increasing our understanding of mechanotransduction in muscle spindles is a prerequisite for finding appropriate strategies to prevent injuries due to unstable gait and frequent falls.


[Leprechaunism (Donohue's syndrome). Clinical and pathologico-anatomical findings].
Leprechaunism is a very rare condition of obscure aetiology. At the age of three weeks the neonate described in this report lost all subcutaneous fat in spite of additional parenteral nutrition. He acquired purulent pneumonia, and finally died of septicaemia. The typical stigmata were a prominent nose, broad mouth with putty lips, and large, hypertrophic , backwards rotated ears, cutis laxa, atrophy of adipose tissue and gynaecomastia with hirsutism. Since the first report (1948), 32 patients have been described in detail. Compared with these reports of dysendocrinism we observed an excessive proliferation of various tissues, e.g. of the epithelia of the epidermis, bronchi, collecting tubules of kidneys, bile-ducts, and pancreatic ducts. Moreover, almost complete atrophy of lymphoid tissue was remarkable.


[Inactivation of formaldehyde by semicarbazide in disinfectant tests with viruses].
In suspension tests with viruses formaldehyde is--even in weak concentrations--toxic for tissue cultures. Through addition of semicarbazide in a ratio of one part of 10% semicarbazide to one part of 0.7% formaldehyde, which is equivalent to a molar ratio of 3.8:1, the toxicity will be neutralized if semicarbazide is added to the tissue cultures before their being inoculated with the virus-disinfectant-mixture. In qualitative experiments the toxicity is completely neutralized, in quantitative ones it is reduced by a factor of 10 up to 100. Thus the evaluation of the virucidal capacity of disinfectants containing formaldehyde is conspicuously improved.


Design of a novel class of protein-based magnetic resonance imaging contrast agents for the molecular imaging of cancer biomarkers.
Magnetic resonance imaging (MRI) of disease biomarkers, especially cancer biomarkers, could potentially improve our understanding of the disease and drug activity during preclinical and clinical drug treatment and patient stratification. MRI contrast agents with high relaxivity and targeting capability to tumor biomarkers are highly required. Extensive work has been done to develop MRI contrast agents. However, only a few limited literatures report that protein residues can function as ligands to bind Gd(3+) with high binding affinity, selectivity, and relaxivity. In this paper, we focus on reporting our current progress on designing a novel class of protein-based Gd(3+) MRI contrast agents (ProCAs) equipped with several desirable capabilities for in vivo application of MRI of tumor biomarkers. We will first discuss our strategy for improving the relaxivity by a novel protein-based design. We then discuss the effect of increased relaxivity of ProCAs on improving the detection limits for MRI contrast agent, especially for in vivo application. We will further report our efforts to improve in vivo imaging capability and our achievement in molecular imaging of cancer biomarkers with potential preclinical and clinical applications.


[Epidemiologic study of autoimmune thyroid disease in south Tunisia].
In order to study incidence and prevalence of autoimmune thyroid diseases (AITDs), we studied a retrospective cohort of 1,079 patients explored in the department of Endocrinology of Sfax (south of Tunisia). The overall incidence of AITDs was 9.9%. Mean age was 39.6+15 years; sex ratio 5 F/1M. Graves' disease was the most frequent (45%). Atrophic thyroiditis was present in 32.2% of patients and Hashimoto's thyroiditis in 22.8%. The incidence of AITDs increased from 1990 to 2000 and by 2003 it had fallen to 67 cases per year. TPO antibody was present in two-thirds of patients with Hashimoto thyroiditis, and half of those with atrophic thyroiditis. TG antibodies were less frequent (one-third of patients). Association with other autoimmune diseases was noted in 6.3% of patients: type I diabetes mellitus, adrenal insufficiency and vitiligo. Statistic analysis did not disclose any association between autoantibody levels and thyroid dysfunction. There was an association between TG antibody and TSH levels among patients with Graves' disease and between TG antibody level and age in atrophic thyroiditis patients (p<0.05); a correlation was also noted between these antibodies and other autoimmune diseases (p=0.05). It is difficult to assess the frequency of ATD in the clinical setting. Characteristic features of AITDs in patients seen in south Tunisia were found to be similar to those described in the literature. Other more large-scale representative studies would be useful to establish the epidemiology of AITDs in Tunisia.


[Update FAST].
For many years, the FAST examination has represented the standard procedure for diagnostics in traumatology. Until just recently, the ultrasound societies in German speaking countries did not recognize this procedure, which is the reason why it has not been included in current educational programs. The acronym FAST stands for «Focused Assessment with Sonography for Trauma» and is defined as the sonographic detection of free fluid in the intraperitoneal, pleural and pericardial spaces in patients who have suffered blunt or penetrating trauma. The extension to eFAST («extended FAST») in the year 2004 to include the additional diagnosis of pneumothorax marked the beginning of the procedure's meteoric development. Nowadays, everybody is talking about FAST-plus in reference to a broad range of applications within the field of airway management, organ injury diagnostics, cerebral hypertension as well as support for invasive procedures. However, the continued rise of FAST will depend on the future role that computed tomography (CT) will be playing. Indeed, it remains unclear whether CT utilized as FACTT («Focused Assessment with Computed Tomography in Trauma») will force out FAST and advance to become the diagnostic gold standard.


Polyethylene-glycol-modified single-walled carbon nanotubes for intra-articular delivery to chondrocytes.
Osteoarthritis (OA) is a common and debilitating degenerative disease of articular joints for which no disease-modifying medical therapy is currently available. Inefficient delivery of pharmacologic agents into cartilage-resident chondrocytes after systemic administration has been a limitation to the development of anti-OA medications. Direct intra-articular injection enables delivery of high concentrations of agents in close proximity to chondrocytes; however, the efficacy of this approach is limited by the fast clearance of small molecules and biomacromolecules after injection into the synovial cavity. Coupling of pharmacologic agents with drug delivery systems able to enhance their residence time and cartilage penetration can enhance the effectiveness of intra-articularly injected anti-OA medications. Herein we describe an efficient intra-articular delivery nanosystem based on single-walled carbon nanotubes (SWCNTs) modified with polyethylene glycol (PEG) chains (PEG-SWCNTs). We show that PEG-SWCNTs are capable to persist in the joint cavity for a prolonged time, enter the cartilage matrix, and deliver gene inhibitors into chondrocytes of both healthy and OA mice. PEG-SWCNT nanoparticles did not elicit systemic or local side effects. Our data suggest that PEG-SWCNTs represent a biocompatible and effective nanocarrier for intra-articular delivery of agents to chondrocytes.


Medication-overuse headache: a worldwide problem.
Medication overuse and subsequent medication-overuse headache (MOH) is a growing problem worldwide. Epidemiological data suggest that up to 4% of the population overuse analgesics and other drugs for the treatment of pain conditions such as migraine and that about 1% of the general population in Europe, North America, and Asia have MOH. Recent clinical studies gave further insights in clinical and pharmacological features, such as critical monthly doses and frequencies. These features seem to vary significantly and depend on the primary headache disorder and the type of drug that is overused. Along with these findings the new international classification of headache disorders has now incorporated additional criteria and new headache entities that will facilitate the diagnosis of MOH. Withdrawal therapy is the only treatment for this disorder and clear restriction of monthly doses is the central requirement for successful prevention.


Bleomycin and radiotherapy in nonresectable thoracic oesophageal carcinoma.
The survival rates of nonresectable thoracic oesophageal carcinoma patients were studied in 50 patients treated by radiotherapy and by a combination of radiotherapy and bleomycin. The patients of two series were very similar. The one-year survival rates were 21 and 10 per cent, in radiotherapy and in radiotherapy with bleomycin group, respectively. In the literature, there were only few reports from survival figures of patients with oesophageal carcinoma treated with bleomycin in combination with radiotherapy. The authors concluded that the combination of bleomycin and radiotherapy has very limited effect on advanced oesophageal carcinoma. The survival rate after this combination therapy is not better with radiotherapy alone, if bleomycin and radiotherapy are used with reduced doses and without severe complications.


The cutaneous immunopathology of necrobiosis lipoidica diabeticorum.
Twelve female patients with necrobiosis lipoidica diabeticorum (six with diabetes and six without) had a 5-mm punch biopsy of the skin lesion performed. The tissue was processed for dermatopathologic examination in 12 cases and for direct immunofluorescence in 11. Vasculopathy with inflammation and thickening of vessel walls, at times leading to occlusion, was found in lesional skin in all 12 cases. Vessels contained deposits of immunoreactants in the involved skin in 11 cases. This included IgM in six, C3 in nine, fibrin in ten, IgG in one, and IgA in two. Vessels contained deposits of immunoreactants in uninvolved skin in seven patients (C3 in four, IgM in three, fibrin in three, C4 in one, and IgA in one), three of whom had type I diabetes.


Assessment of Axillary Lymph Nodes for Metastasis on Ultrasound Using Artificial Intelligence.
The purpose of this study was to evaluate an artificial intelligence (AI) system for the classification of axillary lymph nodes on ultrasound compared to radiologists. Ultrasound images of 317 axillary lymph nodes from patients referred for ultrasound guided fine needle aspiration or core needle biopsy and corresponding pathology findings were collected. Lymph nodes were classified into benign and malignant groups with histopathological result serving as the reference. Google Cloud AutoML Vision (Mountain View, CA) was used for AI image classification. Three experienced radiologists also classified the images and gave a level of suspicion score (1-5). To test the accuracy of AI, an external testing dataset of 64 images from 64 independent patients was evaluated by three AI models and the three readers. The diagnostic performance of AI and the humans were then quantified using receiver operating characteristics curves. In the complete set of 317 images, AutoML achieved a sensitivity of 77.1%, positive predictive value (PPV) of 77.1%, and an area under the precision recall curve of 0.78, while the three radiologists showed a sensitivity of 87.8% ± 8.5%, specificity of 50.3% ± 16.4%, PPV of 61.1% ± 5.4%, negative predictive value (NPV) of 84.1% ± 6.6%, and accuracy of 67.7% ± 5.7%. In the three external independent test sets, AI and human readers achieved sensitivity of 74.0% ± 0.14% versus 89.9% ± 0.06% (p = .25), specificity of 64.4% ± 0.11% versus 50.1 ± 0.20% (p = .22), PPV of 68.3% ± 0.04% versus 65.4 ± 0.07% (p = .50), NPV of 72.6% ± 0.11% versus 82.1% ± 0.08% (p = .33), and accuracy of 69.5% ± 0.06% versus 70.1% ± 0.07% (p = .90), respectively. These preliminary results indicate AI has comparable performance to trained radiologists and could be used to predict the presence of metastasis in ultrasound images of axillary lymph nodes.


Salmonella Intracellular Lifestyles and Their Impact on Host-to-Host Transmission.
More than a century ago, infections by Salmonella were already associated with foodborne enteric diseases with high morbidity in humans and cattle. Intestinal inflammation and diarrhea are hallmarks of infections caused by nontyphoidal Salmonella serovars, and these pathologies facilitate pathogen transmission to the environment. In those early times, physicians and microbiologists also realized that typhoid and paratyphoid fever caused by some Salmonella serovars could be transmitted by "carriers," individuals outwardly healthy or at most suffering from some minor chronic complaint. In his pioneering study of the nontyphoidal serovar Typhimurium in 1967, Takeuchi published the first images of intracellular bacteria enclosed by membrane-bound vacuoles in the initial stages of the intestinal epithelium penetration. These compartments, called Salmonella-containing vacuoles, are highly dynamic phagosomes with differing biogenesis depending on the host cell type. Single-cell studies involving real-time imaging and gene expression profiling, together with new approaches based on genetic reporters sensitive to growth rate, have uncovered unprecedented heterogeneous responses in intracellular bacteria. Subpopulations of intracellular bacteria displaying fast, reduced, or no growth, as well as cytosolic and intravacuolar bacteria, have been reported in both in vitro and in vivo infection models. Recent investigations, most of them focused on the serovar Typhimurium, point to the selection of persisting bacteria inside macrophages or following an autophagy attack in fibroblasts. Here, we discuss these heterogeneous intracellular lifestyles and speculate on how these disparate behaviors may impact host-to-host transmissibility of Salmonella serovars.


Obiltoxaximab: Adding to the Treatment Arsenal for Bacillus anthracis Infection.
To review the safety and efficacy of obiltoxaximab, a monoclonal antibody indicated for the treatment of Bacillus anthracis inhalational anthrax in adult and pediatric patients. A MEDLINE (1946 to May, week 1, 2017) and EMBASE (1980 to 2017, week 19) search was performed using the search terms obiltoxaximab OR ETI-204 OR Anthim AND anthrax. All English-language clinical studies in both animal and human models assessing the safety and efficacy of obiltoxaximab were included. A total of 5 articles have been published on clinical studies examining safety and efficacy of obiltoxaximab. Efficacy studies in 2 animal models, New Zealand White rabbits and cynomolgus macaques, showed higher rates of survival post-anthrax exposure when obiltoxaximab was administered. Safety studies in healthy human volunteers showed that it was tolerated, with a relatively low incidence of adverse events. Based on these clinical studies and the implausibility of conducting a trial in infected individuals, obiltoxaximab is a safe and efficacious addition to the anthrax antitoxin armamentarium to protect against and treat inhalational anthrax.


Mechanism of calcium entry during axon injury and degeneration.
Axon degeneration is a hallmark consequence of chemical neurotoxicant exposure (e.g., acrylamide), mechanical trauma (e.g., nerve transection, spinal cord contusion), deficient perfusion (e.g., ischemia, hypoxia), and inherited neuropathies (e.g., infantile neuroaxonal dystrophy). Regardless of the initiating event, degeneration in the PNS and CNS progresses according to a characteristic sequence of morphological changes. These shared neuropathologic features suggest that subsequent degeneration, although induced by different injury modalities, might evolve via a common mechanism. Studies conducted over the past two decades indicate that Ca2+ accumulation in injured axons has significant neuropathic implications and is a potentially unifying mechanistic event. However, the route of Ca2+ entry and the involvement of other relevant ions (Na+, K+) have not been adequately defined. In this overview, we discuss evidence for reverse operation of the Na+-Ca2+ exchanger as a primary route of Ca2+ entry during axon injury. We propose that diverse injury processes (e.g., axotomy, ischemia, trauma) which culminate in axon degeneration cause an increase in intraaxonal Na+ in conjunction with a loss of K+ and axolemmal depolarization. These conditions favor reverse Na+-Ca2+ exchange operation which promotes damaging extraaxonal Ca2+ entry and subsequent Ca2+-mediated axon degeneration. Deciphering the route of axonal Ca2+ entry is a fundamental step in understanding the pathophysiologic processes induced by chemical neurotoxicants and other types of nerve damage. Moreover, the molecular mechanism of Ca2+ entry can be used as a target for the development of efficacious pharmacotherapies that might be useful in preventing or limiting irreversible axon injury.


Lyssavirus in Japanese Pipistrelle, Taiwan.
A putative new lyssavirus was found in 2 Japanese pipistrelles (Pipistrellus abramus) in Taiwan in 2016 and 2017. The concatenated coding regions of the virus showed 62.9%-75.1% nucleotide identities to the other 16 species of lyssavirus, suggesting that it may be representative of a new species of this virus.


Marinobacter lipolyticus from Red Sea for lipase production and modulation of silver nanomaterials for anti-candidal activities.
In this study, the bacterial strain CEES 33 was isolated from the coastal area of the Red Sea, Jeddah, Kingdom of Saudi Arabia. The bacterium isolate was identified and characterized by using biochemical and molecular methods. The isolate CEES 33 has been identified as Gram-negative rod shaped and cream pigmented spherical colonies. It also demonstrated a positive result for nitrate reduction, oxidase, catalase, citrate utilization, lipase and exopolysaccharide production. Strain CEES 33 was characterized at the molecular level by partial 16S rRNA sequencing and it has been identified as Marinobacter lipolyticus (EMBL|LN835275.1). The lipolytic activity of the isolate was also observed 2.105 nkatml-1. Furthermore, the bacterial aqueous extract was used for green synthesis of silver nanoparticles (AgNPs), which was further confirmed by UV-visible spectra (430 nm), XRD and SEM analysis. Moreover, the biological functional group that involved in AgNPs synthesis was confirmed by FTIR spectra. The biological activities of AgNPs were also investigated, which showed a significant growth inhibition of Candida albicans with 16 ± 2 mm zone of inhibition at 10 μg dose/wells. Therefore, bacterium Marinobacter lipolyticus might be used in future for lipase production and nanoparticles fabrication for biomedical application, to control fungal diseases caused by C. albicans.


KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas.
DNAs from human pancreatic adenocarcinomas were analyzed for the presence of mutations in codons 12, 13 and 61 of the NRAS, KRAS and HRAS gene. Formalin-fixed and paraffin-embedded tissue was used directly in an in vitro amplification reaction to expand the relevant RAS sequences. The mutations were detected by selective hybridization using mutation-specific synthetic oligonucleotides. In 28 of the 30 patients we found a mutation in codon 12 of the KRAS gene. This result confirms the findings of Almoguera et al. [Cell 53 (1988) 549-554] that KRAS mutations occur frequently in adenocarcinomas of the exocrine pancreas. The mutations are predominantly G-T transversions, in contrast to the KRAS mutations in colon tumors which are mainly G-A transitions. Furthermore, in a portion of the tumors the mutation appears to be homozygous.


Isolated dissecting aneurysm of the left posterior inferior cerebellar artery: endovascular treatment with a Guglielmi detachable coil.
An isolated progressive dissecting aneurysm of the left posterior inferior cerebellar artery (PICA) associated with a persistent trigeminal artery was successfully treated by endovascular occlusion of the proximal PICA with a Guglielmi detachable coil.


Shielded ionisation discharge (SID) probe for spatiotemporal profiling of pulsed molecular beam.
Intense pulsed supersonic molecular beams are used in many applications such as tokamak fueling, edge plasma diagnostics, ion beam profile monitors, laser cluster experiments, chemical kinetics, etc. Measurement of absolute density is required to optimize beam sources used in these experiments. Absolute density measurement of a continuous molecular beam is challenging due to its small size and rarefied flow, which makes it even more difficult for a pulsed molecular beam due to its transient nature. In this work, we demonstrate a novel probe to measure the spatiotemporal evolution of the absolute number density of a pulsed supersonic molecular beam. The probe is named the Shielded Ionization Discharge probe. It measures density using localized discharge within the molecular beam created by the thermionic emission of electrons from a hot filament. We describe the design, calibration, and characterization of the developed probe. The performance of the probe is demonstrated by measuring the spatial and temporal profiles of a pulsed supersonic molecular beam of 1.5 ms duration.


Isolated tuberculosis of testis.
Isolated epididymo-orchitis is an uncommon presentation of tuberculosis. We report a case of left sided epididymo-orchitis and scrotal involvement due to tuberculosis in a young male patient. The diagnosis was suspected on clinical examination of scrotum and confirmed by FNAC of scrotal and testis. Patient improved after taking antitubercular treatment. Key words: infection, scrotum, treatment.


Naloxegol , a new drug for the treatment of opioid-induced constipation.
With increasing chronic opioid use, opioid-induced constipation (OIC) is becoming a relevant clinical challenge. Presently, only few treatments have been demonstrated to be more effective than placebo in treating OIC but most of them have a restricted clinical application because of side effects. Naloxegol , an orally administered, peripherally acting, μ-opioid receptor antagonist (PAMORA), was developed for the treatment of OIC. This review summarizes published information and presentations at meetings on the effects of naloxegol in OIC. Pharmacodynamic studies have demonstrated that naloxegol inhibits gastrointestinal opioid effects while preserving central analgesic actions. Phase II and Phase III studies in patients with non-cancer OIC have confirmed the efficacy of naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25 mg dose once daily. Adverse events were mainly gastrointestinal in origin and usually transient and mild. There were no signs of opioid withdrawal in the studies. Safety and tolerability were also shown in a long-term safety study. Regulatory authorities have recently approved the use of naloxegol in OIC. Naloxegol is the first approved, orally available PAMORA. The drug has the potential to substantially improve management of OIC patients.


Neuropsychological lateralization of brain dysfunction in children with mesial temporal sclerosis: a presurgical evaluation.
Presurgical evaluation of children with mesial temporal sclerosis has shown severe neurocognitive impairments. There is debate about lateralized material-specific deficits in memory in children with mesial temporal sclerosis. The authors examined lateralization of brain dysfunction and age appropriate development of cognitive functions in 17 children (7-15 years) with mesial temporal sclerosis who had histories of uncontrolled epilepsy. The National Institute of Mental Health and Neurosciences (NIMHANS) neuropsychological battery for children was employed and each participant's performance was compared with the norms. Results showed that the battery was sensitive to deficits in learning and memory associated with mesial temporal sclerosis. However, a lack of clearly lateralized material-specific memory deficits in children with left/right mesial temporal sclerosis was also observed. Performance on tests that assess learning, attention, working memory, and visuospatial functions was found to be below the age appropriate level. Children with mesial temporal sclerosis showed widely distributed neuropsychological deficits.


Vocoder Simulations Explain Complex Pitch Perception Limitations Experienced by Cochlear Implant Users.
Pitch plays a crucial role in speech and music, but is highly degraded for people with cochlear implants, leading to severe communication challenges in noisy environments. Pitch is determined primarily by the first few spectrally resolved harmonics of a tone. In implants, access to this pitch is limited by poor spectral resolution, due to the limited number of channels and interactions between adjacent channels. Here we used noise-vocoder simulations to explore how many channels, and how little channel interaction, are required to elicit pitch. Results suggest that two to four times the number of channels are needed, along with interactions reduced by an order of magnitude, than available in current devices. These new constraints not only provide insights into the basic mechanisms of pitch coding in normal hearing but also suggest that spectrally based complex pitch is unlikely to be generated in implant users without significant changes in the method or site of stimulation.


Effect of alpha adrenergic agonists and blockers on Purkinje fiber transmembrane potentials and automaticity in the dog.
Previous studies have shown that alpha adrenergic stimulation can reduce the automaticity of canine Purkinje fibers. In the present study, our interest was to determine whether this is an alpha-1 or alpha-2 adrenergic action. We used standard microelectrode techniques to study the effects of the alpha agonists, phenylephrine and clonidine, and the alpha antagonists, prazosin and yohimbine, on phenylephrine-induced decreases in automaticity. Prazosin and yohimbine, 1 X 10(-5) M, alone, significantly reduced the amplitude and upstroke velocity (Vmax) of stimulated action potentials. In addition, yohimbine, 1 X 10(-5) M, accelerated and prazosin, 1 X 10(-5) M, attenuated repolarization. Prazosin, 1 X 10(-5) M, and yohimbine greater than or equal to 1 X 10(-7) M, alone, decreased automaticity. Phenylephrine, 5 X 10(-8) M, alone, significantly increased the cycle length of automatic Purkinje fibers. The effects of phenylephrine on automaticity were blocked by prazosin but not by yohimbine. Clonidine, alone, 1 X 10(-6) and 1 X 10(-5) M, significantly reduced automaticity, an effect that was not blocked by yohimbine or prazosin. Clonidine, 1 X 10(-6) and 1 X 10(-5) M, also significantly reduced Vmax and prolonged action potential duration of driven Purkinje fibers, an action consistent with direct membrane effects. These experiments suggest that the negative chronotropic effects of phenylephrine on Purkinje fiber automaticity are mediated by alpha-1 adrenergic receptors.


Treatment outcomes of substance-abusing physicians.
Publications relating to outcome of physicians treated for substance abuse were obtained from a computerized literature search and a review of Cumulated Index Medicus for the years 1950-1982. The studies were reviewed regarding such factors as study location, sample size, presence of control groups, treatment modalities and setting, treatment duration, follow-up duration, method of determining outcome, and treatment outcome. Variations in these factors make comparisons of the studies difficult. Shortcomings in the methods of determining outcome raise questions concerning reliability of the data. Suggestions are made for further research for the assessment of treatment and outcome of substance-abusing physicians.


Probing for congenital nasolacrimal duct obstruction.
Congenital nasolacrimal duct obstruction (NLDO) is a common condition causing excessive tearing in the first year of life. Infants present with excessive tearing or mucoid discharge from the eyes due to blockage of the nasolacrimal duct system, which can result in maceration of the skin of the eyelids and local infections, such as conjunctivitis, that may require antibiotics. The incidence of nasolacrimal duct obstruction in early childhood ranges from 5% to 20% and often resolves without surgery. Treatment options for this condition are either conservative therapy, including observation (or deferred probing), massage of the lacrimal sac and antibiotics, or probing the nasolacrimal duct to open the membranous obstruction at the distal nasolacrimal duct. Probing may be performed without anesthesia in the office setting or under general anesthesia in the operating room. Probing may serve to resolve the symptoms by opening the membranous obstruction; however, it may not be successful if the obstruction is due to a bony protrusion of the inferior turbinate into the nasolacrimal duct or when the duct is edematous (swollen) due to infection such as dacryocystitis. Additionally, potential complications with probing include creation of a false passage and injury to the nasolacrimal duct, canaliculi and puncta, bleeding, laryngospasm, or aspiration. To assess the effects of probing for congenital nasolacrimal duct obstruction. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register (2016, Issue 8); MEDLINE Ovid (1946 to 30 August 2016); Embase.com (1947 to 30 August 2016); PubMed (1948 to 30 August 2016); LILACS (Latin American and Caribbean Health Sciences Literature Database; 1982 to 30 August 2016), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), last searched 14 August 2014; ClinicalTrials.gov (www.clinicaltrials.gov), searched 30 August 2016; and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en), searched 30 August 2016. We did not use any date or language restrictions in the electronic searches for trials. We included randomized controlled trials (RCTs) that compared probing (office-based or hospital-based under general anesthesia) versus no (or deferred) probing or other interventions (observation alone, antibiotic drops only, or antibiotic drops plus massage of the nasolacrimal duct). We did not include studies that compared different probing techniques or probing compared with other surgical procedures. We included studies in children aged three weeks to four years who may have presented with tearing and conjunctivitis. Two review authors independently screened studies for inclusion and independently extracted data and assessed risk of bias for the included studies. We analyzed data using Review Manager software and evaluated the certainty of the evidence using GRADE. We identified two RCTs and no ongoing studies; one of the included RCTs was registered. The studies reported on 303 eyes of 242 participants who had unilateral or bilateral congenital nasolacrimal duct obstruction. For both included studies, the interventions compared were immediate office-based probing to remove the duct obstruction versus deferred probing, if needed, after 6 months of observation or once the child reached a certain age.The primary outcome of the review, treatment success at 6 months, was reported partially in one study. Treatment success was not reported at this time point for all children in the immediate probing group; however, 77 of 117 (66%) eyes randomized to deferred probing had resolved without surgery 6 months after randomization and 40 (34%) eyes did not resolve without probing. For children who had unilateral NLDO, those randomized to immediate probing had treatment success more often than those who were randomized to deferred probing (RR 1.41, 95% CI 1.12 to 1.78; 163 children; moderate-certainty evidence). Treatment success for all children was assessed in the study at age 18 months; as an ad hoc analysis in the included study, results were presented separately for children with unilateral and bilateral NLDO (RR 1.13, 95% CI 0.99 to 1.28 and RR 0.86, 95% CI 0.70 to 1.06, respectively; very low-certainty evidence).In the other small study (26 eyes of 22 children), more eyes that received immediate probing were cured within one month after surgery compared with eyes that were randomized to deferred probing and analyzed at age 15 months (RR 2.56, 95% CI 1.16 to 5.64). We considered the evidence to be low-certainty due to imprecision from the small study size and risk of bias concerns due to attrition bias.One study reported on the number of children that required reoperation; however, these data were reported only for immediate probing group. Nine percent of children with unilateral NLDO and 13% with bilateral NLDO required secondary procedures.One study reported cost-effectiveness of immediate probing versus deferred probing. The mean cost of treatment for immediate probing was less than for deferred probing; however, there is uncertainty as to whether there is a true cost difference (mean difference USD -139, 95% CI USD -377 to 94; moderate-certainty evidence).Reported complications of the treatment were not serious. One study reported that there were no complications for any surgery and no serious adverse events, while the other study reported that bleeding from the punctum occurred in 20% of all probings. The effects and costs of immediate versus deferred probing for NLDO are uncertain. Children who have unilateral NLDO may have better success from immediate office probing, though few children have participated in these trials, and investigators examined outcomes at disparate time points. Determining whether to perform the procedure and its optimal timing will require additional studies with greater power and larger, well-run clinical trials to help our understanding of the comparison.


A test of two midfacial growth models using path analysis of normal human fetal material.
Predictions about the temporal sequencing (i.e., primacy) and causal relationships between various midfacial growth components, as suggested by two midfacial growth models (functional matrix and septal traction), were examined in the present study. The relationships between quantitative changes in the nasal septum, nasal airway, nasolabial musculature, and premaxilla of 15 normal human fetal specimens, ranging in age from 12 to 20 weeks postmenstrual age, were assessed using the multivariate technique of path analysis. Path analysis results revealed that the causal sequence of variables proposed by the septal-traction model explained more of the variance in premaxillary size (87 percent goodness-of-fit) than did the sequence of variables proposed by the functional matrix model (65 percent goodness-of-fit). These results suggest that the septal-traction model may be a more parsimonious and primary explanation of early human fetal midfacial growth than the functional matrix model. Path analysis results also reiterate the observed complex developmental relationships within the fetal labioseptopremaxillary region, knowledge of which may be important in the surgical management of infants with complete cleft.


Using tertiary structure for the computation of highly accurate multiple RNA alignments with the SARA-Coffee package.
Aligning RNAs is useful to search for homologous genes, study evolutionary relationships, detect conserved regions and identify any patterns that may be of biological relevance. Poor levels of conservation among homologs, however, make it difficult to compare RNA sequences, even when considering closely evolutionary related sequences. We describe SARA-Coffee, a tertiary structure-based multiple RNA aligner, which has been validated using BRAliDARTS, a new benchmark framework designed for evaluating tertiary structure-based multiple RNA aligners. We provide two methods to measure the capacity of alignments to match corresponding secondary and tertiary structure features. On this benchmark, SARA-Coffee outperforms both regular aligners and those using secondary structure information. Furthermore, we show that on sequences in which <60% of the nucleotides form base pairs, primary sequence methods usually perform better than secondary-structure aware aligners. The package and the datasets are available from http://www.tcoffee.org/Projects/saracoffee and http://structure.biofold.org/sara/.


Deuterium NMR of 2HCO-Val1...gramicidin A and 2HCO-Val1-D-Leu2...gramicidin A in oriented DMPC bilayers.
Deuterium NMR is used to study the structure and dynamics of the formyl C-2H bond in selectively deuterated gramicidin molecules. Specifically, the functionally different analogues 2HCO-Val1...gramicidin A and 2HCO-Val1-D-Leu2...gramicidin A are studied by 2H NMR so that any conformational or dynamical differences between the two analogues can be correlated with their difference in lifetime. These analogues are first synthesized, purified, and characterized and then incorporated into oriented bilayers of dimyristoylphosphatidylcholine sandwiched between glass coverslips. Phosphorous NMR line shapes obtained from these samples are consistent with the presence of the bilayer phase and indicate that the disorder exhibited by the lipid matrix is approximately of the same type and degree for both analogues. Deuterium NMR line shapes obtained from these samples indicate that the motional axis of the formyl group of gramicidin is parallel to the coverslip normal, that the distribution of motional axis orientations has a width of 7-9 degrees, and that a similar, major conformational and dynamical state exists for the formyl C-2H bond of both analogues. In this state, if the only motion present is fast axial rotation, then the experimentally derived angle between the formyl C-2H bond and the motional axis is consistent with the presence of a right-handed, single-stranded, beta 6.3 helical dimer but is not consistent with the presence of a left-handed, single-stranded, beta 6.3 helical dimer. However, if fast axial rotation is not the only motion present, then the left-handed, single-stranded, beta 6.3 helical dimer cannot be absolutely excluded as a possibility. Also, a second, minor conformational and dynamical state appears to be present in the spectrum of 2HCO-Val1-D-Leu2...gramicidin A but is not observed in the spectrum of 2HCO-Val1...gramicidin A. This minor conformational and dynamical state may reflect the presence of monomers, while the major conformational and dynamical state may reflect the presence of dimers.


Diagnostic Performance of Dedicated Axillary T2- and Diffusion-weighted MR Imaging for Nodal Staging in Breast Cancer.
To evaluate the diagnostic performance of unenhanced axillary T2-weighted and diffusion-weighted (DW) magnetic resonance (MR) imaging for axillary nodal staging in patients with newly diagnosed breast cancer, with node-by-node and patient-by-patient validation. Institutional review board approval and informed consent were obtained. Fifty women (mean age, 60 years; range, 22-80 years) underwent high-spatial-resolution axillary 3.0-T T2-weighted imaging without fat suppression and DW imaging (b = 0, 500, and 800 sec/mm(2)), followed by either sentinel lymph node biopsy (SLNB) or axillary lymph node dissection. Two radiologists independently scored each lymph node on a confidence level scale from 0 (benign) to 4 (malignant), first on T2-weighted MR images, then on DW MR images. Two researchers independently measured the mean apparent diffusion coefficient (ADC) of each lymph node. Diagnostic performance parameters were calculated on the basis of node-by-node and patient-by-patient validation. With respective node-by-node and patient-by-patient validation, T2-weighted MR imaging had a specificity of 93%-97% and 87%-95%, sensitivity of 32%-55% and 50%-67%, negative predictive value (NPV) of 88%-91% and 86%-89%, positive predictive value (PPV) of 60%-70% and 62%-75%, and area under the receiver operating characteristic curve (AUC) of 0.78 and 0.80-0.88, with good interobserver agreement (κ = 0.70). The addition of DW MR imaging resulted in lower specificity (59%-88% and 50%-84%), higher sensitivity (45%-64% and 75%-83%), comparable NPV (89% and 90%-91%), lower PPV (23%-42% and 34%-60%), and lower AUC (0.68-0.73 and 0.70-0.86). ADC measurement resulted in a specificity of 63%-64% and 61%-63%, sensitivity of 41% and 67%, NPV of 85% and 85%-86%, PPV of 18% and 35%-36%, and AUC of 0.54-0.58 and 0.69-0.74, respectively, with excellent interobserver agreement (intraclass correlation coefficient, 0.83). Dedicated high-spatial-resolution axillary T2-weighted MR imaging showed good specificity on the basis of node-by-node and patient-by-patient validation, with good interobserver agreement. However, its NPV is still insufficient to substitute it for SLNB for exclusion of axillary lymph node metastasis. DW MR imaging and ADC measurement were of no added value.


Small conductance calcium-activated potassium channels: from structure to function.
The cloning of K(Ca)2 channels revealed three subtypes, with each displaying distinct but partially overlapping expression distributions in the mammalian CNS and periphery. Activation of K(Ca)2 channels leads to membrane hyperpolarization and inhibition of action potential firing. Block of K(Ca)2 channels has been suggested as a novel target for cognitive enhancement, depression, myotonic muscular dystrophy and heart arrhythmias. It is clear however, that blockers selective for individual K(Ca)2 channel subtypes would be required to be therapeutically useful. K(Ca)2 channel current is blocked by apamin, with the bee venom toxin being unusual in displaying some selectivity between K(Ca)2 channel subtypes. This suboptimal selectivity is not sufficient to be therapeutically useful and the toxin has been shown in vivo to have a very narrow therapeutic window. Mutational and molecular modelling studies of the K(Ca)2 channels are beginning to determine how selective block might be achieved. Mutagenesis has indicated the importance of the outer pore region and the extracellular loop between transmembrane domains S3 and S4 for block of K(Ca)2 current by apamin. Mapping the sequence of transmembrane domains S5, pore helix and S6 onto the crystal structures of KcsA, MthK and Kv1.2 has provided an approximation of the pore structure. This approach has allowed structural modelling of the interactions between toxins and channel, demonstrating that the toxins that show little discrimination between K(Ca)2 channel subtypes interact with the outer pore and around the K(+) selectivity filter. We present the structural modelling of the interaction of apamin and K(Ca)2.2, which is superimposed onto the crystal structure of Kv1.2. This has shown that apamin interacts only with the outer pore and does not come into contact with channel's selectivity filter. It is clear that by comparing how different toxins interact with each K(Ca)2 channel subtype, a detailed picture will be generated that will aid the development of more specific K(Ca)2 channel blockers.


Metabolic Syndrome in Aging Men as a Factor Affecting the Relationship between Mg, Ca, and P in Serum and Bone.
The objective of this study was to evaluate the relationship between the prevalence of metabolic syndrome (MetS) and selected hormonal disorders and concentrations of magnesium (Mg), calcium (Ca), and phosphorus (P) in both blood serum and bone tissue. This study involved 152 men with and without MetS. In the blood of the patients we examined, we determined levels of: testosterone (TT), estradiol (E2), sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), insulin (I), osteocalcin (OC), and concentrations of markers of bone turnover. The concentration of Mg, Ca, and P was determined in the serum and bone tissue. In patients with MetS, the serum Ca concentration correlated with procollagen type I N-terminal propeptide (PINP) and parathyroid hormone (PTH). Among patients without MetS, the serum Ca concentration correlated with SHBG and OC, while Ca concentration in bone correlated with the lipid accumulation product (LAP) index and the body mass index (BMI). After analyzing the serum Mg concentration, positive correlations were observed with E2, PINP, and PTH in patients with MetS. In patients without MetS, the Mg concentration in bone positively correlated with the BMI and the LAP index. Our study findings suggest that increased Mg levels could have an impact on bone tissue metabolism. Elevated serum Mg levels may be associated with changes in sex hormone concentrations and alterations in bone turnover markers.


Kodoja: A workflow for virus detection in plants using k-mer analysis of RNA-sequencing data.
RNA-sequencing of plant material allows for hypothesis-free detection of multiple viruses simultaneously. This methodology relies on bioinformatics workflows for virus identification. Most workflows are designed for human clinical data, and few go beyond sequence mapping for virus identification. We present a new workflow (Kodoja) for the detection of plant virus sequences in RNA-sequence data. Kodoja uses k-mer profiling at the nucleotide level and sequence mapping at the protein level by integrating two existing tools Kraken and Kaiju. Kodoja was tested on three existing RNA-seq datasets from grapevine, and two new RNA-seq datasets from raspberry. For grapevine, Kodoja was shown to be more sensitive than a method based on contig building and blast alignments (27 viruses detected compared to 19). The application of Kodoja to raspberry, showed that field-grown raspberries were infected by multiple viruses, and that RNA-seq can identify lower amounts of virus material than reverse transcriptase PCR. This work enabled the design of new PCR-primers for detection of Raspberry yellow net virus and Beet ringspot virus. Kodoja is a sensitive method for plant virus discovery in field samples and enables the design of more accurate primers for detection. Kodoja is available to install through Bioconda and as a tool within Galaxy.


Docs on the Hill. ACA still prime target for GOP-dominated physician delegation.
Twenty physicians, including Rep. Tom Price (R-Ga.), left, will be part of the 113th Congress that gets to work early next year. But this GOP-dominated group of doctors will wield influence beyond their numbers on healthcare policy and are armed with focused agendas on what to do next. We looked at the legislative records of these representatives and senators and got their perspectives on some key issues.


[18F]fluorodeoxyglucose triple-head coincidence imaging as an adjunct to 131I scanning for follow-up of papillary thyroid carcinoma.
To evaluate the feasibility of using [(18)F]fluorodeoxyglucose ((18)FDG) triple-head coincidence imaging as a potential cost-effective alternative to positron emission tomography in the setting of suspected recurrence of papillary thyroid carcinoma. We retrospectively studied 10 patients with suspected recurrence of papillary carcinoma of the thyroid, who underwent (18)FDG coincidence imaging,(131)I scanning, and a reference anatomic scan (computed tomography, magnetic resonance imaging, or both) within 1 year in most cases. The (131)I scan detected the recurrence in five patients (62.5%) and failed to reveal recurrent cancer in three patients (37.5%); in contrast,(18)FDG imaging detected the recurrence in eight patients (100%) and was true negative in two patients in whom the scans were performed more than 1 year after effective therapy for the recurrence. The sensitivity of detection was unrelated to lesion size. The (18)FDG imaging results led to additional radiotherapy in all (131)I-negative patients, two of whom had high thyroglobulin levels and one of whom had a low thyroglobulin concentration but the presence of antithy-roglobulin antibodies. We conclude that (18)FDG triple-head coincidence imaging is useful for routine management of patients with thyroid cancer who have no abnormalities detected on (131)I scans but have high serum thyroglobulin levels. This technique, however, may not be as sensitive as a dedicated positron emission tomographic device, particularly for the assessment of small tumors.


A Bayesian group sequential approach to safety signal detection.
Clinical safety data, usually reported as clinically manifested adverse events (AEs) according to the Medical Dictionary for Regulatory Activities (MedDRA), are routinely collected during the course of a clinical trial involving comparative groups, and periodical monitoring of the safety events is often required to determine whether excessive occurrence of a set of AEs is associated with treatment. To accommodate the structure of reported AEs with the MedDRA system, a Bayesian hierarchical model has been proposed for the analysis of clinical safety data. However, the characteristics of sequential use of the Bayesian method has not been studied. In this paper the Bayesian hierarchical model is applied in a group sequential manner for multiple interim analyses of safety events. A decision-theoretic approach is employed to determine threshold values in the safety signaling process. The proposed approach is illustrated through simulations and a real example.


Secretion of chondroitin sulfate from embryonic epidermal cells in Xenopus laevis.
We examined proteoglycans (PGs) in amphibian epidermal cells by immunofluorescence microscopy. Immunoelectron microscopy with pre- and post-embedding methods, combined with HRP- or gold-conjugated secondary antibody, revealed ultrastructural localization of glycosaminoglycans (GAGs). Embryonic epidermis secretion granules in Xenopus laevis contained chondroitin 6-sulfate and unsulfated chondroitin. Immature secretion granules were also labeled with anti-chondroitin 6-sulfate and anti-chondroitin. A step-wise digestion experiment on chondroitinase ABC revealed that fine filaments in the secretion granules were chondroitin sulfate chains. Inhibition experiments with brefeldin A revealed that the life of a secretion granule was 5-10 hr, suggesting that GAG secretion from embryonic epidermis is routed through a regulated pathway.


Evaluation of Peripheral Versus Central Route of Ondansetron as Pretreatment to Prevent Pain on the Injection of Propofol: A Randomized Controlled Study.
We evaluated whether systemic ondansetron was also useful in the attenuation of propofol injection pain similar to ondansetron pretreatment. Eighty patients were enrolled. Patients in group S received ondansetron 4 mg in saline in the right hand followed 30 min later by 5 mL saline in the left hand along with venous occlusion. Group L patients received 4 mL of saline in the right hand followed by 5 mL 4 mg ondansetron in the left hand after 30 min. Two minutes later the occlusion was released. Patients received one-fourth of the calculated total dose of propofol, and their level of pain was graded on a scale of 0 to 3, with 0 denoting no discomfort. Mean blood pressure and heart rates were also recorded. Continuous variables were checked for normality using Shapiro-Wilks test. Normal continuous variables were expressed as mean standard deviation and non-normal continuous variables were expressed as median interquartile range. T-test for the difference in the mean and paired test were used for normally distributed continuous variable whereas Mann-Whitney U test-Wilcoxon test and sign test were used for non-normally distributed variables. Repeated measure analysis of variance was used for a variable measured over different periods of time to control for the baseline effect on subsequent measures. Our results demonstrated that both systemic administration 30 min before and local venous pretreatment with ondansetron were equally beneficial in reducing pain during propofol injection. A systemic administration of ondansetron may play a role in the attenuation of propofol injection pain.


Phase I clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 2B design.
BMS-247550 is a semisynthetic derivative of epothilone B with mechanism of action analogous to paclitaxel. It has shown impressive antitumor activity in preclinical studies including in taxane-resistant models. We conducted a phase I trial, based on accelerated titration "2B" design, of BMS-247550 given as a 1-hour infusion every 3 weeks. Seventeen patients (M:F, 10:7; median age, 54 years; performance status, 0-2) were treated on the trial. Forty-five cycles (1-9 cycles) of BMS-247550 were given at dosages ranging from 7.4 to 56 mg/m2. All patients received prophylaxis for hypersensitivity reactions, related to Cremophor-EL, with steroids and histamine antagonists. First-course dose-limiting toxicity (DLT) was observed in two of three patients at 56 mg/m2 (neutropenic sepsis, prolonged grade 4 neutropenia) and in one of six patients at 40 mg/m2. Nonhematologic grade 3 to 4 toxicities observed were emesis and fatigue and they occurred only at 56 mg/m2. Grade 1 to 2 peripheral neuropathy was also observed. Other grade 1 to 2 toxicities were myalgias, arthralgias, rash, hand/foot syndrome, and mucositis. AUC and C(max) seemed proportional to the dose and the DLT. Development of neutropenia with BMS-247550 is related to the duration of drug exposure above a threshold. The maximum tolerated dose (MTD) of BMS-247550 is 40 mg/m2 given every 3 weeks. Neutropenia is the DLT. The accelerated titration "2B" design may help in determining MTD with fewer patients enrolled and more being treated closer to the MTD. However, the accelerated titration design did not seem to shorten the study duration.


The hospital course of acute myocardial infarction in the Tainan area.
The hospital records of 204 patients with acute myocardial infarction (AMI) admitted from August 1988 through July 1990 were reviewed. Of these, 138 patients who were admitted within 24 hours after onset of symptoms were enrolled in this retrospective study. In 138 patients (110 men, 28 women; aged 62.6 +/- 11.3 years), the mean prehospital time was 4.8 +/- 4.5 hours (median 3.0, range 0.5 to 24.0). Ninety-nine of these 138 patients were classified as an early presentation group (less than 6 hours); their mean prehospital time was 2.5 +/- 1.3 hours. Of these, 60 patients received thrombolytic therapy with intravenous streptokinase (SK), and their prehospital time was 2.3 +/- 1.2 hours, with mean time to SK therapy of 3.7 +/- 1.5 hours. The in-hospital mortality of these 60 patients was 16.7%. The remaining 39 patients, without SK therapy, had a higher in-hospital mortality (28.2%); their mean prehospital time was 2.7 +/- 1.3 hours. For the late presentation group (greater than or equal to 6 hours), the mean prehospital time was 10.6 +/- 4.3 hours and the in-hospital mortality was 7.7%. The frequency of severe congestive heart failure (Killip class III or IV) at admission was significantly higher in patients with early presentation, than with late presentation (30.7% vs 7.6%, p less than 0.05). The overall causes of death included congestive heart failure (79%), ventricular arrhythmia (8%) and underlying medical illness (13%). In conclusion, 43.4% of the AMI patients in this study received SK therapy, within a mean time of 3.7 +/- 1.5 hours after onset.(ABSTRACT TRUNCATED AT 250 WORDS)


Nano-theranostics and Nitroxyl Radical-labeled Antitumor Agents for Magnetic Resonance Imaging.
The advent of functional contrast agents and nanoparticle drug delivery systems (nano-DDS) is opening new pathways to understanding pathophysiology using magnetic resonance imaging (MRI). Nitroxyl radical compounds are promising functional contrast agents for redox evaluation. We have developed a novel nitroxyl radical theranostic compound for noninvasive real-time imaging of blood-brain barrier-permeable antitumor drugs. Divalent manganese ions (Mn(2+)) can also be used as an intracellular functional MRI contrast agent. Manganese-enhanced MRI (MEMRI) provides a unique opportunity to study neuronal activation and architecture. Extracellular Mn(2+) can enter cells through NMDA receptors for glutamate and/or voltage-gated calcium channels. Thus, Mn(2+) can behave as a functional contrast agent depending on the cellular activity/viability. This paper summarizes the recent progress in MEMRI for neuroimaging and cancer research. Nanocarriers for DDS can contain multiple functional elements, such as therapeutic drugs, MRI contrast agents, fluorescent dyes, and radioisotopes, without significant changes in the particle kinetics/dynamics. Various materials have also been reported as nano-DDS carriers, including micelles, liposomes, dendrimers, quantum dots, and carbon materials such as fullerenes, with each material providing a different set of characteristics as a nano-DDS carrier. Our recent research into nano-DDS-based contrast agents and the theranostic applications is also outlined.


Effects of oral conjugated equine estrogens with or without medroxyprogesterone acetate on incident hypertension in the Women's Health Initiative hormone therapy trials.
The aim of the study was to determine the effect of menopausal hormone therapy on incident hypertension in the two Women's Health Initiative hormone therapy trials and in extended postintervention follow-up. A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. This analysis includes the subsample of 18,015 women who did not report hypertension at baseline and were not taking antihypertensive medication. Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 5,994) or placebo (n = 5,679). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 3,108) or placebo (n = 3,234). The intervention lasted a median of 5.6 years in the CEE plus MPA trial and 7.2 years in the CEE-alone trial with 13 years of cumulative follow-up until September 30, 2010. The primary outcome for these analyses was self-report of a new diagnosis of hypertension and/or high blood pressure requiring treatment with medication. During the CEE and CEE plus MPA intervention phase, the rate of incident hypertension was 18% higher for intervention than for placebo (CEE: hazard ratio [HR], 1.18; 95% CI, 1.09-1.29; CEE plus MPA: HR, 1.18; 95% CI, 1.09-1.27). This effect dissipated postintervention in both trials (CEE: HR, 1.06; 95% CI, 0.94-1.20; CEE plus MPA: HR, 1.02; 95% CI, 0.94-1.10). CEE (0.625 mg/d) administered orally, with or without MPA, is associated with an increased risk of hypertension in older postmenopausal women. Whether lower doses, different estrogen formulations, or transdermal route of administration offer lower risks warrant further study.


Occupational exposure to asbestos during renovation of oil-shale fuelled power plants in Estonia.
Many thousands of tonnes of asbestos were used in buildings in the past, especially for thermal insulation of pipes and boilers in power plants. Occupational exposure to asbestos dust now mainly occurs during demolition, renovation and routine maintenance activities. The objective of this study was to evaluate occupational exposure to airborne asbestos during renovation of solid oil-shale fuelled power plants carried out in 2001-2003. Air monitoring inside and outside of the renovation area was performed. The concentration of airborne fibres in the working environment increased during renovation but the valid limit value (0.1 fibres/cm(3)) was not exceeded.


[Evaluation of changes in portal collaterals by single photon emission CT: effects of endoscopic injection sclerotherapy].
The changes in portal collaterals before and after Endoscopic Injection Sclerotherapy (EIS) for esophageal varices were studied by Single Photon Emission CT (SPECT). SPECT was performed for the intra-abdominal blood pool with 99mTc autologous red blood cells (RBC) in 17 patients with liver cirrhosis before and after EIS. Twenty mCi of 99mTc-RBC labeled by in vivo technique were administered intra-venously and tomographic imaging of the intra-abdominal vascular blood pool was performed as follows. For each subjects, 64 views were obtained over 360 degrees of elliptic rotation at 30 seconds per view. In 15 of 17 patients, blood pool images over coronary vein and/or short gastric vein area were clearly demonstrated on coronary images. In 9 of 15 patients, the pool of coronary vein or short gastric vein was disappeared or decreased after EIS. It is considered that intra-abdominal blood pool SPECT study is clinically useful for following up of hemodynamics of portal collaterals before and after EIS.


Prevalence of Smoking and Associated Factors: Evidence From the CHILILAB Demographic Surveillance System in Vietnam.
This study analyzed secondary data from Chi Linh Health and Demographic Surveillance System (CHILILAB) database to identify smoking prevalence and associated demographic factors. Data were extracted from the database of the CHILILAB 2016, which included information on individual smoking behaviors, as well as individual and household demographic data. Descriptive and binary logistic regression analyses were performed with significance level of 0.05. The smoking prevalences were 34.7%, 0.9%, and 16.1% for men, women, and both genders, respectively. A total of 78.2% of current smokers smoked daily inside their houses. Lower smoking status was associated with younger age, being student, rich, and/or single. Future efforts should not only spend on further reduction of smoking rate in Chi Linh Town but should also pay special attention on reducing the prevalence of in-home smoking. This will help to decrease the risk of nonsmokers being exposed to secondhand smoke in their home environment.


Nuclear polyadenylation factors recognize cytoplasmic polyadenylation elements.
In the cytoplasm of oocytes and early embryos, addition of poly(A) to mRNAs can activate their translation. We demonstrate that despite many differences between poly(A) addition in the cytoplasm and nucleus, these two forms of polyadenylation may involve identical trans-acting factors. Nuclear polyadenylation requires the sequence AAUAAA, the AAUAAA-binding cleavage and polyadenylation specificity factor (CPSF), and a poly(A) polymerase (PAP). We show that CPSF and PAP, purified from calf thymus, exhibit the same sequence specificity observed in the cytoplasm during frog oocyte maturation, requiring both AAUAAA and a proximal U-rich sequence. The enhanced polyadenylation of RNAs containing U-rich sequences is caused by their increased affinity for CPSF. Frog nuclear polyadenylation factors display cytoplasmic sequence specificity when dilute, suggesting that a difference in their concentrations in the nucleus and cytoplasm underlies the different sequence specificities in the two compartments. Because polyadenylation in extracts prepared from oocytes before maturation is stimulated by addition of CPSF, the onset of polyadenylation during early development may be attributable to the activation or synthesis of a CPSF-like factor. We suggest that sequences upstream of AAUAAA that are required for cleavage and polyadenylation of certain pre-mRNAs in the nucleus may be functionally equivalent to the upstream, U-rich sequences that function in the cytoplasm, enhancing CPSF binding. We propose that CPSF and PAP comprise a core polyadenylation apparatus in the cytoplasm of oocytes and early embryos.


Efflux Transporter of Siderophore Staphyloferrin A in Staphylococcus aureus Contributes to Bacterial Fitness in Abscesses and Epithelial Cells.
The siderophores staphyloferrin A (SA) and staphyloferrin B (SB) of Staphylococcus aureus are essential for iron acquisition in the iron-restricted environment of the host, such as in subcutaneous abscesses. SA and SB are secreted by SfaA and SbnD transporters, respectively. To assess the further function of SfaA and SbnD in S. aureus fitness, we tested its effect on murine abscess models and intracellular replication in epithelial cells. Bacterial fitness in abscesses and in epithelial cells was studied, by comparing the parental strains RN6390 and MW2 and their ΔsfaA and ΔsbnD mutants using competition assays in a murine abscess model and invasion and replication assays with human lung adenocarcinoma cell line A549. In the murine abscess model using equal inocula of a ΔsfaA or ΔsbnD mutant and the wild-type RN6390 strain, the ΔsfaA mutant exhibited growth defects of 2.2-fold. Additionally, replication of the ΔsfaA mutant within A549 cells was decreased 3.0-fold. In complementation experiments, the ΔsfaA mutant carrying plasmid-borne sfaA restored the growth fitness in abscesses and epithelial cells. The ΔsbnD mutant, in contrast, showed no growth defect in either abscesses or epithelial cells. Our findings demonstrate that the efflux transporter of the siderophore SA contributes to the ability of S. aureus to replicate in abscesses and epithelial cells. Furthermore, fitness of S. aureus in these sites of replication is not compromised by the absence of transporter SbnD.


Coherent light transport in a cold strontium cloud.
We study light coherent transport in the weak localization regime using magneto-optically cooled strontium atoms. The coherent backscattering cone is measured in the four polarization channels using light resonant with a J(g) = 0-->J(e) = 1 transition of the strontium atom. We find an enhancement factor close to 2 in the helicity preserving channel, in agreement with theoretical predictions. This observation confirms the effect of internal structure as the key mechanism for the contrast reduction observed with a rubidium cold cloud [G. Labeyrie et al., Phys. Rev. Lett. 83, 5266 (1999)]. Experimental results are in good agreement with Monte Carlo simulations taking into account geometry effects.


A mus-51 RIP allele for transformation of Neurospora crassa.
This report describes the construction and characterization of mus-51RIP70 , an allele for high-efficiency targeted integration of transgenes into the genome of the model eukaryote Neurospora crassa. Two of the mus-51RIP70 strains investigated in this work (RZS27.10 and RZS27.18) can be obtained from the Fungal Genetics Stock Center. The two deposited strains are, to our knowledge, genetically identical and neither one is preferred over the other for use in Neurospora research.


Construction of Multienzyme Co-immobilized Hybrid Nanoflowers for an Efficient Conversion of Cellulose into Glucose in a Cascade Reaction.
Today, we are seeking an efficient biotransformation of cellulosic material into sustainable biochemical products to meet the increasing global energy demand. Herein, we report the fabrication of multienzyme hybrid nanoflowers (ECG-NFs) by co-immobilizing three recombinant enzymes (cellobiohydrolase (CBH), endo-glucanase (EG), and β-glucosidase (BG)) integrating a binary tag composed of elastin-like polypeptide (ELP) and His-tag to act as a tri-enzyme biocatalyst, which catalyzes the hydrolysis of cellulose into glucose. The prepared ECG-NFs exhibited excellent performance in terms of pH stability, thermal stability, storage stability, and catalytic efficiency compared to free multienzyme system. Notably, ECG-NFs could be recycled for up to eight consecutive runs. The Km and kcat/Km values for ECG-NFs were 9.33 g L-1 and 0.0051 L min-1 g-1, respectively, which were better than those of the free multienzyme system, indicating a better substrate affinity. Finally, the overall enzyme activity of ECG-NFs increased by 1.12 times and the degradation efficiency of ECG-NFs was superior to the free multienzyme system, which revealed that ECG-NFs could facilitate an effective one-pot hydrolysis of cellulose into glucose.


Optimising heart failure pharmacotherapy: the ideal combination.
Good management of all patients with heart failure is complex. Fortunately most patients fall into only one or two categories, making management less daunting. Most patients with heart failure need treatment with loop diuretics and ACE inhibitors and for many these drugs, possibly combined with antithrombotic measures, are all that is needed for optimal treatment, but optimal treatment can only follow adequate diagnosis. This needs a partnership between the specialist and the family doctor, with ease of access to non-invasive investigations such as echocardiography.


Abdominal aortic aneurysm. Experience with the use of the straight tube method of treatment.
Forty-three consecutive patients with an abdominal aortic aneurysm treated by means of a straight Dacron tube inserted inside the aneurysms are reviewed. There were no deaths among the 30 patients who had an elective operation, and three deaths in the group of 13 whose aneurysm had ruptured. The use of a straight tube to treat an abdominal aneurysm has many advantages, including lower mortality and morbidity rates. Experience suggests that this is the operation of choice for all aneurysms, whether for rupture or as an elective procedure, except for a minority of patients with aneurysms of the iliac arteries. A significant delay occurred in referral of 30% of patients, apparently owing to the belief that vascular surgery carried a grave risk. Of the patients with a ruptured aneurysm, 50% had their condition misdiagnosed; this led to delay in the patients receiving treatment. It is clear that clinicians are not sufficiently "aneurysm minded" when they examine the abdomen.


Organoid Models of Glioblastoma to Study Brain Tumor Stem Cells.
Glioblastoma represents an aggressive form of brain cancer characterized by poor prognosis and a 5-year survival rate of only 3-7%. Despite remarkable advances in brain tumor research in the past decades, very little has changed for patients, due in part to the recurrent nature of the disease and to the lack of suitable models to perform genotype-phenotype association studies and personalized drug screening. In vitro culture of cancer cells derived from patient biopsies has been fundamental in understanding tumor biology and for testing the effect of various drugs. These cultures emphasize the role of in vitro cancer stem cells (CSCs), which fuel tumor growth and are thought to be the cause of relapse after treatment. However, it has become clear over the years that a 2D monolayer culture of these CSCs has certain disadvantages, including the lack of heterogeneous cell-cell and cell-environment interactions, which can now be partially overcome by the introduction of 3D organoid cultures. This is a novel and expanding field of research and in this review, I describe the emerging 3D models of glioblastoma. I also discuss their potential to advance our knowledge of tumor biology and CSC heterogeneity, while debating their current limitations.


The ancestor of the adaptive immune system was the CAM system for organogenesis.
The adaptive immune system as we understand it is uniquely possessed by vertebrate species and by none other. Nevertheless, it is generally thought that this system represents the ultimate sophistication of much older cell-cell interaction mechanisms. In this paper, I have suggested that plasma membrane cell adhesion proteins that were involved in ontogenic organogenesis since time immemorial were the ultimate ancestor of the adaptive immune system. N-CAM of the chicken for neuronal organogenesis already possesses four beta 2-microglobulin-like domains and it is this domain from which the adaptive immune system sprang. The germ for this beta 2-microglobulin-like domain is already found in the cell adhesion protein of the slime mold straddling the border between unicellular and multicellular eukaryotes. A slightly different version of the above view has recently been expressed by my colleagues.


Occupational health, integrative and complementary practices in primary care, and the Covid-19 pandemic.
To identify the possible repercussions of the COVID-19 pandemic on the workers' health, the care strategies used, and the provision of Integrative and Complementary Practices in health services in the context of COVID-19. Descriptive study, with a qualitative approach, which used a focus group for data collection and content analysis according to Bardin. Eleven health professionals from the city of Registro (SP) participated and, based on the information analysis, four categories emerged: (1) Changes in work routine caused by the pandemic and the feelings they generate in health professionals; (2) Integrative and Complementary Practices as a self-care strategy in the pandemic; (3) Provision of Integrative and Complementary Practices during the pandemic; and (4) Occupational health as the focus and strategy motivator to resume the provision of Integrative and Complementary Practices in the municipality. This study allowed the identification of the impact of the pandemic, especially on workers' mental health, which influenced the search for care strategies that included the Integrative and Complementary Practices. Professionals with this training began to offer the Integrative and Complementary Practices in the service to other workers, given the interruption of their provision to the population due to the COVID-19 pandemic.


[Level of cortisol in blood serum of maternal and umbilical cord during various methods of delivery].
The effect of stress during labor on the plasma concentration of cortisol was studied in 82 women. The total cortisol levels in the maternal serum and cord blood were measured by radioimmunoassay during spontaneous labor (PSN), oxytocin induced labor (PI), elective cesarean section (CCE), and emergency cesarean section (CCC). The result indicate that cortisol level was higher after PI (710 ng/ml) and CCC (755.4 ng/ml) and lower in CCE (278.9 ng/ml) in the maternal vein. In cord blood after CCC was higher (530.8 ng/ml), and lower after CCE (157.8 ng/ml).


Chromosomal integration of phage lambda by means of a DNA insertion element.
Phage lambdacam112, which contains the chloramphenicol resistance transposon Tn9 and has a deletion of attP and the int gene, will lysogenize Escherichia coli K-12. Prophage integration occurs at different chromosomal sites, including lacY and malB, but not at attB. All lambdacam112 prophages are excised from the chromosome after induction but with various efficiencies for different locations. Heteroduplex analysis of lambdaplacZ transducing phages isolated from a lacY::lambdacam112 prophage reveals an insertion sequence 1 (IS1) element at the joint of viral and chromosomal DNA. Two lines of evidence indicate that lambdacam112 encodes an excision activity that recognizes the IS1 element: (i) prophage derepression increases the frequency of excision from lacY to yield lac+ revertants, and (ii) lambdacam112 infection increases reversion of a galT::IS1 mutation about 50-fold. Our results indicate that the IS1 termini of TN9 can replace attP as a site for lambda insertion in the bacterial chromosome and that excision events are catalyzed by an IS1-encoded protein under lambda repressor and N gene control.


Serum cytokine measurements and biological therapy of psoriasis - Prospects for personalized treatment?
Psoriasis is an immune-mediated disease where the IL-23/Th17 axis as well as TNF comprise main targets of biological therapy. Immune profiling has so far not been embraced as a clinical tool. We aimed to investigate relationships between individual serum cytokine levels in 40 psoriasis patients before and after receiving biological therapy and Psoriasis Area and Severity Index (PASI) and Dermatological Life Quality Index (DLQI). Serum concentration of 25 cytokines was determined by Luminex technology. Mean PASI and DLQI decreased by 71% and 65%, respectively. Increase of IL-2 positively correlated with improvement of PASI and DLQI. Moreover, increase of IL-5, IL-10, IL-12, IL-22 and GM-CSF correlated with treatment effect. Notably, logistic regression revealed four times higher risk of having severe psoriasis when IL-17A increased by 1 pg/mL (OR: 4.06, P < 0.05). Selected serum cytokines might constitute useful biomarkers for monitoring disease activity and optimizing therapeutic strategies in psoriasis patients.


Cancer mortality in women and men who survived the siege of Leningrad (1941-1944).
The population of Leningrad suffered from severe starvation, cold and psychological stress during the siege in World War II in 1941-1944. We investigated the long-term effects of the siege on cancer mortality in 3,901 men and 1,429 women, born between 1910 and 1940. All study subjects were residents of St. Petersburg, formerly Leningrad, between 1975 and 1982. One third of them had experienced the siege as children, adolescents or young adults (age range, 1-31 years at the peak of starvation in 1941-1942). Associations of siege exposure with risk of death from cancer were studied using a multivariable Cox regression, stratified by gender and period of birth, adjusted for age, smoking, alcohol and social characteristics, from 1975 to 1977 (men) and 1980 to 1982, respectively (women), until the end of 2005. Women who were 10-18 years old at the peak of starvation were taller as adults (age-adjusted difference, 1.7 cm; 95% CI, 0.5-3.0) and had a higher risk of dying from breast cancer compared with unexposed women born during the same period (age-adjusted HR, 9.9; 95% CI, 1.1-86.5). Mortality from prostate cancer was nonsignificantly higher in exposed men. The experience of severe starvation and stress during childhood and adolescence may have long-term effects on cancer in surviving men and women.


Comparison of a palm-based biometric solution with a name-based identification system in rural Bangladesh.
Unique identifiers are not universal in low- and middle-income countries. Biometric solutions have the potential to augment existing name-based searches used for identification in these settings. This paper describes a comparison of the searching accuracy of a palm-based biometric solution with a name-based database. To compare the identification of individuals between a palm-based biometric solution to a name-based District Health Information Software 2 (DHIS2) Android application, in a low-resource setting. The study was conducted in Chandpur district, Bangladesh. Trained data collectors enrolled 150 women of reproductive age into two android applications - i) a name-based DHIS2 application, and ii) a palm-based biometric solution - both run on tablets. One week after enrollment, a different research team member attempted to re-identify each enrolled woman using both systems. A single image or text-based name was used for searching at the time of re-identification. We interviewed data collectors at the end of the study. Significantly more women were successfully identified on the first attempt with a palm-based biometric application (84%) compared with the name-based DHIS2 application (61%). The proportion of identifications that required three or more attempts was similar between name-based (7%, CI 3.7-12.3) and palm-based biometric system (5%, CI: 1.9-9.4). However, the total number of attempts needed was significantly lower with the palm-based solution (mean 1.2 vs. 1.5, p < 0.001). In a group discussion, data collectors reported that the palm-based biometric identification system was both accurate and easy to use. A palm-based biometric identification system on mobile devices was found to be an easy-to-use and accurate technology for the unique identification of individuals compared to an existing name-based application. Our findings imply that palm-based biometrics on mobile devices may be the next step in establishing unique identifiers in remote and rural settings where they are currently absent.


A reassessment of diet and osteoporosis--possible role for copper.
Much emphasis has centred on the role of dietary calcium and calcium supplementation in the pathophysiology and prevention of osteoporosis. Yet there is accumulating evidence that current recommendations on preventive measures are at best of little value and are inconsistent with the available epidemiological data. It is proposed that more attention should be given to dietary trace elements, especially copper, in the aetiology of post-menopausal osteoporosis. Osteoporotic lesions attributable to copper deficiency have been described in both man and animals and the hypothesis that a mild dietary copper deficiency may be implicated in the onset and progression of osteoporosis is also consistent with the epidemiological evidence. Many western diets are low in copper but in addition milk and milk products are amongst the poorest sources of copper and lactose may interfere with copper metabolism. Current recommendations, therefore, for the prevention of osteoporosis may actually be detrimental to health.


Effective strategy for pyramiding three bacterial blight resistance genes into fine grain rice cultivar, Samba Mahsuri, using sequence tagged site markers.
Bacterial leaf blight (BB) of rice is a major disease limiting rice production in several rice growing regions of the world. The pathogen, Xanthomonas oryzae pv oryzae, causing the disease is highly virulent to rice crops and is capable of evolving new races. Breeding efforts to incorporate single BB resistant gene often leads to resistance breakdown within a short period. To overcome such breakdown of resistance and develop germplasm with durable disease resistance, we have introgressed three bacterial blight resistance genes, xa5, xa13, and Xa21 into a fine grain rice variety, Samba Mahsuri, using sequence tagged site (STS) markers linked to these genes. Since the efficiency of the STS markers linked to recessive genes to detect homozygotes is less than 100%, we adopted four different pyramiding schemes to minimize loss of recessive resistance genes in advanced backcross generations. Pyramiding scheme A in which a two-gene Samba Mahsuri pyramid line containing Xa21 and xa5 genes was crossed with the Samba Mahsuri line having xa13 gene alone was found to be most effective in preventing the loss of an important recessive gene xa13. We further demonstrated that there was no yield penalty due to pyramiding of multiple genes into the elite indica rice variety.


Molecular characterization of the interaction between the N-terminal region of Potato virus X (PVX) coat protein (CP) and Nicotiana benthamiana PVX CP-interacting protein, NbPCIP1.
Using yeast two-hybrid assays and a Nicotiana benthamiana cDNA library, we previously identified an N. benthamiana protein, NbPCIP1, that interacts with Potato virus X (PVX) coat protein (CP). We also previously determined that NbPCIP1 enhances PVX replication in plants. To determine the domains and/or amino acid residues required for PVX CP and NbPCIP1 interaction, here we used yeast two-hybrid and β-galactosidase filter assays to test the effects of deletion and site-directed mutations on the interaction. Truncation analysis revealed that the N-terminal region of PVX CP interacts with NbPCIP1. To identify which N-terminal region PVX CP amino acid(s) interact with NbPCIP1, we substituted the 12 charged amino acids on the PVX CP N-terminal region to alanine. Yeast two-hybrid, β-galactosidase filter, and bimolecular fluorescence complementation (BiFC) assays confirmed that ten of the 12 alanine-substituted mutations blocked the interaction with NbPCIP1. The results suggest that the N-terminal region of PVX CP including its helical structure is important for interaction with NbPCIP1.


[Simultaneous Traumatic Rupture of Patellar Ligament and Contralateral Rupture of Quadriceps Femoris Muscle].
Our paper presents a unique case of a 64-year-old patient after a fall, treated with oral antidiabetic drugs for type II diabetes mellitus. Following a series of examinations, a bilateral injury was diagnosed - patellar ligament tear on the right side and rupture of quadriceps femoris muscle on the left side. It is a rare injury, complicated by simultaneous involvement of both knee joints. The used therapy consisted of a bilateral surgery followed by gradual verticalisation, first with the support of a walking frame and later with the use of forearm crutches. During the final examination, the patient demonstrated full flexion at both knees, while an extension deficit of approx. 5 degrees was still present on the left side. The right knee X-ray showed a proper position of the patella after the removal of temporary tension band wire. Although the clinical results of operative treatment of both the patellar ligament rupture and rupture of quadriceps femoris muscle are in most cases good, early operative treatment, proper technique and post-operative rehabilitation are a prerequisite for success. Key words: knee injuries, patellar ligament, quadriceps muscle, rupture.


C-reactive protein - My perspective on its first half century, 1930-1982.
C-reactive protein (CRP) was discovered in 1930 in the sera of patients during the acute phase of pneumococcal pneumonia and was so named because it bound to the C-polysaccharide of the pneumococcal cell wall. During the next half century many questions raised by this discovery were answered. Phosphorylcholine was found to be the moiety of the C-polysaccharide to which CRP bound. The molecular structure of CRP was elucidated: five identical subunits arranged in cyclic symmetry, giving rise to the term pentraxin. Initially felt to be not normally present in the blood, CRP was found to be a component of normal serum in trace amounts. Its site of origin was determined to be the hepatocyte. It became clear that the presumed humoral mediator responsible for CRP induction was of leukocytic origin. Binding of CRP to its ligand activated the complement system, one of the important effector mechanisms of innate immunity. CRP was found to stimulate phagocytosis of some bacterial species via binding to Fc receptors and was found to be protective in vivo against the pneumococcus in mice. It appeared likely that a related function of CRP was clearance of necrotic tissue. CRP was recognized as being a highly evolutionary conserved molecule. Its discovery during the acute phase of pneumococcal pneumonia led to its being dubbed an acute phase protein. What we today call "the acute phase response", refers to the large number of behavioral, physiologic, biochemical, and nutritional changes that occur during inflammatory states.


Ascorbic acid content and accumulation by alveolar macrophages from cigarette smokers and nonsmokers.
The lung is at risk for injury from inhaled oxidants, including components of cigarette smoke; therefore, maintaining a chemical antioxidant defense would be advantageous. The potential for ascorbic acid to assume this protective role was investigated by comparing the total ascorbate content of alveolar macrophages obtained from human smokers and nonsmokers, from hamsters that were exposed to cigarette smoke for 4 to 6 weeks, and from a control group of unexposed hamsters. The abilities of alveolar macrophages from these four sources to accumulate 14C-labeled ascorbic acid and dehydroascorbate were also compared. The total ascorbate content in hamster macrophages was 19.5 +/- 1.7 and 44.3 +/- 2.8 nmol/10(7) cells for nonsmokers and smokers, (n = 5) and 73.8 +/- 13.1 nmol/10(7) cells (n = 13, p less than 0.1) for nonsmokers and smokers, respectively. In both humans and hamsters, the rates of accumulation of ascorbic acid and dehydroascorbate were significantly greater (p less than 0.05) for alveolar macrophages from smokers compared with nonsmokers of the same species. After internalization, greater than or equal to 70% of the dehydroascorbate was reduced to ascorbic acid by alveolar macrophages from nonsmokers and smokers of both species. An aqueous extract of cigarette smoke oxidized significantly more ascorbic acid to dehydroascorbate in vitro than a comparable volume of phosphate-buffered saline solution without smoke. The increased content of total ascorbate in alveolar macrophages from smokers and their enhanced ability to accumulate ascorbic acid and dehydroascorbate in vitro may reflect protective utilization of ascorbic acid under conditions of increased oxidant stress, compared with nonsmokers. In addition, alveolar macrophages may internalize dehydroascorbate that has been generated by oxidants in the alveolar space and reduce it to ascorbic acid so it can be reused as an antioxidant.


Vitamin-K-dependent carboxylation. Synthesis and biological properties of diastereoisomeric gamma-substituted glutamic acid containing peptidic substrates.
Pentapeptides Phe-Leu-X-Glu-Val where X is successively L-threo-gamma-fluoro-glutamyl, L-erythro-gamma-fluoro-glutamyl, L-threo-gamma-methyl-glutamyl or L-erythro-gamma-methyl-glutamyl have been synthesized and tested as substrates for the vitamin K-dependent carboxylation. L-threo- or L-erythro-gamma-methyl-glutamyl are not carboxylated but both corresponding peptides are inhibitors of the reaction. The L-threo-gamma-methyl-glutamyl containing peptide has the highest affinity described so far for the active site of the carboxylase (80 microM). In the gamma-fluoro-glutamyl series, only the L-erythro-gamma-fluoro-glutamyl residue is carboxylated, showing that the enzymatic hydrogen abstraction is stereospecific and corresponds to the elimination of the pro S hydrogen of glutamic acid. The lack of in vitro dicarboxylation of model peptides in contrast with the in vivo polycarboxylation of endogenous precursors is discussed along with the regiospecificity of the reaction with the different substrates.


FGF23 induces expression of two isoforms of NAB2, which are corepressors of Egr-1.
Fibroblast growth factor 23 (FGF23) is a key humoral factor in phosphate homeostasis and skeletogenesis, though the nature of its intracellular signaling is still unclear. Recently, Egr-1, a zinc-finger transcription factor, was identified as an immediate early response gene of FGF23 in the kidney. We report here, that FGF23 induces not only Egr-1 but also two isoforms of NAB2, which are specific co-repressors of Egr-1. Both isoforms of NAB2 induced by FGF23 were localized in the nucleus and suppressed the transcriptional activity of Egr-1. A negative feedback loop established by Egr-1 and NAB2 may thus be involved in mediating the physiological effects of FGF23.


Peritoneal dialysis as salvage renal replacement therapy after complete failure of hemodialysis access in an elderly patient with multiple comorbidities.
Although peritoneal dialysis (PD) has been advocated as a suitable substitution therapy in patients with failure of hemodialysis (HD) blood access, documentation of the performance of PD in such patients is limited. Here, we present an elderly patient with total failure of HD blood access who has had a remarkably successful course on PD. A 78-year-old man with several comorbidities started continuous ambulatory PD after a 3.5-year course of HD complicated by repeated vascular access infections and clotting episodes. These access complications resulted in 8 hospitalizations and led to inability to ambulate following a right femoral shaft fracture sustained in a fall secondary to confusion during an episode of access sepsis, and to superior vena cava (SVC) syndrome following SVC thrombosis after internal jugular catheter insertion. Over approximately 3 years, PD has been very successful in this patient, with 2 early routine episodes of peritonitis and 1 early episode of exit-site infection, control of hematologic and biochemical values, no hospitalizations in the 2.5 years before the time of writing, and good quality of life. A dedicated spouse performing the PD tasks has been a major factor in the success of PD in this patient. Peritoneal dialysis can be successful as a renal replacement procedure in incapacitated elderly patients with failure of HD blood access. In these cases, the success of PD is enhanced by dedicated family members taking on PD tasks that the patient cannot perform.


Chronic diseases and multimorbidity among unemployed and employed persons in the Netherlands: a register-based cross-sectional study.
The first objective of this study was to describe the age-specific prevalence of chronic diseases and multimorbidity among unemployed and employed persons. The second objective was to examine associations of employment status and sociodemographic characteristics with chronic diseases and multimorbidity. Data linkage of cross-sectional nationwide registries on employment status, medication use and sociodemographic characteristics in 2016 was applied. Register-based data covering residents in the Netherlands. 5 074 227 persons aged 18-65 years were selected with information on employment status, medication use and sociodemographic characteristics. Multiple logistic regression analysis and descriptive statistics were performed to examine associations of employment and sociodemographic characteristics with the prevalence of chronic diseases and multimorbidity. The age-specific prevalence of six common chronic diseases was described, and Venn diagrams were applied for multimorbidity among unemployed and employed persons. Unemployed persons had a higher prevalence of psychological disorders (18.3% vs 5.4%), cardiovascular diseases (20.1% vs 8.9%), inflammatory diseases (24.5% vs 15.8%) and respiratory diseases (11.7% vs 6.5%) than employed persons. Unemployed persons were more likely to have one (OR 1.30 (1.29-1.31)), two (OR 1.74 (1.73-1.76)) and at least three chronic diseases (OR 2.59 (2.56-2.61)) than employed persons. Among unemployed persons, psychological disorders and inflammatory conditions increased with age but declined from middle age onwards, whereas a slight increase was observed among employed persons. Older persons, women, lower educated persons and migrants were more likely to have chronic diseases. Large differences exist in the prevalence of chronic diseases and multimorbidity among unemployed and employed persons. The age-specific prevalence follows a different pattern among employed and unemployed persons, with a relatively high prevalence of psychological disorders and inflammatory conditions among middle-aged unemployed persons. Policy measures should focus more on promoting employment among unemployed persons with chronic diseases.


Improving adolescent health policy: incorporating a framework for assessing state-level policies.
Many US policies that affect health are made at the state, not the federal, level. Identifying state-level policies and data to analyze how different policies affect outcomes may help policy makers ascertain the usefulness of their public policies and funding decisions in improving the health of adolescent populations. A framework for describing and assessing the role of federal and state policies on adolescent health and well-being is proposed; an example of how the framework might be applied to the issue of teen childbearing is included. Such a framework can also help inform analyses of whether and how state and federal policies contribute to the variation across states in meeting adolescent health needs. A database on state policies, contextual variables, and health outcomes data can further enable researchers and policy makers to examine how these factors are associated with behaviors they aim to impact.


Research of laser-induced damage of aluminum alloy 5083 on micro-arc oxidation and composite coatings treatment.
The laser-induced damage of aluminum alloy 5083 is affected by its surface treatment. Here, we investigate the effects of aluminum alloy's ability of laser-induced damage on micro-arc oxidation and composite coatings treatment. Results demonstrate a distinct difference of damage parameters on laser pulse duration at 355 nm between micro-arc oxidation and composite coatings treatment on aluminum alloy, including the laser-induced damage threshold, particulate pollutants for different surface treatment, and the damage morphology, respectively. We now find that the threshold of laser-induced damage is improved a lot through simulative calculation and experiments. Furthermore, the experimental results suggests that surface treatment contribute to the number of particulate pollutants and the microstructure of damaged pit.