Targets and Quantitative Distribution of GABAergic Synapses in the Visual Cortex of the Cat.
The morphology and postsynaptic targets of GABA-containing boutons were determined in the striate cortex of cat, using a postembedding immunocytochemical technique at the electron microscopic level. Two types of terminals, both making symmetrical synaptic contacts, were GABA-positive. The first type (95% of all GABA-positive boutons) contained small pleomorphic vesicles, the second type (5%) contained larger ovoid vesicles. Furthermore, 99% of all cortical boutons containing pleomorphic vesicles were GABA positive, and all boutons with pleomorphic vesicles made symmetrical synaptic contacts. These results together with previously published stereological data (Beaulieu and Colonnier, 1985, 1987) were used to estimate the density of GABA-containing synapses, which is about 48 million/mm3 in the striate cortex. The postsynaptic targets of GABA positive boutons were also identified and the distribution was calculated to be as follows: 58% dendritic shafts, 26.4% dendritic spines, 13.1% somata and 2.5% axon initial segments. A total of 11% of the postsynaptic targets were GABA immunoreactive and therefore originated from GABAergic neurons. The results demonstrate that the majority of GABAergic synapses exert their action on the membrane of dendrites and spines rather than on the somata and axons of neurons.


Evaluation of the abbott LCx HIV-1 RNA quantitative, a new assay for quantitative determination of human immunodeficiency virus type 1 RNA.
A new quantitative reverse transcription (RT)-PCR assay for human immunodeficiency virus type 1 (HIV-1) RNA (Abbott LCx HIV RNA Quantitative assay) has been compared with the Organon NucliSens assay on 521 retrospective samples obtained from HIV-1-positive patients monitored during highly active antiretroviral therapy, 79 of whom were assayed also by the Chiron Quantiplex 3.0 system and on characterized panels. The LCx system showed a moderate correlation (r = 0.795) and gave higher results than the NucliSens system on 245 of 327 concordant positive samples, with similar sensitivity. Correlation with Quantiplex system results was higher (r = 0.943). LCx reproducibility was very good; the procedure was simple, well controlled, and rapid (up to 48 results in 7 h). The HIV RNA quantitative assay on the LCx system is suitable for routine use.


[Mortality structure following spine and spinal cord injuries].
In a group of 520 patients with injury to the spine and spinal cord 125 died within 10 years. The highest fatality rate (76.0 +/0 3.8) is recorded in the first year after the injury. In the following 10 years the fatality rate was uniform and ranged between 1.6 and 4.1%. This value increases with the patient's age, the severity of the spinal cord injury, and the degree of damage to the spinal ligamento-bursal apparatus. Among the total number of injured, 76% have a survival period of more than 10 years.


Microbial assimilation of hydrocarbons: cellular distribution of fatty acids.
The distribution of cellular fatty acids in defined lipid classes was analyzed in Micrococcus cerificans after growth on specified hydrocarbons. Neutral lipid, phospholipid, and cell residue fatty acids were qualitatively and quantitatively determined for M. cerificans grown on nutrient broth, tetradecane (C(14)), pentadecane (C(15)), hexadecane (C(16)), and heptadecane (C(17)), respectively. Percentage of total cellular fatty acid localized in defined lipid classes from cells grown on the above growth substrates was (i) neutral lipid-11.8, 1.81, 7.74, 23.1, and 2%; (ii) phospholipid-74.5, 65, 66.43, 62.1, and 86%; (iii) cell residue lipid-13.5, 33.29, 25.82, 14.78, and 11.9%. Phospholipid fatty acid chain length directly reflected the carbon number of the alkane substrate, with 40, 84, 98, and 77% of the fatty acids being 14, 15, 16, and 17 carbons when cells were grown on C(14), C(15), C(16), and C(17)n-alkanes, respectively. The bound lipids of the cell residue after chloroform-methanol extraction were characterized by 2-hydroxydodecanoic and 2-hydroxytetradecanoic acids plus a broad spectrum of fatty acids ranging from C(10) to C(17) chain length. An increase in total unsaturated fatty acid localized in the phospholipids was noted from cells grown on alkanes greater than 15 carbons long. An extracellular accumulation of free fatty acid (FFA) was demonstrated in hexadecane-grown cultures that was not apparent in non-hydrocarbon-grown cultures. Identification of extracellular FFA demonstrated direct derivation from hexadecane oxidation. Studies supporting inhibition of de novo fatty acid biosynthesis in relationship to extracellular FFA and hexadecane oxidation are described. The ability to alter the fatty acid composition of membrane polar lipids in a predictable manner by the alkane carbon source provides an excellent model system for the investigation of membrane structure-function relationships in M. cerificans.


Herpes simplex virus infection: problems and prospects as perceived by a peripatetic pediatrician.
The multivaried aspects of the herpes simplex viruses (HSV) types 1 and 2 and the infections they produce are discussed. Points emphasized are: (1) the need for considering these (and other viruses) from an evolutionary perspective; (2) the necessity of disseminating current methods for virus identification; (3) the great progress in molecular-virological aspects and in the genetics of the virus which provide new tools for epidemiological and immunological studies and define more convincingly the possible causal role of HSV-2 in cervical carcinogenesis; (4) the problems with vaccines and the therapeutic advances and failures; (5) the great psychosocial aspect of some herpetic infections and the need to be sympathetic and supportive to afflicted patients and their families; (6) the overreaction regarding HSV that currently exists among physicians, nurses, the public, and the press resulting in increased misery for those afflicted or misdiagnosed, or in poor advice or management given by some physicians pressured in part by the fear of malpractice suits. The problems then are many but the prospects for their solution are in sight as more research at all levels is being conducted today in all corners of the world on the complex herpes simplex viruses.


AUSTWICKIA CHELONAE IN A WILD GOPHER TORTOISE (GOPHERUS POLYPHEMUS) AND EVIDENCE OF POSITIVE SELECTION ON THE DIPHTHERIA-LIKE TOXIN GENE.
Austwickia (Dermatophilus) chelonae is a filamentous, Gram-positive Actinobacteria in the Dermatophilaceae family. It has caused fatal granulomatous disease in diverse captive reptile species on three continents, but its presence in wild or free-ranging populations was unknown. An adult female gopher tortoise (Gopherus polyphemus) was presented euhydrated, but cachectic and infested with ticks, with two firm, encapsulated masses over the cranioventral neck and right stifle. The tortoise had moderate nonregenerative anemia and evidence of inflammation; plasma biochemistry data was within normal limits. Fine needle aspirate of the neck lesion revealed abundant necrosis and aggregates of cocci. Computed tomography delineated the masses and revealed an additional mass adjacent to the left zygomatic bone. After surgical excision, histology identified chronic granulomas with intralesional filamentous bacteria. Pan-bacterial 16S rRNA PCR and sequencing of the masses identified A. chelonae. Despite treatment with oxytetracycline and ceftazidime, the tortoise deteriorated and was euthanatized. An esophageal lesion consistent with A. chelonae was seen on postmortem examination, although it was determined that the tortoise ultimately succumbed to fungal pneumonia caused by Metarhizium robertsii, an entomopathogenic biotoxin sprayed as insect control. This case reveals A. chelonae is present in free-ranging chelonians in North America. This organism produces a toxin gene similar to diphtheria toxin, one of the most potent known biotoxins, which has not been previously identified outside the genus Corynebacterium. Novel PCR primers were designed for the toxin and rpoB genes, which were amplified and sequenced from two cases and compared with two available genomes. Selection analysis revealed that the toxin gene is under positive selection, which implies it interacts significantly with the immune system, making it a good candidate for immunodiagnostic test development.


Can we trust population surveys to count Medicaid enrollees and the uninsured?
Health foundations, such as the Robert Wood Johnson Foundation (RWJF), make multimillion-dollar investments in programs to expand insurance coverage. These efforts are driven largely by estimates of the number of uninsured people derived from population surveys, which might overestimate the number of uninsured people if they under-count people enrolled in Medicaid. This paper reports the results of the RWJF-funded California Medicaid Undercount Experiment (CMUE) to estimate the extent of underreporting of Medicaid in the California Health Interview Survey (CHIS) and its effect on estimates of uninsurance. Although some over- and underreporting occurs, overall CHIS Medicaid estimates match administrative counts for adults.


Surgical Outcomes after Abdominoperineal Resection with Sacrectomy and Soft Tissue Reconstruction: Lessons Learned.
Abdominoperineal resection (APR), which involves resection of the rectum, anal canal, and perianal skin, results in a large dead space in the pelvis, devascularized tissues, and high bacterial loads. This predisposes to wound complications, especially in the setting of neoadjuvant chemoradiotherapy. Additional sacral resection further compounds these effects. We aimed to assess perineal wound outcomes and complications in patients who underwent flap reconstruction for APR with sacrectomy (APRS) at our institution. We reviewed the charts of all patients who underwent flap reconstruction for APRS over a 20-year period (1999-2018). Medical comorbidities, details of the surgical procedure, and major and minor wound complications were recorded and analyzed. Forty-six patients underwent flap reconstruction following APRS-28 (60%) for colorectal cancer, 8 (17%) for sacral chordoma, and 10 diagnosed with other malignant histologies. Rectus abdominis myocutaneous (RAM) flap reconstruction was used in 42 patients (91%). The median time to the first major perineal complication was 111 days (interquartile range: 22-660 days). Half of our cohort (n = 23) experienced a major perineal complication. No significant differences were found in major or minor perineal or abdominal wall complications between RAM flap and other flaps. APR with high sacrectomy was performed in 27 patients (59%) and was associated with significantly increased full-thickness dehiscence in the perineal region when compared with APR with low sacrectomy, 33 versus 0%, respectively (p = 0.0076). Complete flap loss occurred in one patient. The RAM flap was the workhorse flap for pelvic reconstruction following APRS in our cohort. Wound complications are common following APRS. High sacrectomy is associated with higher incidence of complications compared with low sacrectomy. Optimal surgical planning and patient counseling is fundamental to improve current surgical outcomes.


Fosfomycin vs Ertapenem for Outpatient Treatment of Complicated Urinary Tract Infections: A Multicenter, Retrospective Cohort Study.
We sought to determine the comparative efficacy of fosfomycin vs ertapenem for outpatient treatment of complicated urinary tract infections (cUTIs). We conducted a multicenter, retrospective cohort study involving patients with cUTI treated with outpatient oral fosfomycin vs intravenous ertapenem at 3 public hospitals in Los Angeles County between January 2018 and September 2020. The primary outcome was resolution of clinical symptoms 30 days after diagnosis. We identified 322 patients with cUTI treated with fosfomycin (n = 110) or ertapenem (n = 212) meeting study criteria. The study arms had similar demographics, although patients treated with ertapenem more frequently had pyelonephritis or bacteremia while fosfomycin-treated patients had more retained catheters, nephrolithiasis, or urinary obstruction. Most infections were due to extended-spectrum β-lactamase-producing E. coli and Klebsiella pneumoniae, 80%-90% of which were resistant to other oral options. Adjusted odds ratios for clinical success at 30 days, clinical success at last follow-up, and relapse were 1.21 (95% CI, 0.68-2.16), 0.84 (95% CI, 0.46-1.52), and 0.94 (95% CI, 0.52-1.70) for fosfomycin vs ertapenem, respectively. Patients treated with fosfomycin had significant reductions in length of hospital stay and length of antimicrobial therapy and fewer adverse events (1 vs 10). Fosfomycin outcomes were similar irrespective of duration of lead-in intravenous (IV) therapy or fosfomycin dosing interval (daily, every other day, every third day). These results would support the conduct of a randomized controlled trial to verify efficacy. In the meantime, they suggest that fosfomycin may be a reasonable stepdown from IV antibiotics for cUTI.


Local brain atrophy accounts for functional activity differences in normal aging.
Functional brain imaging studies of normal aging typically show age-related under- and overactivations during episodic memory tasks. Older individuals also undergo nonuniform gray matter volume (GMv) loss. Thus, age differences in functional brain activity could at least in part result from local atrophy. We conducted a series of voxel-based blood oxygen level-dependent (BOLD)-GMv analyses to highlight whether age-related under- and overrecruitment was accounted for by GMv changes. Occipital GMv loss accounted for underrecruitment at encoding. Efficiency reduction of sensory-perceptual mechanisms underpinned by these areas may partly be due to local atrophy. At retrieval, local GMv loss accounted for age-related overactivation of left dorsolateral prefrontal cortex, but not of left dorsomedial prefrontal cortex. Local atrophy also accounted for age-related overactivation in left lateral parietal cortex. Activity in these frontoparietal regions correlated with performance in the older group. Atrophy in the overrecruited regions was modest in comparison with other regions as shown by a between-group voxel-based morphometry comparison. Collectively, these findings link age-related structural differences to age-related functional under- as well as overrecruitment.


Second-generation Platelet Concentrate (Platelet-rich Fibrin) as a Scaffold in Regenerative Endodontics: A Case Series.
The purpose of this case series was to report the clinical and radiographic results of a pulp regenerative procedure using platelet-rich fibrin (PRF), a second-generation platelet concentrate, in immature teeth with necrotic pulps. Root canal revascularization using PRF was performed on 4 immature teeth with necrotic pulps. After access cavity preparation, the root canals were irrigated with low concentration sodium hypochlorite solution (1.5% sodium hypochlorite [20 mL/canal, 5 minutes]) and then irrigated with saline (20 mL/canal, 5 minutes). Equal proportions (167 mg) of ciprofloxacin, metronidazole, and cefaclor were mixed and diluted to a final concentration of 1 g/mL. Finally, the canal was sealed with 3-4 mm of a temporary restorative material, and patients were dismissed for 2 to 3 weeks. At the second appointment, 9 mL of the patient's whole blood was obtained and centrifuged to prepare a PRF clot. Canals were irrigated with 17% EDTA, and a sharp spreader was inserted beyond the apex. Then, the PRF clot was placed inside the root canals, and Biodentine (Septodont, Saint-Maur, France) was placed directly over the PRF. The teeth were restored permanently with glass ionomer cement and composite resin. Clinical examinations revealed that all cases were asymptomatic at the recall appointments at 1, 3, 6, 12, and 18 months. Radiographs revealed resolution of the periapical lesions, further root development, and apical closure in all cases. On the basis of the short-term results up to 12 months, PRF clots acted as successful scaffolds for the regeneration of pulpal contents in immature teeth with necrotic pulps.


Burst Conditions of Explosive Volcanic Eruptions Recorded on Microbarographs
Explosive volcanic eruptions generate pressure disturbances in the atmosphere that propagate away either as acoustic or as shock waves, depending on the explosivity of the eruption. Both types of waves are recorded on microbarographs as 1- to 0.1-hertz N-shaped signals followed by a longer period coda. These waveforms can be used to estimate burst pressures and gas concentrations in explosive volcanic eruptions and provide estimates of eruption magnitudes.


An autoradiographical study of [3H]thymidine incorporation into subcutaneously transplanted mouse molar teeth. Cell proliferation and migration in transplanted teeth.
Mice bearing either allografts or isografts of 10 day old molar teeth were injected with [3H]thymidine to identify proliferating and migrating cells within the graft and surrounding tissues. In isografts proliferating cells were found successively in the area underlying the cervix, in the cervical pulp and the coronal pulp. However, cells did not migrate from the cervical host tissue into the pulp, and it was concluded that donor cells are responsible for reparative processes in tooth isografts. Very few labelled cells were identified at any time in tooth allografts, which were not repaired. It is suggested that allografts are not repaired because allogeneic inhibition prevents the residual donor tissue from proliferating and differentiating. Inhibition of proliferation of residual cells may also account for the absence of a cell-mediated immune response to tooth allografts.


Lithium-sodium countertransport: physiological moorings for red cell transport disorders in hypertension.
Erythrocyte lithium-sodium countertransport, a mode of ouabain-insensitive monovalent cation metabolism, is increased in human essential hypertension, but no pathophysiological link to hypertension has yet been established. Similarities between red cell lithium-sodium countertransport and renal proximal tubular sodium-hydrogen ion exchange suggest a possible role for a countertransport analogue in the control of proximal fluid reabsorption. To test this hypothesis, we measured red cell countertransport and renal lithium clearance, a reliable measure of proximal tubular sodium reabsorption, in normotensives and hypertensives. We found that lithium clearance is (a) inversely correlated with red cell countertransport, (b) decreased in essential hypertensives (reflecting increased proximal sodium reabsorption), and (c) lower in normotensive subjects with a family history of hypertension than in those without such a history. The mechanism by which enhanced proximal tubular sodium reabsorption is related to essential hypertension is unknown, but in addition to its connection to lithium clearance, red cell countertransport is correlated with total peripheral resistance and diastolic compliance of the left ventricle. It is therefore possible that alterations of transport demonstrated in red cells reflect generalized membrane characteristics shared by cardiovascular and renal tissues. Measurements of lithium clearance provide a useful tool for further characterizing the control of renal proximal tubular fluid reabsorption in hypertension. Studies using these measurements may help to explain mechanisms of salt sensitivity and differential responses to antihypertensive therapies as well as yield insights into the heritable basis of human hypertension.


Update on human cytomegalovirus in destructive periodontal disease.
Human cytomegalovirus (HCMV), a herpesvirus, is discussed in this review as it relates to destructive periodontal disease in humans. HCMV genomic sequences, detected by polymerase chain reaction identification, occur with elevated frequency in severe adult periodontitis, localized and generalized aggressive (juvenile) periodontitis, Papillon-Lefèvre syndrome periodontitis, acute necrotizing ulcerative gingivitis, and periodontal abscesses. Herpesviruses establish lifelong persistent infections. HCMV infection involves an asymptomatic latent phase interrupted by periods of recrudescence where viral replication and possibly clinical disease become manifest. HCMV reactivation is triggered by a number of immunosuppressive factors, some of which have been shown also to be risk factors/indicators of periodontitis. HCMV periodontal infection may cause release of tissue-destructive cytokines, overgrowth of pathogenic periodontal bacteria, and initiation of cytotoxic or immunopathologic events. A growing body of data supports the concept that HCMV contributes to severe types of periodontal disease. HCMV infection of the periodontium may alter the immune control of resident microorganisms and be important in a multistage pathogenesis of periodontitis involving viral activation, periodontopathic bacteria, and host immune responses. Understanding the significance of HCMV and other herpesviruses in the development of periodontal disease may have important therapeutic implications. Vaccines against HCMV, which are in various stages of development, need to be evaluated for their ability to decrease the incidence of destructive periodontal disease.


A trait-based framework for predicting foodborne pathogen risk from wild birds.
Recent foodborne illness outbreaks have heightened pressures on growers to deter wildlife from farms, jeopardizing conservation efforts. However, it remains unclear which species, particularly birds, pose the greatest risk to food safety. Using >11,000 pathogen tests and 1565 bird surveys covering 139 bird species from across the western United States, we examined the importance of 11 traits in mediating wild bird risk to food safety. We tested whether traits associated with pathogen exposure (e.g., habitat associations, movement, and foraging strategy) and pace-of-life (clutch size and generation length) mediated foodborne pathogen prevalence and proclivities to enter farm fields and defecate on crops. Campylobacter spp. were the most prevalent enteric pathogen (8.0%), while Salmonella and Shiga-toxin producing Escherichia coli (STEC) were rare (0.46% and 0.22% prevalence, respectively). We found that several traits related to pathogen exposure predicted pathogen prevalence. Specifically, Campylobacter and STEC-associated virulence genes were more often detected in species associated with cattle feedlots and bird feeders, respectively. Campylobacter was also more prevalent in species that consumed plants and had longer generation lengths. We found that species associated with feedlots were more likely to enter fields and defecate on crops. Our results indicated that canopy-foraging insectivores were less likely to deposit foodborne pathogens on crops, suggesting growers may be able to promote pest-eating birds and birds of conservation concern (e.g., via nest boxes) without necessarily compromising food safety. As such, promoting insectivorous birds may represent a win-win-win for bird conservation, crop production, and food safety. Collectively, our results suggest that separating crop production from livestock farming may be the best way to lower food safety risks from birds. More broadly, our trait-based framework suggests a path forward for co-managing wildlife conservation and food safety risks in farmlands by providing a strategy for holistically evaluating the food safety risks of wild animals, including under-studied species.


Roses Have Thorns: Understanding the Downside of Oncological Care Delivery Through Visual Analytics and Sequential Rule Mining.
Personalized head and neck cancer therapeutics have greatly improved survival rates for patients, but are often leading to understudied long-lasting symptoms which affect quality of life. Sequential rule mining (SRM) is a promising unsupervised machine learning method for predicting longitudinal patterns in temporal data which, however, can output many repetitive patterns that are difficult to interpret without the assistance of visual analytics. We present a data-driven, human-machine analysis visual system developed in collaboration with SRM model builders in cancer symptom research, which facilitates mechanistic knowledge discovery in large scale, multivariate cohort symptom data. Our system supports multivariate predictive modeling of post-treatment symptoms based on during-treatment symptoms. It supports this goal through an SRM, clustering, and aggregation back end, and a custom front end to help develop and tune the predictive models. The system also explains the resulting predictions in the context of therapeutic decisions typical in personalized care delivery. We evaluate the resulting models and system with an interdisciplinary group of modelers and head and neck oncology researchers. The results demonstrate that our system effectively supports clinical and symptom research.


Telehealth Competencies: Leveled for Continuous Advanced Practice Nurse Development.
The COVID-19 pandemic spurred a rapid uptake of telehealth utilization, with advanced practice registered nurses (APRNs) at the forefront of telehealth care delivery. To advance training of nurse practitioners and support curricular development, essential APRN student competencies in telehealth were developed. Although telehealth competencies have been developed, little is understood about their evaluation across the curricula. Moving to competency-based nursing education involves leveling broad competencies into subcompetencies, including those for telehealth. Subcompetencies support frequent, multimodal evaluation of student progress across APRN curricula. Adapting Benner's Novice to Expert Theory, faculty experts in telehealth and graduate nursing education used an iterative process to develop and level subcompetencies aligned with the Four Ps of Telehealth framework. Telehealth subcompetencies were leveled for preclinical and clinical rotations and for readiness for practice. The leveled subcompetencies, aligned with the Four Ps of Telehealth framework, will support APRN faculty in diverse programs as they implement competency-based education in telehealth.


Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment.
The First Key Symposium was held in Stockholm, Sweden, 2-5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.


Ordering the reductive and cytochrome P450 oxidative steps in demethylsterigmatocystin formation yields general insights into the biosynthesis of aflatoxin and related fungal metabolites.
The biosynthesis of the potent environmental carcinogen aflatoxin B1 involves ca. 15 steps beyond the first polyketide intermediate. Central among these is the rearrangement of the anthraqinone versicolorin A to the xanthone demethylsterigmatocystin. Genetic evidence strongly suggests that two enzymes are required for this process, a cytochrome P450, AflN, and a probable NADPH-dependent oxidoreductase, AflM. Given the overall redox change evident in this skeletal rearrangement, two rounds of oxidation and a reduction necessarily occur. Earlier experiments indicated that reductive deoxygenation of versicolorin A is not the first step. In the present report we consider a mechanistic alternative that AflM-mediated reduction is instead the last of these three reactions prior to formation of the xanthone intermediate. To this end, 9-hydroxydihydrodemethylsterigmatocystin was prepared by total synthesis as was its 9-deoxy analogue, an established aflatoxin precursor. During the final isolation of the "angular" synthetic xanthone targets it was found that acid catalysis promoted their isomerization to thermodynamically favored "linear" xanthones. Whole-cell and ground-cell incubations of the 9-hydroxy- and 9-deoxyxanthones were conducted with a mutant strain of Aspergillus parasiticus blocked at the first step of the pathway and examined for their ability to support aflatoxin production. The 9-deoxyxanthone gave dramatically enhanced levels of the mycotoxin. The 9-hydroxyxanthone, on the other hand, afforded no detectable increase in aflatoxins above controls, indicating that reductive deoxygenation at C-9 of a xanthone precursor does not take place in aflatoxin biosynthesis. Constraints imposed by earlier studies and the experiments in this paper serve to eliminate simple and intuitive conversions of versicolorin A to demethylsterigmatocystin and lead inescapably to a more subtle reaction sequence of oxidation-reduction-oxidation. Previous puzzling observations of extensive A-ring hydrogen exchange in the course of the rearrangement of versicolorin A to demethylsterigmatocystin have now been explained by a new mechanism that is consistent with all extant data. We propose that P450-mediated aryl epoxidation (AflN) initially disrupts the aromatic A-ring of versicolorin A. Oxirane opening enables A-ring proton exchange, as does the subsequent AflM-mediated reductive step. A second cycle of P450 oxidation (AflN), this time a Baeyer-Villiger cleavage, enables decarboxylation and the formation of demethylsterigmatocystin. Mechanistic and stereoelectronic principles that underlie this proposal are described and may prove general as illustrated in biogenetic hypotheses for four other fungal anthraquinone --> xanthone transformations.


The International Classification of Functioning, Disability and Health-based factors related to physical activity level in adults with muscle diseases.
The aim of this study was to investigate the physical activity (PA) level of adults with muscle diseases and the association of factors affecting PA behaviour. Forty-five adults with muscle diseases and 44 healthy participants were included. The PA was assessed by a SenseWear Armband and the International Physical Activity Questionnaire. The muscle strength, pain, fatigue severity, activity limitations, functional mobility level and quality of life were also assessed. Compared with the healthy group, adults with muscle diseases had significantly lower step counts and duration of moderate and vigorous PA (P < 0.05). The BMI of the patients was related to total energy expenditure (P < 0.05). The total number of steps, energy expenditure and duration of moderate PA of the patients were related to the 6-min walk test (P < 0.05). There was a correlation between total, moderate and vigorous PA and mental health in adults with muscle diseases (P < 0.05). The most important factors in reflecting PA in adults with muscle diseases are considered as BMI from personal factors, functional mobility from activity limitations and quality of life in the dimension of participation.


Tympanic pressure gradients and otoacoustic emissions.
The purpose of this study was to investigate the immediate effects of tympanic over- and under-pressure, induced by variations in ambient pressure on click-evoked otoacoustic emissions (CEOAEs) in healthy individuals. It was of particular interest to elucidate whether changes in the CEOAE response in both spectral and time domains could be attributed not only to tympanic, but also to cochlear influence. Nine healthy subjects with normal hearing and middle ear pressure were exposed to ambient pressure changes in a pressure chamber. The pressure was progressively changed in 100 daPa steps to accomplish an increase and a decrease in tympanic pressure. Pressure equilibration of the middle ear was avoided. The relative tympanic over- and under-pressure (+/- 320daPa) was monitored by tympanometry and the CEOAEs recorded at every step of tympanic pressure change. There was a statistically significant reduction of the otoacoustic emission (OAE) response levels and reproducibility already at 100 daPa of ambient pressure change. The OAE response was progressively reduced by increased pressure gradients. The CEOAEs recorded during progressive tympanic over- and under-pressure also had increasingly shorter latencies. These changes of the OAE response characteristics were most pronounced in the 750 to 3000 Hz frequency bands. The progressive attenuation of the OAE response and the concomitant shortening of the OAE response latencies were observed during a combination of altered middle and inner ear pressure. Although the middle and inner ear influence cannot be separated we suggest, based on our findings, that the shortening of latencies may partly be caused by inner ear pressure changes and stiffening of the labyrinthine membranes. Further studies are needed to more specifically clarify the relative contribution of the tympanic and labyrinthine influence, respectively, for the various aspects of pressure influence on the OAE response.


CoQ10 exerts hepatoprotective effect in fructose-induced fatty liver model in rats.
Excess dietary sugar is associated with deleterious metabolic effects, liver injury, and coenzyme-Q10 (CoQ10) deficiency. This study investigates the ability of CoQ10 to protect against fructose-induced hepatic damage. Rats were fed tap water or 30% fructose for 12 weeks with or without CoQ10 (10 mg/kg, po). An additional group of rats were allowed to feed on either water or 30% fructose for 12 weeks, followed by four weeks of treatment with either the vehicle or CoQ10. Fructose-fed rats showed lower CoQ10 levels, increased systolic pressure, increased body weight, higher liquid consumption, decreased food intake and hyperglycemia. Fructose-fed rats also showed deteriorated serum and liver lipid profiles, impaired liver function tests and oxidative status, and lower expression of adiponectin receptor 1 and 2 along with higher GLUT-2 levels. Furthermore, following fructose treatment, tyrosine kinase-PI3K pathway was inhibited. Additionally, there was an increase in the levels of apoptotic markers and serum visfatin and a decrease in the levels of adiponectin and soluble receptor of the advanced glycated end product. Consequently, several histopathological changes were detected in the liver. Concurrent or three months post-exposure administration of CoQ10 in fructose rats significantly reversed or attenuated all the measured parameters and hepato-cytoarchitecture alterations. This study suggests CoQ10 supplement as a possible prophylaxis or treatment candidate for fructose-induced liver injury.


Drinking Ice-Cold Water Reduces the Severity of Anticancer Drug-Induced Taste Dysfunction in Mice.
Taste disorders are common adverse effects of cancer chemotherapy that can reduce quality of life and impair nutritional status. However, the molecular mechanisms underlying chemotherapy-induced taste disorders remain largely unknown. Furthermore, there are no effective preventive measures for chemotherapy-induced taste disorders. We investigated the effects of a combination of three anticancer drugs (TPF: docetaxel, cisplatin and 5-fluorouracil) on the structure and function of mouse taste tissues and examined whether the drinking of ice-cold water after TPF administration would attenuate these effects. TPF administration significantly increased the number of cells expressing apoptotic and proliferative markers. Furthermore, TPF administration significantly reduced the number of cells expressing taste cell markers and the magnitudes of the responses of taste nerves to tastants. The above results suggest that anticancer drug-induced taste dysfunction may be due to a reduction in the number of taste cells expressing taste-related molecules. The suppressive effects of TPF on taste cell marker expression and taste perception were reduced by the drinking of ice-cold water. We speculate that oral cryotherapy with an ice cube might be useful for prophylaxis against anticancer drug-induced taste disorders in humans.


Impact of Self-Care and Mobility on One or More Post-Acute Care Transitions.
Objective: To investigate the association between functional status and post-acute care (PAC) transition(s). Methods: Secondary analysis of 2013-2014 Medicare data for individuals aged ≥66 years with stroke, lower extremity joint replacements, and hip/femur fracture discharged to one of three PAC settings (inpatient rehabilitation facilities, skilled nursing facilities, and home health agencies). Functional scores were co-calibrated into a 0-100 scale across settings. Multilevel logistic regression was used to test the partition of variance (%) and the probability of PAC transition attributed to the functional score in the initial PAC setting. Results: Patients discharged to inpatient rehabilitation facilities with higher function were less likely to use additional PAC. Function level in an inpatient rehabilitation facility explained more of the variance in PAC transitions than function level while in a skilled nursing facility. Discussion: The function level affected PAC transitions more for those discharged to an inpatient rehabilitation facility than to a skilled nursing facility.


Factors preventing gun acquisition and carrying among incarcerated adolescent males.
Despite the wide availability of guns in the United States, not all delinquent adolescents own guns and not all adolescent gun owners carry them at all times. Research about the factors that prevent high-risk youth from acquiring and carrying guns is limited. To determine, from the perspective of incarcerated adolescent males, factors that prevent acquiring or carrying guns, either on a temporary or permanent basis. In-depth, semistructured interviews were conducted with randomly selected incarcerated adolescent males at a residential juvenile justice facility from January to May 1998. Transcribed interviews were examined for recurrent themes. Forty-five incarcerated adolescent males. Reported factors limiting gun acquisition and carrying. Seventy-one percent of the sample had either owned or carried a gun out of their home. We identified 6 recurring themes that, at least on occasion, prevented or delayed delinquent youth from acquiring or carrying guns. The most commonly cited factors were fear of being arrested and incarcerated and lack of perceived need for a gun. Other themes included not wanting to hurt oneself or others, respect for the opinions of others, inability to find a source for a desired gun, and lack of money to acquire a desired gun. We identified 6 factors that limited gun acquisition and carrying among a sample of incarcerated male adolescents. Knowledge of these factors should inform intervention efforts to reduce youth gun acquisition and carrying.


Periocular capillary hemangiomas: indications and options for treatment.
Capillary hemangiomas are the most common periocular and orbital tumors of childhood that typically arise in infancy. Though the diagnosis is frequently made on clinical examination, various diagnostic modalities may be helpful in initial evaluation and follow-up. Tests may be necessary in diagnosing suspect cases or aid in the differentiation of potential malignant tumors. In the vast majority of cases these tumors undergo spontaneous involution without sequelae. However, some periocular and orbital capillary hemangiomas require intervention to prevent serious complications. Other tumors require treatment to lessen the surgical burden for cosmetic repair. When treatment is necessary, there are a number of therapeutic options available. As there is no standard, potential risks and benefits must be discussed with the family and treatment should be specific in each case. A complete understanding of the natural history of the tumor, indications for treatment, and response to different therapies is imperative in managing this common lesion.


Platelet function, coagulation and fibrinolysis in patients with previous coronary and cerebrovascular ischemic events.
Ischemic stroke (IS) or transient ischemic attack (TIA) history is present in 4-17% of patients with coronary artery disease (CAD). This subgroup of patients is at high risk for both ischemic and bleeding events. The aim of this study was to determine the role of platelet aggregability, coagulation and endogenous fibrinolysis in patients with CAD and previous IS or TIA. A prospective case-control study that included 140 stable CAD patients divided into two groups: the CASE group (those with a previous IS/TIA, n=70) and the CONTROL group (those without a previous IS/TIA, n=70). Platelet aggregability (VerifyNow Aspirin® and VerifyNow P2Y12®), coagulation (fibrinogen and thromboelastography by Reorox®) and endogenous fibrinolysis (D dimer and plasminogen activator inhibitor-1) were evaluated. Patients in the CASE group presented significantly higher systolic blood pressure levels (135.84±16.09 vs 123.68±16.11, p<0.01), significantly more previous CABG (25.71% vs 10%, p=0.015) and significantly higher calcium channel blocker usage (42.86% vs 24.29%, p=0.02) than those in the control group. In the adjusted models, low triglyceride values, low hemoglobin values and higher systolic blood pressure were significantly associated with previous IS/TIA (CASE group). Most importantly, platelet aggregability, coagulation and fibrinolysis tests were not independently associated with previous cerebrovascular ischemic events (CASE group). Platelet aggregability, coagulation and endogenous fibrinolysis showed similar results among CAD patients with and without previous IS/TIA. Therefore, it remains necessary to identify other targets to explain the higher bleeding risk presented by these patients.


Development of excitatory and inhibitory neurotransmitters in transitory cholinergic neurons, starburst amacrine cells, and GABAergic amacrine cells of rabbit retina, with implications for previsual and visual development of retinal ganglion cells.
Starburst amacrine cells (SACs), the only acetylcholine (ACh)-releasing amacrine cells (ACs) in adult rabbit retina, contain GABA and are key elements in the retina's directionally selective (DS) mechanism. Unlike many other GABAergic ACs, they use glutamic acid decarboxlyase (GAD)(67), not GAD(65), to synthesize GABA. Using immunocytochemistry, we demonstrate the apoptosis at birth (P0) of transitory putative ACs that exhibit immunoreactivity (IR) for the ACh-synthetic enzyme choline acetyltransferase (ChAT), GAD(67), and the GABA transporter, GAT1. Only a few intact, displaced ChAT-immunoreactive SAC bodies are detected at P0. At P2, ChAT-IR is detected in the two narrowly stratified substrata of starburst dendrites in the inner plexiform layer (IPL). Quantitative analysis reveals that in the first postnatal week, only a small fraction of SACs cells express ChAT- and GABA-IR. Not until the end of the second week are they expressed in all SACs. At P0, a three-tiered stratification of GABA-IR is present in the IPL, entirely different from the adult pattern of seven substrata, emerging at P3-P4, and optimally visualized at P13. At P0, GAD(65) is detectable in normally placed AC bodies. At P1, GAD(65)-IR appears in dendrites of nonstarburst GABAergic ACs, and by P5 is robust in the adult pattern of four substrata in the IPL. GAD(65)-IR never co-localizes with ChAT-IR. In a temporal comparison of our data with physiological, pharmacological, and ultrastructural studies, we suggest that transitory ChAT-immunoreactive cells share with SACs production of stage II (nicotinic) waves of previsual synchronous activity in ganglion cells (GCs). Further, we conclude that (1) GAD(65)-immunoreactive, non-SAC GABAergic ACs are the most likely candidates responsible for the suppression of stage III (muscarinic/AMPA-kainate) waves and (2) DS responses first appear in DS GCs, when about 50% of SACs express ChAT- and GABA-IR, and in 100% of DS GCs, when expression occurs in all SACs.


ERKs in cancer: friends or foes?
The extracellular signal-regulated kinase ERK1 and ERK2 (ERK1/2) cascade regulates a variety of cellular processes by phosphorylating multiple target proteins. The outcome of its activation ranges from stimulation of cell survival and proliferation to triggering tumor suppressor responses such as cell differentiation, cell senescence, and apoptosis. This pathway is intimately linked to cancer as several of its upstream activators are frequently mutated in human disease and are shown to accelerate tumorigenesis when engineered in the mouse genome. However, measurement of activated ERKs in human cancers or mouse models does not always support a role in tumorigenesis, and data consistent with a role in tumor suppression have been reported as well. The intensity of ERK signaling, negative feedback loops that regulate the pathway, and cross-talks with other signaling pathways, seem to be of primary importance in determining the final cellular outcome. Cell senescence, a putative tumor-suppression mechanism, depends on high-intensity ERK signals that trigger phosphorylation-dependent protein degradation of multiple proteins required for cell-cycle progression. This response may be circumvented during carcinogenesis by a variety of mechanisms, some of them yet to be discovered, which in essence turn ERK functions from tumor suppression to tumor promotion. The use of pharmacologic inhibitors targeting this pathway must be carefully evaluated so they are applied to cases in which ERKs are mainly oncogenic.


Electric field controllable magnetic coupling of localized spins mediated by itinerant electrons: a toy model.
In this paper, we propose a toy model to describe the magnetic coupling between the localized spins mediated by the itinerant electron in partially delocalized mixed-valence (MV) systems. This minimal model takes into account the key interactions that are common for all such systems, namely, electron transfer in the valence-delocalized moiety and magnetic exchange between the localized spins and the delocalized electrons. The proposed descriptive model is exactly solvable which allows us to qualitatively and quantitatively discuss the main features of the whole class of partially delocalized MV systems. In the case of relatively strong exchange coupling, the combined action of these two interactions is shown to give rise to a specific kind of double exchange coupling termed here as "external core" double exchange. In the opposite case of relatively strong electron transfer, the general Hamiltonian is shown to be reduced to the effective Hamiltonian of indirect exchange of the localized spins. We argue a possibility to efficiently control the magnetic coupling of the localized spins using an external electric field acting on the delocalized part of the system. Finally, we discuss the perspectives of the present model for molecular spintronics and spin qubits.


An efficient HPLC method for the quantification of isoflavones in soy extracts and soy dietary supplements in routine quality control.
Food supplements containing soy extracts are increasingly used to treat menopausal complaints. For the quality control of such products a RP-HPLC method for the quantification of daidzein, genistein, glycitein and their respective glucosides and acetylglucosides in soy extracts and nutraceuticals was developed and validated. The extraction of the samples is very simple and avoids time-consuming handling and expensive cartridges or reagents. The compounds are quantified by internal standardization with 4'-hydroxyflavanon which is easily available at a reasonable price. On a base-deactivated C18 column good separation and excellent peak shape of the analytes are achieved in short time by gradient elution with water and acetonitrile. Accompanying substances do not interfere. The method was applied to the analysis of different commercial soy preparations.


Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean.
Fundamental to biological decision-making is the ability to generate bimodal expression patterns where 2 alternate expression states simultaneously exist. Here, we use a combination of single-cell analysis and mathematical modeling to examine the sources of bimodality in the transcriptional program controlling HIV's fate decision between active replication and viral latency. We find that the HIV transactivator of transcription (Tat) protein manipulates the intrinsic toggling of HIV's promoter, the long terminal repeat (LTR), to generate bimodal ON-OFF expression and that transcriptional positive feedback from Tat shifts and expands the regime of LTR bimodality. This result holds for both minimal synthetic viral circuits and full-length virus. Strikingly, computational analysis indicates that the Tat circuit's noncooperative "nonlatching" feedback architecture is optimized to slow the promoter's toggling and generate bimodality by stochastic extinction of Tat. In contrast to the standard Poisson model, theory and experiment show that nonlatching positive feedback substantially dampens the inverse noise-mean relationship to maintain stochastic bimodality despite increasing mean expression levels. Given the rapid evolution of HIV, the presence of a circuit optimized to robustly generate bimodal expression appears consistent with the hypothesis that HIV's decision between active replication and latency provides a viral fitness advantage. More broadly, the results suggest that positive-feedback circuits may have evolved not only for signal amplification but also for robustly generating bimodality by decoupling expression fluctuations (noise) from mean expression levels.


Detection of staphylococcal membrane receptors on virus-infected cells by direct adhesin overlay.
We partially characterized the interaction between 125I-labeled surface proteins of Staphylococcus aureus, obtained by thermal extraction, and purified plasma membranes from uninfected and influenza virus A/FM/1/47-infected Madin-Darby canine kidney cells. The radioactivity profile of surface-labeled proteins, derived from anion-exchange high-pressure liquid chromatography, showed a mixture of acidic polypeptides in a peak which contained approximately 5% of the total protein injected; adsorption with purified plasma membranes reduced radioactivity by 5 to 7% and altered elution profiles. Using a direct adhesin overlay procedure, we found that these surface-labeled proteins reacted with polypeptides located on the external surface of plasma membranes which were shared by both virus-infected and uninfected cells or were unique to virus-infected cells. Our data may help explain the enhanced adherence of S. aureus to influenza virus A-infected cells in vitro.


Integrins and mechanotransduction of the vascular myogenic response.
This review summarizes what is currently known about the role of integrins in the vascular myogenic response. The myogenic response is the rapid and maintained constriction of a blood vessel in response to pressure elevation. A role for integrins in this process has been suggested because these molecules form an important mechanical link between the extracellular matrix and the vascular smooth muscle cytoskeleton. We briefly summarize evidence for a general role of integrins in mechanotransduction. We then describe the integrin subunit combinations known to exist in smooth muscle and the vascular wall matrix proteins that may interact with these integrins. We then discuss the effects of integrin-specific peptides and antibodies on vascular tone and on calcium entry mechanisms in vascular smooth muscle. Because integrin function is linked to the cytoskeleton, we discuss evidence for the role of the cytoskeleton in determining myogenic responsiveness. Finally, we analyze evidence that integrin-linked signaling pathways, such as those involving protein tyrosine phosphorylation cascades and mitogen-activated protein kinases, are required for myogenic tone.


The feasibility of matching and quota sampling in epidemiologic studies.
Matching is often used to eliminate the effects of potential confounders. The practical execution of a matched design will usually involve additional sampling effort to find appropriate quotas of persons who satisfy the matching criteria. If this effort is substantial, it may render the matched design less attractive than using unmatched samples with covariance adjustment in the analysis. This paper presents numerical results on the sampling effort needed to complete various matched designs: The effort is measured by the number of candidates (N) that must be sampled to identify the matches for analysis. Feasibility of matched sampling is described by the ratio of the expected value of N to its theoretical minimum, and by its coefficient of variation. Feasibility must be weighed against the resulting quality of matches and the possibility of residual confounding. The results show that designs with smaller matching quotas in larger numbers of categories are more difficult to execute. However, the relative variation in N is mainly a function of the category quotas and is only weakly dependent on the number of categories. Recommendations are made regarding the number of categories and the quota sizes that lead to acceptable matched designs. The results are applicable to both observational and experimental studies in which matching or other quota sampling is used.


What impact do prescription drug charges have on efficiency and equity? Evidence from high-income countries.
As pharmaceutical expenditure continues to rise, third-party payers in most high-income countries have increasingly shifted the burden of payment for prescription drugs to patients. A large body of literature has examined the relationship between prescription charges and outcomes such as expenditure, use, and health, but few reviews explicitly link cost sharing for prescription drugs to efficiency and equity. This article reviews 173 studies from 15 high-income countries and discusses their implications for important issues sometimes ignored in the literature; in particular, the extent to which prescription charges contain health care costs and enhance efficiency without lowering equity of access to care.


ZRF1: a novel epigenetic regulator of stem cell identity and cancer.
The Zuotin-related factor 1, ZRF1, has recently been identified as an epigenetic regulator of gene transcription in stem cells and cancer. During differentiation of human teratocarcinoma cells, ZRF1 promotes transcriptional induction of developmental genes that are repressed by Polycomb complexes. Importantly, ZRF1 has recently been shown to be required for both neural differentiation of embryonic stem cells (ESCs) and for maintenance of neural progenitor cell (NPC) identity. Moreover, a dual role has now emerged for ZRF1 in cancer: on the one hand, ZRF1 plays a crucial role in oncogene-induced senescence (OIS) by activating the INK4/ARF locus, thus working as a tumor suppressor; on the other hand, ZRF1 promotes leukemogenesis in acute myeloid leukemia (AML) in a Polycomb-independent fashion. Therefore, increasing evidence points to ZRF1 as a novel target for therapy of neurodegenerative diseases and cancer.


Rabbit model of Staphylococcus aureus implant-associated spinal infection.
Post-surgical implant-associated spinal infection is a devastating complication commonly caused by Staphylococcus aureus Biofilm formation is thought to reduce penetration of antibiotics and immune cells, contributing to chronic and difficult-to-treat infections. A rabbit model of a posterior-approach spinal surgery was created, in which bilateral titanium pedicle screws were interconnected by a plate at the level of lumbar vertebra L6 and inoculated with a methicillin-resistant S.aureus (MRSA) bioluminescent strain. In vivo whole-animal bioluminescence imaging (BLI) and ex vivo bacterial cultures demonstrated a peak in bacterial burden by day 14, when wound dehiscence occurred. Structures suggestive of biofilm, visualized by scanning electron microscopy, were evident up to 56 days following infection. Infection-induced inflammation and bone remodeling were also monitored using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and computed tomography (CT). PET imaging signals were noted in the soft tissue and bone surrounding the implanted materials. CT imaging demonstrated marked bone remodeling and a decrease in dense bone at the infection sites. This rabbit model of implant-associated spinal infection provides a valuable preclinical in vivo approach to investigate the pathogenesis of implant-associated spinal infections and to evaluate novel therapeutics.


Pulmonary Neuroendocrine Neoplasms Overexpressing Epithelial-Mesenchymal Transition Mechanical Barriers Genes Lack Immune-Suppressive Response and Present an Increased Risk of Metastasis.
Typical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC), and small cell lung carcinomas (SCLC) encompass a bimodal spectrum of metastatic tumors with morphological, histological and histogenesis differences, The hierarchical structure reveals high cohesiveness between neoplastic cells by mechanical desmosomes barrier assembly in carcinoid tumors and LCNEC, while SCLC does not present an organoid arrangement in morphology, the neoplastic cells are less cohesive. However, the molecular mechanisms that lead to PNENs metastasis remain largely unknown and require further study. In this work, epithelial to mesenchymal transition (EMT) transcription factors were evaluated using a set of twenty-four patients with surgically resected PNENs, including carcinomas. Twelve EMT transcription factors (BMP1, BMP7, CALD1, CDH1, COL3A1, COL5A2, EGFR, ERBB3, PLEK2, SNAI2, STEAP1, and TCF4) proved to be highly expressed among carcinomas and downregulated in carcinoid tumors, whereas upregulation of BMP1, CDH2, KRT14 and downregulation of CAV2, DSC2, IL1RN occurred in both histological subtypes. These EMT transcription factors identified were involved in proliferative signals, epithelium desmosomes assembly, and cell motility sequential steps that support PNENs invasion and metastasis in localized surgically resected primary tumor. We used a two-stage design where we first examined the candidate EMT transcription factors using a whole-genome screen, and subsequently, confirmed EMT-like changes by transmission electron microscopy and then, the EMT-related genes that were differentially expressed among PNENs subtypes were predicted through a Metascape analysis by in silico approach. A high expression of these EMT transcription factors was significantly associated with lymph node and distant metastasis. The sequential steps for invasion and metastasis were completed by an inverse association between functional barrier created by PD-L1 immunosuppressive molecule and EMT transcriptional factors. Our study implicates upregulation of EMT transcription factors to high proliferation rates, mechanical molecular barriers disassembly and increased cancer cell motility, as a critical molecular event leading to metastasis risk in PNENs thus emerging as a promising tool to select and customize therapy.


[Mechanism of fibrinolysis and thrombolytic therapy].
The thrombolytic treatment with plasminogen activators, such as physiological tissue-type plasminogen activator (t-PA), suffers from a number of significant limitations. There is a resistance to reperfusion and acute coronary reocclusion. The peculiarity of t-PA and one-chain urokinase treatment is their using in very high doses. Thus the process of thrombolytic therapy is proceeding with a deviation from the fibrinolytic mechanism, which is needs of a little quantity of tissue-type plasminogen activator and provides the physiologic thrombolysis without systemic complication. The estimation of this disaccordance suggests, the possible reasons of these complications.


Cognitive dysfunction in Nigerians with Parkinson's disease.
Despite the original description of Parkinson's disease (PD) as a disorder in which "the senses and intellect remain uninjured," there is now sufficient evidence that cognitive dysfunction does occur. This research determined the frequency, pattern, and predictors of cognitive dysfunction among 51 Nigerian patients with PD compared with 50 demographically matched controls using the modified Community Screening Instrument for Dementia (CSI'D') and selected items from the Ibadan Neuropsychological Battery (I-NB). In all, 21.6% patients with PD (4% of controls) exhibited cognitive impairment (P = 0.008) defined, for the purposes of this study, as total modified CSI'D' score below 2 SD of the mean score of the control group. Cognitive dysfunction in patients with PD encompassed memory, language, and executive dysfunction. Correlates of cognitive dysfunction included older age at PD onset (P = 0.001), older current age (P < 0.001), and higher UPDRS motor score (P = 0.005). After logistic regression, older age at onset of PD was the only independent predictor of cognitive dysfunction. (O.R = 1.29; 95% CI = 1.08-1.57, P = 0.006). Cognitive dysfunction occurs more frequently in Nigerians with PD compared to controls. Older age at disease onset is an important determinant of cognitive dysfunction in PD.


Uptake of fentanyl in pulmonary endothelium.
Fentanyl is a basic amine shown to have extensive first-pass pulmonary uptake. To evaluate the role of the pulmonary endothelium in this uptake process, the simultaneous pharmacokinetics of [3H]fentanyl and two marker drugs, blue dextran, and [14C]antipyrine, were evaluated in a flow-through system of pulmonary endothelial cells. Fentanyl equilibrium kinetics were determined in a static culture system. The flow-through system consisted of monolayers of bovine pulmonary artery endothelial cells cultured on solid microcarrier beads placed in a chromatography column and perfused at 1.0 ml/min (37 degreesC). Fentanyl and the markers were injected into the perfusate at the top of the column and samples were collected from the eluate at 9-s intervals for 10 min. The pharmacokinetic analyses were based on determinations of mean transit time and flow. Fentanyl was partitioned into the pulmonary endothelial cells 60 times more than the tissue water space marker antipyrine. In the static system, monolayers of bovine pulmonary artery endothelial cells were cultured in 3.8-cm2 wells to which were added 0 to 946 micromol (0-500 microgram/ml) of unlabeled fentanyl citrate and 0.14 micromol of [3H]fentanyl. After a 10-min incubation, solubilized cells were assayed for [3H]fentanyl. Pulmonary endothelial cells contained a higher relative fentanyl concentration at lower fentanyl supernatant concentrations than would be expected if uptake occurred by diffusion alone. These observations can be explained with a model of fentanyl uptake that includes both passive diffusion and saturable active uptake. This suggests that the extensive first-pass pulmonary uptake of fentanyl observed in vivo is due largely to vascular endothelial drug uptake by both a passive and a saturable active uptake process.


[Differential effectiveness of youth welfare measures: a comparative study on the effectiveness of day care measures].
Single parent families not only differ from traditional families regarding socioeconomic problems and missing a parent, but also concerning the duration of using youth welfare measures, psychological problems in single parents, and the way youth welfare measures are ended. Due to different basic parameters in these two family settings, this study investigates the differential effectiveness of youth day care measures. In total, 55 children and adolescents (aged 6 to 14 years) and their parents were involved. Using axis I, II and V, ICD-10 multiaxial presentation, data on the general burden of problems, externalizing problems, emotional problems, and parenting skills were recorded before care measures began and again after they had ended. Although day care measures were very effective in both family settings, traditional families showed a significantly stronger decline of externalizing problems than single parent families, exceptions being emotional problems and burdens.


Optimized calibration methodology of VIIRS day-night band low-gain stage using a solar diffuser.
An enhanced methodology of the standard on-orbit calibration of the day-night band (DNB) of the visible infrared imaging radiometer suite on board the Suomi National Polar-orbiting Partnership satellite is presented, specifically for the low-gain stage. The range of the "sweet spot" for the fully illuminated scans in the calibration events is expanded from 4° to 7.8° in order to increase the number of fully illuminated scans to 72, which then permits a complete calibration of the DNB to be carried out within one orbit for all 36 aggregated modes and the two mirror sides. This improves over the current operational methodology, which is with a more restricted range for the sweet spot that requires multiple orbits to complete a calibration. The expansion necessarily requires the expansion of a key calibration input, the product of the bidirectional reflectance factor of the solar diffuser (SD) with the vignetting function describing the transmission of the attenuation screen in front of the SD port, or BVP for short. The expanded BVP is derived by fitting the function in three separate intervals and joining them smoothly to form a single function. Additional enhancements include the adaptation of the previously improved SD degradation and all other improvements developed for reflective solar bands from the previous work. The time-dependent relative spectral response is also characterized and implemented, and its impact and improvements are studied and discussed. The result shows that the improved DNB calibration coefficients are more stable and smooth, and less noisy.


Nonlinear interaction of KrF laser radiation with small water droplets.
Results have been obtained for the interaction of KrF excimer laser radiation (lambda = 248 nm, t(pulse) = 17 ns) with 60-microm diam distilled water droplets for irradiance values ranging from 3 to 230 GW/cm(2). Laser images of the droplet breakup during the time intervals from 0 to 100 ns indicate that the dynamic breakup processes are highly nonlinear. At low irradiance (3 GW/cm(2)) material is ejected from both the illuminated and shadow hemispheres of the droplet in qualitative agreement with the location of the electric field peaks predicted by plane wave Lorenz-Mie theory calculations. As the irradiance is increased, the interaction on the shadow hemisphere becomes stronger while the interaction on the illuminated hemisphere decreases. This nonlinear behavior is attributed to rapid electrical breakdown of the droplet near the shadow surface. The breakdown region destroys the ability of the droplet to redirect energy toward the front hemisphere of the droplet. Without this mechanism, the localized electric field maxima near the illuminated surface of the droplet cannot arise. Measurements were also taken of the average material velocities during the time intervals from 0 to 50 ns after arrival of the high energy pulse. Velocities ranged from 1000 m/s at 3 GW/cm(2) to 6000 m/s at 230 GW/cm(2).


Music therapy for coma patients: preliminary results.
The application of quantitative EEG (δ+θ/α+β value) and GCS value to evaluate the role of music therapy for traumatic brain injury coma patients. Forty patients of traumatic brain injury coma were selected to meet the inclusion criteria. Twenty cases were selected for the rehabilitation, neurology and neurosurgery ward, whose families could actively cooperate with, and the patients could receive a long-term fixed nursing staff with formal music therapy (music group). Twenty cases were in the intensive care unit of the rehabilitation, neurology and neurosurgery ward. Their families members cooperated poorly, had often changing nursing staff, and without a formal music therapy (control group). After a one monthe follow up, the GCS value and quantitative EEG (δ+θ/α+β value) were compared between the two groups. Between the two groups, except for the presence or absence of formal music therapy, the rest of treatment had no significant difference and was matched by age, gender, and injury types. In 40 cases of traumatic brain injury patients, the GCS value increased in the music group after treatment when compared to the control group. The difference between the two groups was significant (p < 0.05). The quantitative EEG value (δ+θ/α+β value) of music group values were decreased after treatment, and the difference was significant compared with the control group (p < 0.05). Through the quantitative EEG (δ+θ/α+β value) and the GCS observation score, music therapy in patients with craniocerebral trauma coma has obviously an effect on promoting to regain consciousness. The quantitative EEG (δ+θ/α+β value) can be used as an objective index to evaluate the state of brain function.


Effect of Adenomatous Polyposis Coli Loss on Tumorigenic Potential in Pancreatic Ductal Adenocarcinoma.
Loss of the Adenomatous Polyposis Coli (APC) tumor suppressor in colorectal cancer elicits rapid signaling through the Wnt/β-catenin signaling pathway. In contrast to this well-established role of APC, recent studies from our laboratory demonstrated that APC functions through Wnt-independent pathways to mediate in vitro and in vivo models of breast tumorigenesis. Pancreatic ductal adenocarcinoma (PDAC) has an overall median survival of less than one year with a 5-year survival rate of 7.2%. APC is lost in a subset of pancreatic cancers, but the impact on Wnt signaling or tumor development is unclear. Given the lack of effective treatment strategies for pancreatic cancer, it is important to understand the functional implications of APC loss in pancreatic cancer cell lines. Therefore, the goal of this project is to study how APC loss affects Wnt pathway activation and in vitro tumor phenotypes. Using lentiviral shRNA, we successfully knocked down APC expression in six pancreatic cancer cell lines (AsPC-1, BxPC3, L3.6pl, HPAF-II, Hs 766T, MIA PaCa-2). No changes were observed in localization of β-catenin or reporter assays to assess β-catenin/TCF interaction. Despite this lack of Wnt/β-catenin pathway activation, the majority of APC knockdown cell lines exhibit an increase in cell proliferation. Cell migration assays showed that the BxPC-3 and L3.6pl cells were impacted by APC knockdown, showing faster wound healing in scratch wound assays. Interestingly, APC knockdown had no effect on gemcitabine treatment, which is the standard care for pancreatic cancer. It is important to understand the functional implications of APC loss in pancreatic cancer cells lines, which could be used as a target for therapeutics.


Molecular mechanisms of androgen-independent growth of human prostate cancer LNCaP-AI cells.
The goal of this study is to investigate the molecular mechanisms of androgen-independent growth in prostate cancer. We have established an androgen-independent prostatic carcinoma LNCaP-AI (defined as a LNCaP cell line that is capable of growing in charcoal-stripped serum) from the androgen-dependent LNCaP-FGC cells. In contrast to the androgen-independent PC-3 human prostate cancer cells, LNCaP-AI cells still express a similar level of androgen receptor as their parental cells and are sensitive to androgen stimulation. Compared with the parental LNCaP-FGC cells, LNCaP-AI cells are more resistant to apoptosis induced by 12-O-tetradecanoylphorbol-13-acetate and express a much higher level of antiapoptotic gene bcl-2 and cyclin-dependent kinase inhibitor p21, which may confer an enhanced antiapoptosis phenotype. On the other hand, expression of cyclin-dependent kinase inhibitor p16 is significantly reduced in the LNCaP-AI cells, implying the release of an inhibitory effect of p16 on cell cycle progression. Taken together, our results suggest that multiple factors contribute to the development of androgen-independent growth of prostatic carcinoma cells, including enhancement of cell antiapoptosis function, release of cell cycle inhibition, and stimulation of cell proliferation by alternative signaling pathways.


The role of transforming growth factor-beta in suppression of hepatic metastasis from colon cancer.
The role of transforming growth factor-beta (TGF-beta) in the development of hepatic metastasis from colon cancer is not clearly elucidated. The aim of this study was to determine the role of TGF-beta in the development of such metastasis. Two human colon cancer cell lines were utilized: FET-alpha cells (intact TGF-beta inhibitory response), and CBS cells (defects in TGF-beta inhibitory response caused by a deficiency in type II receptor activity). The ability of these cell lines to metastasize was analysed in an orthotopic colon cancer mouse model. FET-alpha cells did not metastasize to the liver, but showed lung metastasis in 10% of the animals, whereas CBS cells gave rise to metastasis in 65%. Following the elimination of TGF-beta activity by transfection and overexpression of dominant negative type II receptor, FET-alpha cells demonstrated liver and lung metastasis in 70% of the animals. Similarly, after the restoration of type II receptor activity by ectopic expression, CBS cells formed metastasis in fewer (10%) animals. The results of our study demonstrate for the first time that TGF-beta displays selective metastasis suppressor activity. These abnormal pathways can serve as selective targets for future development of targeted therapies.


[Mechanisms of tooth eruption].
Tooth eruption is of the utmost importance for the normal development of the dentition and the face. Since the 1980s, it has been known that the tooth germ itself is not essential for facilitating the processes that make tooth eruption possible. For that reason, recent research on the regulatory mechanisms of tooth eruption has focused mainly on the enamel organ and the dental follicle. Different regulatory mechanisms act on the occlusal and the apical sides of an erupting tooth. On the occlusal side osteoclast differentiation is stimulated. This leads to the development of an eruption canal, a process in which macrophages and matrix metalloproteases also play an important role. On the apical side the most important factors are the transcription factor RUNX2 and the bone morphogenic protein 2. They are responsible for the deposition of trabecular bone in that area. Many regulatory mechanisms which are involved in tooth eruption are also active in other developmental processes. This explains that certain syndromes can also have an effect on the tooth eruption process.


Granulocyte/macrophage colony-stimulating factor is essential for the viability and function of cultured murine epidermal Langerhans cells.
A panning method has been developed to enrich Langerhans cells (LC) from murine epidermis. In standard culture media, the enriched populations progressively lose viability over a 3-d interval. When the cultures are supplemented with keratinocyte-conditioned medium, LC viability is improved and the cells increase in size and number of dendritic processes. Accessory function, as monitored by stimulating activity in the mixed lymphocyte reaction (MLR), increases at least 10-20-fold. The conditioned media of stimulated macrophages and T cells also support the viability and maturation of cultured LC. A panel of purified cytokines has been tested, and only granulocyte/macrophage colony-stimulating factor (GM-CSF) substitutes for bulk-conditioned medium. The recombinant molecule exhibits half-maximal activity at 5 pM. Without activity are: IL-1-4; IFN-alpha/beta/gamma; cachectin/TNF; M- and G-CSF. A rabbit anti-GM-CSF specifically neutralizes the capacity of keratinocyte-conditioned medium to generate active LC. However, GM-CSF is not required for LC function during the MLR itself. We conclude that the development of immunologically active LC in culture is mediated by GM-CSF. The observation that these dendritic cells do not respond to lineage-specific G- and M-CSFs suggests that LC represent a distinct myeloid differentiation pathway. Because GM-CSF can be made by nonimmune cells and can mediate the production of active dendritic cells, this cytokine provides a T-independent mechanism for enhancing the sensitization phase of cell-mediated immunity.


Fathers' Representation in Observational Studies on Parenting and Childhood Obesity: A Systematic Review and Content Analysis.
The involvement of fathers in caregiving has increased substantially over the past 30 years. Yet in child and adolescent psychopathology, few studies include fathers as research participants and few present results for fathers separate from those for mothers. We test for the first time whether a similar pattern exists in research on parenting and childhood obesity. To conduct a systematic review and quantitative content analysis of observational studies on parenting and childhood obesity to (1) document the inclusion of fathers, relative to mothers, as research participants and (2) examine characteristics of studies that did and did not include fathers. This study presents new data on the number and gender of parent research participants. We searched title, abstract, and Medical Subject Headings term fields in 5 research databases (PubMed, EMBASE, Academic Search Premier, PsycINFO, and CINAHL) using terms combining parents or parenting (e.g., mother, father, caregiver, parenting style, food parenting) and obesity (e.g., obesity, body weight, overweight) or obesity-related lifestyle behaviors (e.g., diet, snacking, physical activity, outdoor play, exercise, media use). We identified and screened studies as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) published between January 2009 and December 2015, examining links between parenting and childhood obesity, including parents or caregivers as research participants, and written in English. We excluded interventions, nonhuman studies, dissertations, conference abstracts, and studies on youths with specific medical conditions. Of 5557 unique studies, 667 studies were eligible. For each of the 667 studies, 4 coders were trained to code characteristics of the study (e.g., publication year, geographic region, journal, study focus) and parent research participants (e.g., parent gender, demographic background, biological relationship with child, and residential status). We established intercoder reliability before coding the full sample of studies (mean Krippendorf's alpha = .79; average percentage agreement = 94%). Of the studies, 1% included only fathers. By contrast, 36% included only mothers. Although slightly more than 50% of studies (n = 347) included at least 1 father, only 57 studies reported results for fathers separate from those for mothers. When we combined them with studies including only fathers, 10% of studies overall reported results for fathers. Samples sizes of fathers were small compared with mothers. Of studies with fathers, 59% included 50 or fewer fathers, whereas 22% of studies with mothers included 50 or fewer mothers. The mean sample size for fathers across all eligible studies was 139, compared with 672 for mothers. Overall, fathers represented 17% of parent participants across all eligible studies. This study unequivocally demonstrates that fathers are underrepresented in recent observational research on parenting and childhood obesity. Public health implications. The underrepresentation of fathers in obesity research compromises the development of effective family interventions for childhood obesity prevention. Targeted opportunities and incentives are needed to support research with fathers.


Recently released Black men's perceptions of the impact of incarceration on sexual partnering.
Evidence suggests that men with recent histories of incarceration are more likely to engage in high-risk sexual activity, however there is limited research exploring how having been recently released from prison might impact men's sexual risk behaviours or sexual partnering. This qualitative study explores the ways in which exposure to incarceration impacts the dynamics of sexual partnering among recently released Black men in Baltimore, USA. In-depth interviews were conducted with 19 recently released Black men between 21-45 years of age living in the city. Data were analysed using a combination of inductive and deductive approaches. Participants reported that women living in the neighbourhoods to which they returned found recently released men to be highly desirable sexual partners because they offered increased potential for sexual gratification, were perceived as healthier than other sexual partners in their communities and represented opportunities for attaining financial stability and the potential for establishing romantic partnerships. As a result, men reported they had more opportunities for sex and more power to negotiate sex with women. Recently released Black men's perceptions of their own sexual desirability among women raise important implications regarding power in the sexual relationships of recently released men that may increase HIV- and sexually transmitted infection-related risk for recently released men and their sexual partners.


Changes of infection of the prostate tissue by Herpesviridae family viruses and HPV in prostate cancer patients depending on the stage of the pathological process.
The role of infection in the beginning and progression of prostate cancer is not known to the end at the moment. Experimental data, presented in the article, are obtained by hybridization in situ and demonstrate high degree of infection of the prostate tissue by viruses with the oncogenic and oncomodulation properties HCMV, EBV, HHV8 and HPV. The authors revealed that in patients at different substages of T2 stage infection of the prostate tissue increased from T2a to T2c. The importance of these findings is discussed.


Malignant fibrous histiocytoma: outcome and prognostic factors following conservation surgery and radiotherapy.
Malignant fibrous histiocytoma is the most common type of soft tissue sarcoma. This communication presents an analysis of outcome and prognostic factors based on a retrospective review of patients with this disease treated by conservation surgery and radiotherapy. From 1966 to 1991, 271 consecutive patients with malignant fibrous histiocytoma were treated with conservation surgery and radiotherapy. The outcome with local control, metastatic relapse, and survival as end points was evaluated by univariate and multivariate statistics to delineate independently significant prognostic factors. Postoperative radiation at a mean dose of 62.8 Gy was used in 195 patients and preoperative radiation at a mean dose of 50 Gy was used in 76 patients. At a median follow-up of 7.3 years, 123 patients (45%) developed disease relapse at some site. Fifty-seven (21%) developed local recurrence leading to an actuarial local relapse rate of 26% at 10 years, 83 (31%) developed metastatic relapse for a 10-year actuarial metastatic rate of 33%, and the 5-, 10-, and 15-year survival rates were 68, 60, and 46%, respectively. For local control, prior local recurrence (in 53 patients) was identified as an adverse factor, yielding a 10-year recurrence rate of 42% compared to 22% for 218 patients without prior disease (p < 0.01). Also, a positive surgical margin (in 46 patients) was adverse with a 10-year local recurrence rate of 39% compared to a recurrence rate of 17% with negative margins (167) (p=0.01). Patients with pathologically undocumented resection margins (58) had a local recurrence rate similar to those with positive margins (41% at 10 years). Tumor site (extremity vs. nonextremity), location (proximal vs. distal), size (< or = 5 cm vs. > 5 cm), and histology (myxoid vs. nonmyxoid) were not significant determinants of local outcome. For metastatic relapse, the major determinants of outcome were histology (myxoid vs. nonmyxoid) and tumor size. Myxoid tumors (59 patients) had a low metastatic propensity (13% 10-year metastatic rate) compared to nonmyxoid tumors (212 patients) (40% 10-year metastatic rate) (p < 0.01). Size was an important covariate for metastases for both myxoid and nonmyxoid tumors. For nonmyxoid tumors the 10-year metastatic rates were 23 and 51% for lesions less than or greater than 5 cm. For myxoid tumors a significant metastatic rate appeared only for tumors exceeding 10 cm (10-year metastatic rates of 8% vs. 44% for tumors less than vs. greater than 10 cm). In this retrospective review we found no evidence that adjuvant chemotherapy decreased the metastatic rate. In multivariate analysis for metastatic relapse and survival, tumor histology (nonmyxoid vs. myxoid) and size (< 5 cm vs. > 5 cm) were the only independent determinants of outcome. Malignant fibrous histiocytoma is a heterogeneous disease and its myxoid variant must be recognized as a distinct entity. Both variants are locally aggressive and require equally aggressive local therapy. Conservation surgery striving for negative margins with radiation therapy provides acceptable local control and is the treatment of choice for this disease. Patients with myxoid tumors do not require systemic therapy; patients with nonmyxoid disease exceeding 5 cm are at significant risk for metastases and the development of effective adjuvant treatment is an important research tool.


Effects of multimodal exercise on clinical status and patient-reported outcomes in children undergoing hematopoietic stem cell transplantation.
There are limited data available regarding effectiveness of exercise training in children undergoing hematopoietic stem cell transplantation (HSCT). We aimed to investigate effects of multimodal exercise program on clinical status and patient-reported outcomes including pain, fatigue, depression, and quality of life (QOL) level of children and their parents' QOL level. Twenty-six children undergoing HSCT participated in this study. Clinical status, pain, fatigue, depression, and QOL level of children were assessed three times: before HSCT, at discharge, and one month later. For intervention group (IG, n = 15), multimodal exercise program was performed five days a week, throughout hospitalization and children were advised to continue exercise program at home. For control group (CG, n = 11), being active as much as possible was advised. The number of painful day and pain intensity was significantly lower in IG than in CG during hospitalization (p < .05). Depression level decreased in IG at the time points (p ˂ .05); however, there was no significantly difference between groups. The QOL level was higher in IG than CG only at control measurements (p ˂ .05). In addition, QOL level of the parents decreased in both groups (p ˂ .05). There was no statistically difference between groups in terms of other clinical variables. The multimodal supervised exercise program has positive effects on children's pain and QOL level. Exercise program was also well tolerated by children during hospitalization. In addition, QOL levels of the parents were also negatively affected during hospitalization, and interventions aiming to increase QOL level of the parents should be considered.


Superhydrophobic Al2O3/MMT-PDMS Coated Fabric for Self-Cleaning and Oil-Water Separation Application.
This study introduces a novel superhydrophobic coating applied to the fabric surface through spray coating of the Al2O3/MMT nanocomposite and PDMS polymer to enhance the surface roughness and reduce the surface tension, respectively. The as-prepared coating exhibits a remarkable superhydrophobic property with a water contact angle (WCA) of ∼174.6° and a water sliding angle (WSA) < 5°. Notably, the fabric demonstrates a self-cleaning property through removing dust and dirt via adhering to water droplets. Moreover, the insignificant loss of WCA (3.2 and 1%) after exposure to alkaline and acidic media for 10 days verifies the promising chemical stability of the coated layer, whereas WCA > 160° after 24 h of immersion in various organic solvents further indicates the layer resistance. Besides, the layer sustains WCA of 174.5, 172.5, and 168.45° after 1 month of air exposure, ultrasonic washing, and 50 cycles of home laundry. The mechanical resistance of the fabric was verified by maintaining a WCA of 158.73° after 200 abrasion cycles. Also, the layer exhibits thermal resistance with <4.1% of WCA loss in the temperature range of -10 to 180 °C. Additionally, the superhydrophobic coating excels in oil-water separation, achieving >99% separation efficiency for various oils. These exceptional properties position the fabric for diverse applications, including protective clothing, outdoor gear, medical textiles, and sportswear, emphasizing its versatility and novelty in the realm of superhydrophobic materials.


Comparison of Clinical Outcomes After Anterior Cervical Discectomy and Fusion Versus Cervical Total Disk Replacement in Patients With Modic-2 Changes on MRI.
A retrospective investigation. The aim of this research is to compare the clinical and radiologic outcomes of patients with Modic-2 changes who underwent anterior cervical discectomy and fusion (ACDF) or cervical total disk replacement (TDR) in single level. There were few studies focused on the clinical and radiologic outcomes of patients with Modic-2 changes who underwent ACDF or cervical TDR in single level. A total of 76 patients with Modic-2 changes who underwent TDR or ACDF with complete follow-up data were analyzed retrospectively. Patients with chronic axial symptoms resulting from single-level cervical spine disease manifested as radiculopathy or myelopathy following 6 months of invalid conservative treatment. Clinical evaluations were performed preoperatively and repeated at 5 years after operation. In this study, a total of 72 patients (94.7%) with a minimum of 5 years of follow-up data were available for analysis. There were 35 (18 men and 17 women) in the TDR group and 37 (20 men and 17 women) in the ACDF group. There was no difference in preoperative Japanese Orthopedic Association, Neck Disability Index, range of motion (ROM), and Visual Analogue Scale (VAS), on arm pain and neck pain between the 2 groups (P=0.663), but the TDR group showed significant differences in VAS for neck pain and ROM compared with that of the ACDF group at the last follow-up (P<0.05). Both groups reported significant improvements in Japanese Orthopedic Association, Neck Disability Index, ROM, and VAS, on arm pain and neck pain from the preoperative means (P<0.05). Patients with Modic-2 changes in TDR group received a large discectomy and leading to the removal of the majority of the inflammatory disk tissue. TDR is a significantly better maintenance of index-level ROM than ACDF. The mid-term outcomes demonstrated that the both TDR and ACDF groups maintain favorable clinical results on patients with Modic-2 changes, who received TDR have significantly better maintenance of ROM than ACDF.


Inflammatory cues acting on the adult intestinal stem cells and the early onset of cancer (review).
The observation that cancer often arises at sites of chronic inflammation has prompted the idea that carcinogenesis and inflammation are deeply interwoven. In fact, the current literature highlights a role for chronic inflammation in virtually all the steps of carcinogenesis, including tumor initiation, promotion and progression. The aim of the present article is to review the current literature on the involvement of chronic inflammation in the initiation step and in the very early phases of tumorigenesis, in a type of cancer where adult stem cells are assumed to be the cells of origin of neoplasia. Since the gastrointestinal tract is regarded as the best-established model system to address the liaison between chronic inflammation and neoplasia, the focus of this article will be on intestinal cancer. In fact, the anatomy of the intestinal epithelial lining is uniquely suited to study adult stem cells in their niche, and the bowel crypt is an ideal developmental biology system, as proliferation, differentiation and cell migration are all distributed linearly along the long axis of the crypt. Moreover, crypt stem cells are regarded today as the most likely targets of neoplastic transformation in bowel cancer. More specifically, the present review addresses the molecular mechanisms whereby a state of chronic inflammation could trigger the neoplastic process in the intestine, focusing on the generation of inflammatory cues evoking enhanced proliferation in cells not initiated but at risk of neoplastic transformation because of their stemness. Novel experimental approaches, based on triggering an inflammatory stimulus in the neighbourhood of adult intestinal stem cells, are warranted to address some as yet unanswered questions. A possible approach, the targeted transgenesis of Paneth cells, may be aimed at 'hijacking' the crypt stem cell niche from a status characterized by the maintenance of homeostasis to local chronic inflammation, with the prospect of initiating neoplastic transformation in that site.


[A better understanding of clinical pain. Experimental data on 3 animal models of pain].
For a better understanding of clinical pain, several groups involved in the study of basic pain mechanisms have proposed the use of various experimental models close to clinical situations. These models are based either on neurogenic or inflammatory process. Data obtained with three of these models will be developed in the paper: rats rendered arthritic by Freund's adjuvant injection into the tail, rats with an intraplantar injection of carrageenin in one hindpaw, rats with a moderate ligature of one common sciatic nerve. The various pharmacological approaches revealed dramatic changes of the analgesic effects of morphine and other opioid substances, and a spectacular modification of the endogenous opioid reactivity. A further enhancement of the initial hyperalgesia was observed with high doses (1-3 mg/kg i.v.) of naloxone (known as an antagonist of morphine), contrasting with the paradoxical analgesia induced with the low dose (peaking up for 3 micrograms/kg i.v.). Electrophysiological studies emphasized dramatic changes of neuronal responsiveness in structures involved in the transmission of the nociceptive messages, from the periphery to the cortex. In each of these models electrophysiological data provide new insights on the physiopathological mechanisms of the related clinical pain.


MP-AzeFlu provides rapid and effective allergic rhinitis control: results of a non-interventional study in Romania.
Allergic Rhinitis and its Impact on Asthma (ARIA) and the European Union (EU) recommend a shift to guide allergic rhinitis (AR) treatment decisions from symptom severity to disease control, using a simple visual analogue scale (VAS). Using this VAS we assessed, in a real-life study in Romania, the effectiveness of MP-AzeFlu nasal spray. In this multi-centre, prospective, non-interventional study, 253 patients (over 11 years old) with moderate-to-severe AR were prescribed MP-AzeFlu and assessed their symptoms on a VAS (0 (not at all bothersome) to 100 mm (very bothersome)) on Days 0, 1, 3, 7 and 14. The proportion of patients who achieved a defined VAS score cut-off for well-controlled (38 mm) AR were also calculated. Patients perception of disease control was assessed on Day 3. MP-AzeFlu use was associated with a mean (standard deviation) VAS score reduction from 78.4 (15.1) mm at baseline to 14.7 (15.1) mm on the last day. Effectiveness was consistent irrespective of disease severity, phenotype or patient age. 83.4% of patients achieved the smaller than 39 mm well-controlled VAS score cut-off by last day and 95.2% considered their symptoms to be well- or partly controlled at Day 3. MP-AzeFlu provided rapid, effective and sustained AR symptom control in a real-life setting in Romania, irrespective of severity, phenotype or patient age, aligning with ARIA and EU recommendations and supporting the position of MP-AzeFlu as the drug of choice for the treatment of moderate-to-severe AR.


Hepatitis B virus antibody levels 7 to 9 years after booster vaccination in Alaska native persons.
Hepatitis B antibody persistence was assessed in individuals who had previously received a vaccine booster. We measured hepatitis B surface antigen antibody (anti-HBs) levels 7 to 9 years post-hepatitis B booster in individuals with primary vaccination at birth. While 95 (91.3%) of 104 participants had detectable anti-HBs (minimum, 0.1 mIU/ml; maximum, 1,029 mIU/ml), only 43 (41%) had protective levels of ≥10 mIU/ml. Pre- and week 4 postbooster anti-HBs levels were significant predictors of hepatitis B immunity at follow-up (P < 0.001). Almost all participants had detectable anti-HBs 7 to 9 years after the hepatitis B vaccine booster, but less than half had levels ≥10 mIU/ml.