Approaching "Elective" Surgery in the Era of COVID-19.
The coronavirus disease 2019 pandemic created unprecedented challenges for the health care system. To meet capacity demands, hospitals around the world suspended surgeries deemed to be elective. In hand surgery, numerous pathologies are treated on an elective basis, but a delay or absence of care may result in poorer outcomes. Here, we present an ethical framework for prioritizing elective surgery during a period of resource scarcity. Instead of using the term "elective," we define procedures that can be safely delayed on the basis of 3 considerations. First, a safe delay is possible only if deferral will not result in permanent injury. Second, a delay in care will come with tolerable costs and impositions that can be appropriately managed in the future. Third, a safe delay will preserve the bioethical principle of patient autonomy. In considering these criteria, 3 case examples are discussed considering individual patient characteristics and the pathophysiology of the condition. This framework design is applicable to ambulatory surgery in any period of crisis that may strain resources, but further considerations may be important if an operation requires hospital admission.


Proximity to the Southern Border and Sociodemographic Correlates of Drinking and Driving Arrests in California.
About 30% of all motor vehicle fatalities in the United States are associated with alcohol-impaired motor vehicle crashes. Arrests for drinking and driving (Driving under the influence [DUI]) are 1 of the most important deterrence actions to minimize DUI. This paper examines trends and population-level correlates of drinking driving arrests (DUI) from 2005 to 2017 in California. Arrest data come from the Monthly Arrest and Citation Register compiled by the California Department of Justice. Sociodemographic and community characteristic data from the U.S. Census, alcohol outlet density, and distance to the U.S.-Mexico border from Law Enforcement Reporting Areas (LERA) centroids were aggregated at the level of 499 LERA contributing to the report. Reported arrest rates were related to area sociodemographic characteristics using hierarchical Bayesian Poisson space-time models. Both among men and women rates showed an upward trend until 2008, decreasing after that year. DUI arrest rates were greater among Hispanics than Whites for the 2 younger age groups, 18 to 29 (p < 0.001) and 30 to 39 years (p < 0.001). DUI arrest rates in LERA areas are positively related to proximity to the California/Mexico border; a higher percent of bar/pub outlets; a higher percent of Hispanic population; a higher percent of population 18 to 29, 30 to 39, and 40 to 49 years of age; a higher percent of US-born population; a higher percent of population with annual income of $100,000 or more; a higher percent of population 150% below the federal poverty line; and a higher level of law-enforcement activities. Results of this analysis of spatial correlates of DUI arrests overlap well with the literature on individual-level data and arrest rates. The decrease in arrest rates as distance to the California/Mexico border increases is potentially associated with the greater availability of alcohol in the border area.


The critical role of amygdala subnuclei in nociceptive and depressive-like behaviors in peripheral neuropathy.
The amygdala is an important component of the limbic system that participates in the control of the pain response and modulates the affective-motivational aspect of pain. Neuropathic pain is a serious public health problem and has a strong affective-motivational component that makes it difficult to treat. The central (CeA), basolateral (BLA) and lateral (LA) nuclei of the amygdala are involved in the processing and regulation of chronic pain. However, the roles of these nuclei in the maintenance of neuropathic pain, anxiety and depression remain unclear. Thus, the main objective of this study was to investigate the role of amygdala subnuclei in the modulation of neuropathic pain, including the affective-motivational axis, in an experimental model of peripheral neuropathy. The specific goals were as follows: (1) To evaluate the nociceptive responses and the patterns of activation of the CeA, BLA and LA in neuropathic rats; and (2) To evaluate the effect of inactivating the amygdala nuclei on the nociceptive response, anxiety and depressive behaviors, motor activity, and plasma stress hormones in animals with neuropathic pain. Thus, mechanical hyperalgesia and allodynia, and the pattern of c-Fos staining in the amygdala subnuclei were evaluated in rats with chronic constriction of the sciatic nerve, as well as sham-operated and naïve rats. Once the amygdala subnuclei involved in neuropathic pain response were defined, those subnuclei were pharmacological inactivated. The effect of muscimol inactivation on the nociceptive response (hyperalgesia and allodynia), anxiety (elevated plus-maze), depressive-like behavior (forced swim test), motor activity (open field), and plasma stress hormone levels (corticosterone and adrenocorticotropic hormone) were evaluated in sham-operated and neuropathic animals. The results showed that the anterior and posterior portions of the BLA and the central portion of the CeA are involved in controlling neuropathic pain. The inactivation of these nuclei reversed hyperalgesia, allodynia and depressive-like behavior in animals with peripheral neuropathy. Taken together, our findings improve our understanding of the neurocircuitry involved in persistent pain and the roles of specific amygdala subnuclei in the modulation of neuropathic pain, including the neurocircuitry that processes the affective-motivational component of pain.


CXC chemokine ligand 12 (CXCL12) and its receptor CXCR4.
Chemokines were recognized originally for their ability to dictate the migration and activation of leukocytes. However, CXC chemokine ligand 12 (CXCL12, also known as stromal cell-derived factor-1) and its receptor CXCR4 are the first chemokine and receptor that have been shown to be critical for developmental processes, including homing and maintenance of hematopoietic stem cells (HSCs), production of immune cells, homing of primordial germ cells (PGCs), cardiogenesis, arterial vessel branching in some organs, and appropriate assemblies of particular types of neurons. This review focuses on the pathophysiological relevance of CXCL12-CXCR4 signaling in mammals.


Erratum: Predictive validity of a parental questionnaire for identifying children with developmental language disorders.
[This corrects the article DOI: 10.3389/fpsyg.2023.1110449.].


Regulation of neurological and neuropsychiatric phenotypes by locus coeruleus-derived galanin.
Decades of research confirm that noradrenergic locus coeruleus (LC) neurons are essential for arousal, attention, motivation, and stress responses. While most studies on LC transmission focused unsurprisingly on norepinephrine (NE), adrenergic signaling cannot account for all the consequences of LC activation. Galanin coexists with NE in the vast majority of LC neurons, yet the precise function of this neuropeptide has proved to be surprisingly elusive given our solid understanding of the LC system. To elucidate the contribution of galanin to LC physiology, here we briefly summarize the nature of stimuli that drive LC activity from a neuroanatomical perspective. We go on to describe the LC pathways in which galanin most likely exerts its effects on behavior, with a focus on addiction, depression, epilepsy, stress, and Alzheimer׳s disease. We propose a model in which LC-derived galanin has two distinct functions: as a neuromodulator, primarily acting via the galanin 1 receptor (GAL1), and as a trophic factor, primarily acting via galanin receptor 2 (GAL2). Finally, we discuss how the recent advances in neuropeptide detection, optogenetics and chemical genetics, and galanin receptor pharmacology can be harnessed to identify the roles of LC-derived galanin definitively. This article is part of a Special Issue entitled SI: Noradrenergic System.


Publisher Correction: Exuberant fibroblast activity compromises lung function via ADAMTS4.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Anthropometric characteristics of Australian junior representative rugby league players.
To comprehensively describe anthropometric characteristics of Australian junior elite rugby league players and assess potential anthropometric dissimilarities between players of varying positional groups, ethnicity (Polynesian vs. non-Polynesian) and playing level (junior vs. professional; using published data from Australian professional players). Cross-sectional study. Height, body mass, eight skinfolds, five girths and two bone breadths were measured with body fat (BF%) and somatotype calculated using population-appropriate equations. mean ± SD. This study recruited 116 junior players. Mean age, mass and BF% were 17 ± 1 y, 87.0 ± 11.6 kg and 14.0 ± 4.6% respectively. Compared to backs, forwards had greater mass (92.6 ± 12.2 vs. 80.9 ± 7.1 kg), skinfolds, girths, femur breadth, BF% (16.1 ± 4.8% vs. 11.8 ± 3.2%) (all p<0.01), and were more endo- and mesomorphic, but less ectomorphic (all p<0.001). Compared to other positional groups, props had greater mass, adiposity, calf girth and endomorphy, while adjustables (fullbacks, five-eighths, halfbacks, hookers) had the shortest stature (all p<0.01). Polynesians exhibited greater height (181.0 ± 5.7 vs. 178.7 ± 6.3 cm), mass (90.6 ± 11.7 vs. 84.7 ± 11.1 kg), arm and calf girths, bone breadths and mesomorphy (7.6 ± 1.2 vs. 6.7 ± 1.1) than non-Polynesians (all p<0.05). Juniors had lower height, mass, waist and smaller sum of skinfolds than professional players (all p<0.05). Greater mass, mesomorphy, adiposity and bone size in forwards is desirable for tackling and attacking and may protect against high impact forces sustained in this position. Advantageous anthropometric attributes exhibited in Polynesian players may influence selection into junior elite rugby league teams. Anthropometric data from this study may assist other junior players and coaches with training, dietary modification and position allocation.


Aggregation and calcium-induced fusion of phosphatidylcholine vesicle-tubulin complexes.
Insertion of tubulin into the bilayer of dipalmitoyl phosphatidylcholine vesicles at the phase transition results in the formation of stable vesicle-tubulin complexes (Klausner, R. D., Kumar, N., Weinstein, J. N., Blumenthal, R., and Flavin, M. (1981) J. Biol. Chem. 256, 5879-5885). These complexes aggregated when maintained below phase transition for 10-20 min. Addition of millimolar concentrations of Ca2+, Mn2+, Zn2+, and Co2+, but not Mg2+, caused the vesicle-tubulin complexes to fuse into larger structures as shown by (a) electron microscopy, (b) increased trapped volume, and (c) changes ion resonance energy transfer between two fluorescent lipid probes incorporated into the same vesicle. There was no loss of internal aqueous contents from the vesicle-tubulin complexes during Ca2+-induced fusion. Anti-tubulin drugs had no effect on the aggregation or fusion, and vesicle-bound tubulin did not associate with microtubules when tubulin was assembled in vitro. Trypsin-treated vesicle-tubulin complexes were incapable of supporting Ca2+-induced fusion. This system provides a model for Ca2+-induced and protein-mediated nonleaky fusion of uncharged lipid bilayers.


Assessment of vibrational-translational relaxation dynamics of in a wet-nitrogen matrix through QEPAS.
Here we report on a study of the non-radiative relaxation dynamic of 12CH4 and 13CH4 in wet nitrogen-based matrixes by using the quartz-enhanced photoacoustic spectroscopy (QEPAS) technique. The dependence of the QEPAS signal on pressure at fixed matrix composition and on H2O concentration at fixed pressure was investigated. We demonstrated that QEPAS measurements can be used to retrieve both the effective relaxation rate in the matrix, and the V-T relaxation rate associated to collisions with nitrogen and water vapor. No significant differences in measured relaxation rates were observed between the two isotopologues.


Red Blood Cell Count: An Unrecognized Risk Factor for Nonalcoholic Fatty Liver Disease.
Nonalcoholic fatty liver disease (NAFLD) is becoming a global public health challenge. A convenient NAFLD indicator will greatly facilitate risk appraisal and prevention. As a readily available and inexpensive hematological index in routine clinical examinations, red blood cells (RBCs) are gaining increasing attention in many diseases, such as metabolic syndrome, but their association with NAFLD is unknown. This health management cohort study included 27,112 subjects (17,383 non-NAFLD and 9,729 NAFLD) with up to 5 years of follow-up (median 2.8 years). NAFLD was diagnosed by ultrasonography. NAFLD severity was categorized as mild, moderate, or severe. The generalized estimation equation (GEE), an extension of generalized linear models that allows for analysis of repeated measurements, was used to analyze the association between RBC count and NAFLD. Overall, 4,332 of 17,383 (24.9%) subjects without NAFLD at baseline developed NAFLD. Incident NAFLD risk was positively associated with RBC count. After adjustment for hemoglobin and other confounders, the risk of incident NAFLD was 21%, 32%, and 51% higher in the second, third, and fourth RBC count quartiles, respectively, than in the lowest quartile. In 1,798 of 9,476 (19.0%) subjects with NAFLD at baseline, the severity of NAFLD increased. NAFLD progression risk increased progressively as RBC count increased (P for trend < 0.001). Every one-unit (1012 cells/L) increase in RBC count was associated with a 53% [OR 1.53 (95% CI 1.32-1.77)] increased risk for NAFLD progression. Elevated RBC count was independently associated with a high risk of NAFLD incidence and progression. This finding revealed a convenient NAFLD risk indicator.


Isolated sternoclavicular joint arthritis in heroin addicts and/or HIV positive patients: three cases.
The authors describe three patients in whom septic arthritis of the sternoclavicular joint (SCJ) occurred, drug addiction and human immunodeficiency virus (HIV) infection representing the predisposing conditions. Infectious arthritis is well known in intravenous drug users, but it is rare in HIV positive patients, who are prone to bacterial infections from usual or unusual microorganisms. In one case, staphylococcus aureus methicillin sensitive was responsible for septic arthritis. In another case, SCJ infection was associated with pneumonitis.


Copper nanoparticles on controlled pore glass (CPG) as highly efficient heterogeneous catalysts for "click reactions".
We herein report that supported copper nanoparticles (CuNPs) on commercially available controlled pore glass (CPG), which exhibit high mechanical, thermal and chemical stability as compared to other silica-based materials, serve as a useful heterogeneous catalyst system for 1,3-dipolar cycloadditions ("click" reactions) between terminal alkynes and organic azides under green chemistry conditions. The supported CuNPs-CPG catalyst exhibited a broad substrate scope and gave the corresponding triazole products in high yields. The CuNPs-CPG catalyst exhibit recyclability and could be reuced multiple times without contaminating the products with Cu.


Comparative Analysis of Primers Used for 16S rRNA Gene Sequencing in Oral Microbiome Studies.
Recent advances in genomic technologies have enabled more in-depth study of the oral microbiome. In this study, we compared the amplicons generated by primers targeting different sites of the 16S rRNA gene found in the Human Oral Microbiome Database (HOMD). Six sets of primer targeting V1-V2, V1-V3, V3-V4, V4-V5, V5-V7 and V6-V8 regions of 16S rRNA were tested via in silico simulation. Primers targeting the V1-V2, V3-V4, and V4-V5 regions generated more than 90% of the original input sequences. Primers targeting the V1-V2 and V1-V3 regions exhibited a low number of mismatches and unclassified sequences at the taxonomic level, but there were notable discrepancies at the species level. Phylogenetic tree comparisons showed primers targeting the V1-V2 and V3-V4 regions showed performances similar to primers targeting the whole 16s RNA region in terms of separating total oral microbiomes and periodontopathogens. In an analysis of clinical oral samples, V1-V2 primers showed superior performance for identifying more taxa and had better resolution sensitivity for Streptococcus than V3-V4 primers. In conclusion, primers targeting the V1-V2 region of 16S rRNA showed the best performance for oral microbiome studies. In addition, the study demonstrates the need for careful PCR primer selections.


Ultrastructural localization of inositol 1,4,5-trisphosphate 3-kinase in rat cerebellar cortex.
Subcellular localization of inositol 1,4,5-trisphosphate 3-kinase in the rat cerebellar cortex was studied immunohistochemically using a monoclonal antibody. Electron microscopy revealed intense immunoreactivity in the dendritic spines of Purkinje cells forming synapses with the parallel fibers, climbing fibers and recurrent collaterals of Purkinje cell axons. The labelling was associated with the hypolemmal cisternae, surrounding matrix and plasmalemma including the postsynaptic densities. Weaker immunoreactivity was present in the dendritic spines of basket cells and in certain segments of Purkinje cell recurrent collaterals. The postsynaptic regions of the dendritic trunks of Purkinje and basket cells were negative. These results indicate that inositol 1,4,5-trisphosphate 3-kinase is distributed amongst the spines of various synaptic relations with different electrophysiological properties, and that axon terminals of certain cell types are another functional site for the enzyme.


Transmission risk of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) to healthcare personnel following unanticipated exposure to aerosol-generating procedures: Experience from epidemiologic investigations at an academic medical center.
Healthcare personnel (HCP) with unprotected exposures to aerosol-generating procedures (AGPs) on patients with coronavirus disease 2019 (COVID-19) are at risk of infection with severe acute respiratory coronavirus virus 2 (SARS-CoV-2). A retrospective review at an academic medical center demonstrated an infection rate of <1% among HCP involved in AGPs without a respirator and/or eye protection.


The evolution of an acute care hospital unit to a DRG-exempt rehabilitation unit. A preliminary communication.
The Health Care Financing Administration's decision to adopt a prospective based payment system has caused many institutions to implement new policies and practices. A recent area of interest for many hospitals has been the creation of diagnosis-related group (DRG) exempt units to maximize reimbursement practices. We analyzed changes which occurred when an eight bed acute care stroke unit (SU) was converted to a DRG exempt eight bed rehabilitation unit (RU). The time period involved was 1 1/2 months before and 1 1/2 months after the transition occurred. Analysis of data from the pre- and posttransition periods revealed that: (1) length of stay increased significantly from 11.7 to 15.3 days (P less than 0.001); (2) functional independence measure (FIM) score improvement was significantly greater (P less than 0.05) for RU patients (0.84/day) than for SU patients (0.39/day); (3) disposition to home v other facilities increased significantly from 50 to 81% (P less than 0.05); (4) the overall occupancy increased from 94 to 100% and all beds were filled with rehabilitation patients; (5) the proportion of patients with Medicare as their primary insurer was comparable before (64%) and after (67%) unit conversion; (6) gross income from rehabilitation patients increased by 43%. Indirect savings via reduction of acute hospital length of stay for Medicare patients increased total income from operation of this unit. We conclude that patients on the RU stayed longer, had greater daily improvements in functional status, and were more likely to be discharged to home. This appears to be due to a more efficient use of rehabilitation beds and a concomitant overall improvement in reimbursement to the hospital.(ABSTRACT TRUNCATED AT 250 WORDS)


Determination of a hepatic volumetric index by ultrasonic scanning.
A prospective study was carried out to calculate, by a fast and simple ultrasonic method, the size of the liver. Seventy-five normal subjects, 38 men and 37 women, average age 51 +/- 17 years (range 19-85) were studied. The three main diameters of the liver, breadth, thickness, and height, were obtained using a compound scan technique; each diameter was measured at its largest dimension. These measurements were multiplied together and the product arbitrarily divided by 27, which is the cube of the three diameters. This yielded the hepatic volumetric index (HVI), which was between 95 and 140 in 95% of normal subjects below 65 years of age and ranged from 80 to 135 in those above 65 years. These last data proved to be in accordance with the well-known involution of liver size in the elderly and with our retrospective study on 207 normal subjects. Then, using the criteria previously proposed by us, the population studied in the prospective study was divided into three groups of morphotypes: endomorphs, ectomorphs, and mesomorphs. The ectomorphs had an HVI slightly lower than that of the endomorphs. This HVI determination, based on standardized measurements and on a statistically controlled method, allows us to separate normal from pathological livers in 10 min and plays an important part in day-to-day clinical practice.


Acute epididymitis in children: the role of radiologic studies.
Assessment of the role of radiologic studies in the detection of significant urologic anomalies in boys with acute epididymitis. Retrospective chart reviews of patients with a diagnosis of acute epididymitis over a period of 15 years (January 1989 to December 2003). Patients presented with an acute scrotum and documented ipsilateral testicular/epididymal hyperemia on Doppler ultrasound plus any 2 of the following criteria: (1) high-grade fever (higher than 38.5 degrees C), (2) peripheral leukocytosis, (3) pyuria greater than 10 pus cells per high-power field, and (4) positive urine culture. The results of upper tract imaging and voiding cystourethrogram (VCUG) were reviewed for any anatomic abnormality. Sixteen patients were included in this review, age range 3 weeks to 16 years (median 10.5 years). Fifteen of 16 patients had upper tract imaging (13 renal ultrasound and 2 intravenous pyelogram [IVP]). All upper tract imaging studies were normal. VCUG was performed in 13 of 16 patients, and was normal in 12 of 13 patients. One patient had reflux to right seminal vesicle, which resolved spontaneously on a follow-up study. The follow-up period ranged from 1 month to 11 years (median 2 months). None of the patients had recurrent epididymitis, except the individual who had reflux to seminal vesicle. A full radiologic workup to include a renal ultrasound and VCUG should be obtained in children with acute epididymitis and a positive urine culture, or recurrent epididymitis. In a child with acute epididymitis and negative urine culture, urinary tract ultrasound is adequate. Because VCUG is of low yield in this population, its routine use should be questioned.


Modelling shows that stimulation of the semicircular canals depends on the rotation centre.
The vestibular system in the inner ear senses head movements, which is indispensable for balance during locomotion. The semicircular canals of the vestibular system are stimulated during head rotations, due to the interplay between its endolymph fluid and its cupula membrane. Until now, it has been assumed that the stimulation of the canals is independent of the rotation centre. However, Fluid-Structure Interaction investigation now shows that the horizontal canal is more strongly stimulated when the rotation centre lies further from the canal. Such eccentric rotations result in a different stimulation of the left and the right canal, because the distance to the rotation centre differs between both ears. The dissimilar stimulation enables localization of the rotation centre based on information from the canals alone, similar to sound localization based on the interaural time difference for hearing. Additionally, a rotation centre further away from the canal will probably elicit a larger reflexive eye movement. This is exactly what is required to compensate the larger change in viewing angle, and it corresponds to experimental findings. Two fictitious forces (d'Alembert forces), the centrifugal force and the Euler force, cause the rotation centre-dependency of the canal stimulation. Implications for (pre)clinical eccentric rotation experiments are discussed.


Evolutionary processes in suicide.
Suicidal behavior contains several dynamic elements. Due to its complexity, empirical science may approach suicide through various avenues. One underutilized approach is taking an evolutionary perspective. Our review of the literature presents two evolutionary processes that may be implicated in suicidal behavior, namely eusocial behavior and antipredator response behaviors. Studies have indicated that aspects of suicidal behavior parallel self-sacrificial behavior in eusocial animals, and that systems similar to hyperarousal-shutdown systems involved in antipredator behaviors may be activated among suicidal individuals. Research on brain activity and decision-making processes among suicidal individuals also suggests that eusociality and antipredator response behaviors in suicide may not be mutually exclusive. These processes represent novel sources of information and potential solutions regarding suicide.


Chemotherapy Resistance Molecular Mechanism in Small Cell Lung Cancer.
The malignancy of small cell lung cancer (SCLC) is the highest amongst all lung cancer types. It is characterized by rapid growth, early occurrence of distant sites metastasis, poor survival rates and is initially sensitive to chemotherapy and radiotherapy. However, most patients eventually relapse or disease progresses because of chemotherapy resistance. Because of lack of effective second-line therapies, the prognosis of SCLC patients is usually poor. For the development of novel therapies, it is necessary to understand the mechanisms of chemotherapy resistance in SCLC. The mechanism is complex, because multiple factors could lead to chemotherapy resistance. An overview of multiple events triggering the formation of chemotherapy resistance phenotypes of SCLC cells is discussed.


Reduction of the drug-induced nephrotoxicity by ATP-MgCl2. II. Effects on gentamicin-treated isolated perfused kidneys.
Drug-induced nephrotoxicity (NT) has become an increasingly significant clinical problem. An in vitro model of drug-induced NT was therefore developed using gentamicin and the effects of ATP-MgCl2 on reduction or prevention of NT were determined. To study this, non-pulsatile perfusion in isolated rat kidneys was maintained at 100 mm Hg during 2 hr of perfusion at 37 degrees C. The oxygenated Krebs-HCO3 perfusate contained 7.5 g/dl albumin as colloid, glucose, creatinine, amino acids, trace amounts of [3H]inulin and 125I-lysozyme, and either 0, 0.4, 0.8, or 1.2 mg/ml of gentamicin. In some studies, 2 mM ATP-MgCl2 was added with 0.8 mg/ml of gentamicin at 0 and 60 min of perfusion. During each 10-min clearance period, glomerular filtration rates, sodium absorption, water absorption, and fractional clearance of TCA-precipitable lysozyme were measured. The results indicate that renal perfusate flow, glomerular filtration rate, urinary flow and tubular absorption of protein (a sensitive indicator of tubular function), sodium, and water were affected by gentamicin in a dose-dependent manner. An isolated kidney preparation can therefore be used to study gentamicin-induced NT. Higher in vitro perfusate concentrations of the drug were needed, however, to acutely mimic the in vivo cumulative effects. Nonetheless, renal perfusate flow, glomerular filtration rate, and the depression in protein reabsorption which occurred with gentamicin treatment were markedly improved by simultaneous treatment with ATP-MgCl2. Thus, ATP-MgCl2 may be useful in reducing drug-induced nephrotoxicity.


Physiologic origins of age-related beta-amyloid deposition.
Brain beta-amyloid (Abeta) deposition is an extremely common accompaniment of aging in humans and many other mammalian species. We hypothesized that normal physiological changes of aging cause Abeta deposition. Three normal physiological aging changes were induced in young adult rabbits to determine their effects on brain Abeta concentrations and deposition. The three changes were cortical cholinergic deafferentation, hypercholesterolemia and estrogen deprivation. Cortical cholinergic deafferentation was achieved through intracerebroventricular immunotoxin injection. Hypercholesterolemia was induced with a 2% cholesterol diet. Estrogen deprivation was modeled with ovariectomy. Cortical cholinergic deafferentation resulted in an 8-fold increase in cortical Abeta(42) concentrations and cerebrovascular Abeta deposition. Hypercholesterolemia increased cortical Abeta(42) 4.6-fold while ovariectomy increased cortical Abeta(42) 1.6-fold. At least three physiological changes of normal aging may underlie age-related brain Abeta accumulation and Alzheimer's disease.


Dose dependent pharmacokinetics of prednisolone.
The pharmacokinetics of prednisolone elimination have been studied in both arthritic patients and normal volunteers using tritiated prednisolone alone, and in conjunction with unlabelled prednisolone in doses of 0.15 mg-kg-1 and 0.3 mg-kg-1 body weight. With increasing dose there is prolongation of the plasma half-life and increase in the volume of distribution and plasma clearance of prednisolone. It is proposed that these changes in pharmacokinetic parameters may be associated with non-linear binding of the steroid to plasma proteins.


Cost-Utility Analysis of the Integrated Care Models for the Management of Hypertension Patients: A Quasi-Experiment in Southwest Rural China.
Background: Hypertension has become the second-leading risk factor for death worldwide. However, the fragmented three-level "county-township-village" medical and healthcare system in rural China cannot provide continuous, coordinated, and comprehensive health care for patients with hypertension, as a result of which rural China has a low rate of hypertension control. This study aimed to explore the costs and benefits of an integrated care model using three intervention modes-multidisciplinary teams (MDT), multi-institutional pathway (MIP), and system global budget and performance-based payments (SGB-P4P)-for hypertension management in rural China. Methods: A Markov model with 1-year per cycle was adopted to simulate the lifetime medical costs and quality-adjusted life-years (QALYs) for patients. The interventions included Option 1 (MDT + MIP), Option 2 (MDT + MIP + SGB-P4P), and the Usual practice (usual care). We used the incremental cost-effectiveness ratio (ICER), net monetary benefit (NMB), and net health benefit (NHB) to make economic decisions and a 5% discount rate. One-way and probability sensitivity analyses were performed to test model robustness. Data on the blood pressure control rate, transition probability, utility, annual treatment costs, and project costs were from the community intervention trial (CMB-OC) project. Results: Compared with the Usual practice, Option 1 yielded an additional 0.068 QALYs and an additional cost of $229.99, resulting in an ICER of $3,373.75/QALY, the NMB was -$120.97, and the NHB was -0.076 QALYs. Compared with the Usual practice, Option 2 yielded an additional 0.545 QALYs, and the cost decreased by $2,007.31, yielding an ICER of -$3,680.72/QALY. The NMB was $2,879.42, and the NHB was 1.801 QALYs. Compared with Option 1, Option 2 yielded an additional 0.477 QALYs, and the cost decreased by $2,237.30, so the ICER was -$4,688.50/QALY, the NMB was $3,000.40, and the NHB was 1.876 QALYs. The one-way sensitivity analysis showed that the most sensitive factors in the model were treatment cost of ESRD, human cost, and discount rate. The probability sensitivity analysis showed that when willingness to pay was $1,599.16/QALY, the cost-effectiveness probability of Option 1, Option 2, and the Usual practice was 0.008, 0.813, and 0.179, respectively. Conclusions: The integrated care model with performance-based prepaid payments was the most beneficial intervention, whereas the general integrated care model (MDT + MIP) was not cost-effective. The integrated care model (MDT + MIP + SGB-P4P) was suggested for use in the community management of hypertension in rural China as a continuous, patient-centered care system to improve the efficiency of hypertension management.


Neo-clerodane diterpenoids and phenylethanoid glycosides from Teucrium chamaedrys L.
A neo-clerodane type diterpenoid, 12(S)-15,16-epoxy-19-hydroxy-neo-cleroda-13(16),14-dien-18,6alpha:20,12-diolide, and two phenylethanoid glycosides, teucrioside-3(IIII)-O-methylether and teucrioside-3(IIII),4(IIII)-O-dimethylether were isolated from the aerial parts of Teucrium chamaedrys. Their structures were identified on the basis of extensive NMR spectra, LC-ESIMS analysis, and molecular modeling studies.


Exploring the effective elements on the personal and professional development among health-care providers: A qualitative study.
A new domain of "personal and professional development" was introduced as a core competency of health-care providers. This study aimed to explore the experiences of learners and faculty members about what competencies or skills were essential for the professional development and success of health-care providers. This is a qualitative study using an inductive content analysis approach in 2019-2020. In the present study, 58 academic faculty members participated by purposeful sampling including ten associate professors (17.24%) and 24 assistance professors (41.37%), in addition to 23-year medical residents (20.65%) and 4th-year nursing students (20.65%). Individual and group interviews were conducted. Data were analyzed by the inductive content analysis approach introduced by Graneheim and Lundman. The qualitative data were classified in 953 open codes and eight categories, which were further divided into four main categories: "socio-emotional skills," "life-long learning skills," "coping skills," and "well-being strategies." The present results showed socioemotional and coping skills affect interpersonal and professional interactions that contributed to their improved health-care providers' capabilities. Participants also considered lifelong learning as influential in developing professional capabilities and keeping their knowledge and skills up-to-date for accountability to duties. Moreover, using well-being strategies protects the mental and physical health of health-care providers. These skills are synergistic, and their combination can have a significant role in improving the personal and professional capabilities.


Storage and oxidation of long-chain fatty acids in the C57/BL6 mouse heart as measured by NMR spectroscopy.
Triglyceride turnover in the isolated C57/BL6 mouse heart was measured by dynamic 13C edit-(1)H observe NMR and the rate of fatty acid oxidation was determined by 13C NMR isotopomer analysis. In the presence of a physiological mixture of substrates, energy was produced in the citric acid cycle by oxidation of long-chain fatty acids (18%), ketones (34%), lactate (24%), pyruvate (7%), and other sources (17%). Exogenous fatty acids appeared in the triglyceride pool at 0.24 micromol/g dry wt/min, similar to the rate of oxidation of long-chain fatty acids, 0.16 micromol/g dry wt/min. Isoproterenol decreased the rate of de novo triglyceride synthesis and increased the rate of fatty acid oxidation.


Molecular detection and characterization of tick-borne hemoparasites and Anaplasmataceae in dogs in major cities of Malawi.
Tick-borne pathogens (TBPs) in dogs have attracted much attention over the last decade since some are now known to be zoonotic and pose a threat to both animal and human health sectors. Despite the increase in the number of studies on canine TBPs worldwide, only a few studies have been conducted in resource-limited countries where research priority is given to food animals than companion animals. In the present study, the occurrence of TBPs of the genera Babesia, Hepatozoon, Anaplasma, and Ehrlichia was investigated in 209 owned and stray dogs in three major cities in Malawi through molecular techniques. Among the examined dogs, 93 (44.5%) were infected with at least one TBP. The detection rates were 23.1% for Babesia rossi, 2.9% for B. vogeli, 19.1% for Hepatozoon canis, 2.4% for Anaplasma platys, and 3.8% for Ehrlichia canis. This is the first molecular study that has provided evidence that dogs in Malawi are infected with TBPs. Sensitization is required for veterinary practitioners, dog handlers, and pet owners as the detected pathogens affect the animals' wellbeing. Further studies focusing on rural areas with limited or no access to veterinary care are required to ascertain the extent of the TBP infection in dogs.


Pulmonary Rehabilitation for Post-COVID-19.
Patients with COVID-19 often report persistent respiratory symptoms. Limited data exist on how to mitigate long-term sequelae of exercise intolerance and dyspnea. We aimed to study the role of pulmonary rehabilitation (PR) in patients with post-COVID-19. This was an observational study. Consecutive patients with post-COVID-19, admitted to three separate outpatient PR programs, were enrolled. The program consisted of 8-12 wk of PR sessions (3 times/wk). Data were gathered at the initial visit and discharge. The primary outcome was the change in the 6-min walk test (6MWT) distance. Secondary outcomes included the Shortness of Breath Questionnaire (SOBQ), modified Borg dyspnea scale, Patient Health Questionnaire-9 (PHQ-9), and Lung Information Needs Questionnaire (LINQ). A total of 56 patients completed the PR program (age 62.8 ± 14.7 yr, 57% were men). At baseline, the mean 6MWT was 313.3 ± 193.8 m. On average, the 6MWT improved by 84.3 m after PR ( P < .0001). Apart from the modified Borg dyspnea scale, there was improvement across secondary outcomes: SOBQ (-16.9 points), PHQ-9 (-2.6 points), and LINQ (-4.2 points); all P < .05. Pulmonary rehabilitation showed a promising positive effect on patients with with post-COVID-19. It improved exercise capacity, perception of dyspnea, depressive symptoms, and patient knowledge needed to manage their lung disease. Pulmonary rehabilitation should be considered for post-COVID-19 patients.


Adhesion of human pathogenic bacteria to endothelial cells is facilitated by fibronectin interaction.
Human pathogenic bacteria circulating in the bloodstream need to find a way to interact with endothelial cells (ECs) lining the blood vessels to infect and colonise the host. The extracellular matrix (ECM) of ECs might represent an attractive initial target for bacterial interaction, as many bacterial adhesins have reported affinities to ECM proteins, in particular to fibronectin (Fn). Here, we analysed the general role of EC-expressed Fn for bacterial adhesion. For this, we evaluated the expression levels of ECM coding genes in different ECs, revealing that Fn is the highest expressed gene and thereby, it is highly abundant in the ECM environment of ECs. The role of Fn as a mediator in bacterial cell-host adhesion was evaluated in adhesion assays of Acinetobacter baumannii, Bartonella henselae, Borrelia burgdorferi, and Staphylococcus aureus to ECs. The assays demonstrated that bacteria colocalised with Fn fibres, as observed by confocal laser scanning microscopy. Fn removal from the ECM environment (FN1 knockout ECs) diminished bacterial adherence to ECs in both static and dynamic adhesion assays to varying extents, as evaluated via absolute quantification using qPCR. Interactions between adhesins and Fn might represent the crucial step for the adhesion of human-pathogenic Gram-negative and Gram-positive bacteria targeting the ECs as a niche of infection.


Screening of nursing home residents for colonization with carbapenem-resistant Enterobacteriaceae admitted to acute care hospitals: Incidence and risk factors.
There are increasing reports of multidrug-resistant gram-negative bacilli in nursing homes and acute care hospitals. We performed a point prevalence survey to detect fecal carriage of gram-negative bacteria carrying carbapenem resistance genes or which were otherwise resistant to carbapenem antibiotics among 500 consecutive admissions from local nursing homes to 2 hospitals in Providence, Rhode Island. We performed a case-control study to identify risk factors associated with carriage of carbapenem-resistant Enterobacteriaceae (CRE). There were 404 patients with 500 hospital admissions during which they had rectal swab samples cultured. Fecal carriage of any carbapenem-resistant or carbapenemase- producing gram-negative bacteria was found in 23 (4.6%) of the 500 hospital admissions, including 7 CRE (1.4%), 2 (0.4%) of which were Klebsiella pneumoniae carbapenemase (ie, blaKPC) producing (CPE) Citrobacter freundii, 1 of which was carbapenem susceptible by standard testing methods. Use of a gastrostomy tube was associated with CRE carriage (P = .04). We demonstrated fecal carriage of carbapenem-resistant or carbapenemase-producing gram-negative bacteria in 4.6% of nursing home patients admitted to 2 acute care hospitals, but only 0.4% of such admissions were patients with fecal carriage of CPE. Use of gastrostomy tubes was associated with fecal carriage of gram-negative bacteria with detectable carbapenem resistance. CRE fecal carriage is uncommon in our hospital admissions from nursing homes.


Evaluation of failing hemodialysis fistulas with multidetector CT angiography: comparison of different 3D planes.
To evaluate failing hemodialysis fistula complications using 16-detector MDCTA, and to assess the accuracies of different 3D planes. Thirty patients (16 men, 14 women, aged 27-79 years) were referred for hemodialysis access dysfunction. Thirty-one MDCTA exams were done prior to fistulography. For MDCTA, contrast was administered (2mL/kg at 5mL/s) via a peripheral vein in the contralateral arm. Axial MIP, coronal MIP, and VRT images were constructed. Venous complications were evaluated on axial source images, on each 3D plane, and on all-planes together. Results were analyzed using McNemar test. Axial MIP, VRT and all-planes evaluations were most sensitive for fistula site detection (93%). Coronal MIP had the highest sensitivity, specificity and accuracy (35%, 96%, and 85%, respectively) for detecting venous stenosis. VRT and all-planes had the highest sensitivity and accuracy for detecting aneurysms (100%). All-planes and axial MIP were most sensitive for detecting venous occlusion (61% and 54%). Comparisons of detection frequencies for each venous pathology between the five categories of MDCTA revealed no significant differences (P>0.05). MDCTA additionally showed 3 partially thrombosed aneurysms, 4 anastomosis site stenosis and 12 arterial complications. MDCTA overall gives low sensitivity for detection of central vein stenosis and moderate sensitivity for occlusion. For most pathology, all-planes evaluation of MDCTA gives highest sensitivity and accuracy rates when compared to other planes. For venous stenosis and occlusion, MDCTA should be considered when ultrasonography and fistulography are inconclusive. MDCTA is helpful in identifying aneurysms, collaterals, partial venous thromboses and additional arterial, anastomosis site pathologies.


Oral structural and neuromuscular characteristics in children with normal and disordered articulation.
The primary purpose of this study was to determine whether there were any signs of structural and/or neuromuscular aberrations in the speech mechanisms of children who were previously diagnosed as having "functional" articulation disorders. These children were compared with a group of normally articulating children. Results of in-depth oral mechanism examinations revealed no significant differences between these groups on any of the measures made. The clinical implications of such findings are discussed.


[Fine needle aspiration cytology in the diagnosis of head and neck tumors].
The authors studied 166 head and neck tumors of patients admitted to the A.C. Camargo Hospital using the method of fine needle aspiration cytology (FNAC) in order to correlate these findings with pathohistological diagnoses. The correlation was possible in 81 cases: 3 cases were false negative and 1 was false positive. FNAC sensibility was 90.6%, specificity was 97.9%, and efficiency was 95%.


Peptide concentrations and mRNA expression of IGF-I, IGF-II and IGFBP-3 in breast cancer and their associations with disease characteristics.
To measure peptide concentrations and mRNA expression of the IGF Family in breast cancer and to examine their associations with the disease features. Fresh tumor samples were collected from 348 patients who underwent surgery for breast cancer. Tissue levels of mRNA and peptide of IGF-I, IGF-II, and IGFBP-3 were analyzed with real-time RT-PCR and ELISA, respectively. Cox proportional hazards regression model was used to examine the associations of IGF markers with patient survival. Age was inversely associated with IGF-I, IGF-II and IGFBP-3 at both mRNA and peptide levels. Small tumors, early TNM stages, or low grades were associated with high mRNA expression of IGFs and IGFBP-3. Hormone receptors were positively correlated with IGF-I and IGF-II expression. Survival analysis showed that patients with high expression of one of the IGF-I transcripts, IGF-IA, had lower risk of disease recurrence (HR = 0.47, 95%CI: 0.27-0.81) and death (HR = 0.35, 95%CI: 0.18-0.70) compared to those with low expression. High IGFBP-3 expression was also inversely associated with reduced risk of death (HR = 0.47, 95%CI: 0.23-0.95). Similar associations, however, were not observed when tissue levels of IGF-I peptide or IGFBP-3 protein were analyzed. High IGF-II peptide was related to increased risk of relapse (HR = 1.91, 95%CI: 1.12-3.27). Our findings of high mRNA expression of IGFs and IGFBP-3 being associated with less aggressive tumors and favorable prognosis were consistent with previous observations, but were not supported by the measurement of tissue levels of IGF-I peptide and IGFBP-3 protein, suggesting that IGF mRNA expression and tissue levels of IGF peptides are regulated by different mechanisms and assessing these molecules in tumor tissue may have different implications.


Determination of limonin in grapefruit juice and other citrus juices by high-performance liquid chromatography.
A method has been developed for the quantitation of the bitter component limonin in grapefruit juice and other citrus juices. The sample clean-up consisted of centrifugation, filtration and a selective, rapid and reproducible purification with a C2 solid-phase extraction column. The limonin concentration was determined by high-performance liquid chromatography on a C18 column with UV detection at 210 nm. A linear response was obtained from 0.0 to 45 ppm limonin. The minimum detectable amount was 2 ng. The minimum concentration which was detected without concentration with good precision was 0.1 ppm. The method was also used for the determination of limonin in different types of oranges, including navel oranges, mandarins, lemons, limes, pomelos and uglis.


lin28 proteins promote expression of 17∼92 family miRNAs during amphibian development.
Lin28 proteins are post-transcriptional regulators of gene expression with multiple roles in development and the regulation of pluripotency in stem cells. Much attention has focussed on Lin28 proteins as negative regulators of let-7 miRNA biogenesis; a function that is conserved in several animal groups and in multiple processes. However, there is increasing evidence that Lin28 proteins have additional roles, distinct from regulation of let-7 abundance. We have previously demonstrated that lin28 proteins have functions associated with the regulation of early cell lineage specification in Xenopus embryos, independent of a lin28/let-7 regulatory axis. However, the nature of lin28 targets in Xenopus development remains obscure. Here, we show that mir-17∼92 and mir-106∼363 cluster miRNAs are down-regulated in response to lin28 knockdown, and RNAs from these clusters are co-expressed with lin28 genes during germ layer specification. Mature miRNAs derived from pre-mir-363 are most sensitive to lin28 inhibition. We demonstrate that lin28a binds to the terminal loop of pre-mir-363 with an affinity similar to that of let-7, and that this high affinity interaction requires to conserved a GGAG motif. Our data suggest a novel function for amphibian lin28 proteins as positive regulators of mir-17∼92 family miRNAs.


Metacognitive impairment in active cocaine use disorder is associated with individual differences in brain structure.
Dysfunctional self-awareness has been posited as a key feature of drug addiction, contributing to compromised control over addictive behaviors. In the present investigation, we showed that, compared with healthy controls (n=13) and even individuals with remitted cocaine use disorder (n=14), individuals with active cocaine use disorder (n=8) exhibited deficits in basic metacognition, defined as a weaker link between objective performance and self-reported confidence of performance on a visuo-perceptual accuracy task. This metacognitive deficit was accompanied by gray matter volume decreases, also most pronounced in individuals with active cocaine use disorder, in the rostral anterior cingulate cortex, a region necessary for this function in health. Our results thus provide a direct unbiased measurement - not relying on long-term memory or multifaceted choice behavior - of metacognition deficits in drug addiction, which are further mapped onto structural deficits in a brain region that subserves metacognitive accuracy in health and self-awareness in drug addiction. Impairments of metacognition could provide a basic mechanism underlying the higher-order self-awareness deficits in addiction, particularly among recent, active users.


Haematological effects of betamethasone treatment in late pregnancy.
To assess the maternal haematological effects of betamethasone administered in late pregnancy, an automated full blood count was performed before and daily for 5 days after betamethasone in 25 women with a singleton pregnancy between 23 and 33 weeks' gestation. From a mean (+/- SD) baseline level of 11.0+/-2.2 x 10(9)/L, the total white cell count increased significantly to 13.2+/-2.9 x 10(9)/L and 13.5+/-3.1 x 10(9)/L on the first and second day after treatment respectively, returning to baseline on day 3 (p<0.0001, ANOVA). These changes represented a mean increase in the neutrophil count of 35% and a mean decrease in the lymphocyte count of 23%. While there was considerable intersubject variation in the extent of the changes, this study has quantified the leucocytosis induced by betamethasone in late pregnancy, information that may assist with the clinical evaluation of a woman at risk of preterm delivery.


Pharmacophore modeling and parallel screening for PPAR ligands.
We describe the generation and validation of pharmacophore models for PPARs, as well as a large scale validation of the parallel screening approach by screening PPAR ligands against a large database of structure-based models. A large test set of 357 PPAR ligands was screened against 48 PPAR models to determine the best models for agonists of PPAR-alpha, PPAR-delta, and PPAR-gamma. Afterwards, a parallel screen was performed using the 357 PPAR ligands and 47 structure-based models for PPARs, which were integrated into a 1537 models comprising in-house pharmacophore database, to assess the enrichment of PPAR ligands within the PPAR hypotheses. For these purposes, we categorized the 1537 database models into 181 protein targets and developed a score that ranks the retrieved targets for each ligand. Thus, we tried to find out if the concept of parallel screening is able to predict the correct pharmacological target for a set of compounds. The PPAR target was ranked first more often than any other target. This confirms the ability of parallel screening to forecast the pharmacological active target for a set of compounds.


[Apixaban: pharmacology and action profile].
Vitamin K antagonists are currently the most frequently used anticoagulants. However, practical limitations of their application, such as variability in dose response, a narrow therapeutic index and numerous drug and dietary interactions, have lead to development of new oral anticoagulants with better efficacy and safety profile. Recent advances included the development of orally active FXa inhibitors rivaroxaban and apixaban. Rivaroxaban received its marketing approval in September 2008. Apixaban has recently been approved for prevention of venous thromboembolism after total hip or knee replacement. This review describes the pharmacological properties of apixaban and discusses the latest findings from clinical trials.


β3-Adrenoceptor, a novel player in the round-trip from neonatal diseases to cancer: Suggestive clues from embryo.
The role of the β-adrenoceptors (β-ARs) in hypoxia-driven diseases has gained visibility after the demonstration that propranolol promotes the regression of infantile hemangiomas and ameliorates the signs of retinopathy of prematurity (ROP). Besides the role of β2-ARs, preclinical studies in ROP have also revealed that β3-ARs are upregulated by hypoxia and that they are possibly involved in retinal angiogenesis. In a sort of figurative round trip, peculiarities typical of ROP, where hypoxia drives retinal neovascularization, have been then translated to cancer, a disease equally characterized by hypoxia-driven angiogenesis. In this step, investigating the role of β3-ARs has taken advantage of the assumption that cancer growth uses a set of strategies in common with embryo development. The possibility that hypoxic induction of β3-ARs may represent one of the mechanisms through which primarily embryo (and then cancer, as an astute imitator) adapts to grow in an otherwise hostile environment, has grown evidence. In both cancer and embryo, β3-ARs exert similar functions by exploiting a metabolic shift known as the Warburg effect, by acquiring resistance against xenobiotics, and by inducing a local immune tolerance. An additional potential role of β3-AR as a marker of stemness has been suggested by the finding that its antagonism induces cancer cell differentiation evoking that β3-ARs may help cancer to grow in a nonhospital environment, a strategy also exploited by embryos. From cancer, the round trip goes back to neonatal diseases for which new possible interpretative keys and potential pharmacological perspectives have been suggested.


Differential expression of double-band apolipoprotein(a) phenotypes in healthy Spanish subjects detected by SDS-agarose immunoblotting.
A sodium dodecyl sulphate-agarose apolipoprotein(a) [apo(a)] phenotyping method was set up to attain accurate scanning densitometry of proteins. Serum samples from 99 healthy Spanish men were analysed and twenty-five different apo(a) isoforms (12 to 37 kringle 4 repeats) were detected. Double-band phenotypes accounted for 39.4% (n = 39) and three different patterns of protein expression were identified: pattern A (20.5% of double-band phenotyped samples) predominantly expressed the highest molecular weight isoform; pattern B (53.9%) mainly the lowest molecular weight isoform, and pattern AB (25.6%), expressed both isoforms equally. A significant linear association between expression pattern and lipoprotein(a) [Lp(a)] concentration > or = 0.30 g/l was observed. Single-band phenotyped samples (n = 60) were stratified according to apo(a) kringle 4 repeat categories and showed that 90% of isoforms < 20 K4 repeats had high Lp(a) concentrations (> or = 0.30 g/l), whereas isoforms with 20 to 24 or more than 24 kringle 4 repeats had Lp(a) concentrations > or = 0.30 g/l in 47% and 14%, respectively. A logistic regression model was fitted to test the association between apo(a) size, expression pattern and Lp(a) concentration. In this model, apo(a) isoform < 25 kringle 4 repeats was significantly associated with serum Lp(a) concentration > or = 0.30 g/l in both single and double-band phenotyped samples (odds ratio = 8.9, p < 0.001). In the latter, a differential expression pattern with respect to smaller size isoforms (pattern AB vs A) was significantly associated with Lp(a) concentration > or = 0.30 g/l (odds ratio = 17.97, P = 0.045). Heterogeneity in protein apo(a) size expressed according to kringle 4 repeat number could be categorized in heterozygous phenotypes as three patterns. When small-sized isoform was expressed (pattern B) or both isoforms were equally expressed (pattern AB), the probability of having Lp(a) > or = 0.30 g/l is higher.


Primary cutaneous adenoid cystic carcinoma.
Primary cutaneous adenoid cystic carcinoma is a rare, slow-growing malignancy first described by Boggio in 1975. This tumor characteristically consists of basophilic cells with a distinct adenoid or cribriform pattern in the mid to deep reticular dermis. Modified myoepithelial cells with prominent basement membrane material often surround true lumina. Definitive diagnosis relies on the characteristic histologic features and the exclusion of metastatic disease. We describe two patients who presented with painful papules of the scalp and were successfully treated with wide local excision.


Conference on insulin pump therapy in diabetes. Multicenter study of effect on microvascular disease. The Central Biochemistry Laboratory in the Multicenter Kroc Study. Problems and proposals.
The advantages of a multicenter trial can easily be lost if results from individual centers cannot be safely combined for statistical analysis. One objective of the Kroc Study was to develop methods that would allow valid amalgamation of results from laboratories at the six clinical centers and a central biochemical laboratory at the University of Newcastle upon Tyne. Responsibilities of the local laboratories, in addition to measurement of plasma glucose, creatinine, and glycosylated hemoglobin, were to obtain and prepare samples for measurement of plasma glucose, glycosylated hemoglobin, and serum lipids at the central laboratory, of C-peptide at the University of Chicago, and to collect and prepare samples for measurement of urinary albumin excretion at Guy's Hospital. The central laboratory was additionally to provide a system to ensure the comparability of plasma glucose determinations between and within centers, and to advise on common procedures for sample handling. Major problems were encountered with sample labeling, dispatch, and transport to the central laboratory. Although central determinations of plasma glucose and serum lipids were still possible in transported specimens, central assay of glycosylated hemoglobin proved inaccurate and useless. Compliance with the plasma glucose quality control program was variable among centers. Although the difference between the centers recording the highest and lowest values was 24.6% of the mean estimate of plasma glucose level, correlation between local and central plasma glucose determinations was good (r = 0.99, see pages 22-26).(ABSTRACT TRUNCATED AT 250 WORDS)


Association of anxiety, depression and resilience with overall health and functioning in axial spondyloarthritis (axSpA): a cross-sectional study.
To evaluate the association between anxiety, depression and resilience with overall health and functioning in axial spondyloarthritis (axSpA). Cross-sectional evaluation of baseline data from a prospective cohort study, with recruitment from January 2018 to March 2021. Outpatient clinic in a tertiary hospital in Singapore. Patients aged 21 years and above who were diagnosed with axSpA. The Hospital Anxiety and Depression Scale (HADS) was used for assessing anxiety and depression, 10-item Connor Davidson Resilience Scale (CD-RISC-10) for resilience, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for disease activity, Bath Ankylosing Spondylitis Functional Index (BASFI) for functional limitation and Assessment of SpondyloArthritis International Society Health Index (ASAS HI) for overall health and functioning. Univariable and multivariable linear regression analyses were performed to assess the association between anxiety, depression and resilience with health and functioning. We included 296 patients in this study. The median (IQR) score for HADS-Anxiety was 5.0 (2.0-8.0), with 13.5% and 13.9% having borderline abnormal and abnormal anxiety, respectively. The median (IQR) score for HADS-Depression was 3.0 (1.0-7.0), with 12.8% and 8.4% having borderline abnormal and abnormal depression, respectively. The median (IQR) CD-RISC-10 score was 29.0 (23.0-32.0) while the median (IQR) ASAS HI score was 4.0 (2.0-7.0). Apart from BASDAI, BASFI and disease duration, anxiety and depression were associated with overall health and functioning (β: 0.12, 95% CI 0.03, 0.20; β: 0.20, 95% CI 0.09, 0.31) in the multivariable linear regression. Level of resilience was not associated with health and functioning. Anxiety and depression, but not resilience, were associated with poorer health and functioning. Clinicians could consider routinely screening for anxiety and depression in their patients, especially in patients with more severe symptoms.


Unlicensed and off-label drug use in children: implications for safety.
A significant number of children receive either an unlicensed or an off-label drug during their stay in hospital. Studies throughout Europe have shown that at least one-third of children in hospital and up to 90% of neonates in a neonatal intensive care unit receive such drug prescriptions. The medicines that are most frequently used off-label include analgesics, antibiotics and bronchodilators. The purpose of licensing a drug is to ensure safety, efficacy and quality. If a drug is used in a different manner, one would expect a greater risk of toxicity. Only three studies have commented on the risk of toxicity in relation to unlicensed or off-label drug use. Only one of these three studies prospectively tried to evaluate the risk associated with off-label and unlicensed drug prescription. This study suggested that the percentage of unlicensed and off-label drug use was significantly associated with the risk of an adverse drug reaction. Two studies looking at adverse drug reactions suggest that there is a greater risk of a severe adverse drug reaction occurring in association with the off-label or unlicensed use of drugs. One study found that five out of eight severe adverse drug reactions were associated with the off-label use of a medicine. The other study found that 14 of 19 drug prescriptions associated with 17 severe adverse drug reactions were either unlicensed or off-label. The risk of prescribing off-label and unlicensed drugs in children is not clear from the limited data available.


Degradation of crystal violet by an FeGAC/H2O2 process.
Because of the growing concern over highly contaminated crystal violet (CV) wastewater, an FeGAC/H(2)O(2) process was employed in this research to treat CV-contaminated wastewater. The experimental results indicated that the presence of iron oxide-coated granular activated carbon (FeGAC) greatly improved the oxidative ability of H(2)O(2) for the removal of CV. For instance, the removal efficiencies of H(2)O(2), GAC, FeGAC, GAC/H(2)O(2) and FeGAC/H(2)O(2) processes were 10%, 44%, 40%, 43% and 71%, respectively, at test conditions of pH 3 and 7.4mM H(2)O(2). FeGAC/H(2)O(2) combined both the advantages of FeGAC and H(2)O(2). FeGAC had a good CV adsorption ability and could effectively catalyze the hydrogen peroxide oxidation reaction. Factors (including pH, FeGAC dosage and H(2)O(2) dosage) affecting the removal of CV by FeGAC/H(2)O(2) were investigated in this research as well. In addition, the reaction intermediates were separated and identified using HPLC-ESI-MS. The N-demethylation step might be the main reaction pathway for the removal of CV. The reaction mechanisms for the process proposed in this research might be useful for future application of this technology to the removal of triphenylmethane (TPM) dyes.


Plasma levels of somatostatin-like immunoreactivity-independence of kidney function.
Plasma levels of somatostatin-like immunoreactivity (SLI) and gastrin were determined by radioimmunoassay in patients with varying degrees of renal dysfunction. The plasma SLI was not increased in patients with end-stage renal failure as compared to healthy controls. In patients with varying degrees of renal insufficiency no significant correlation was found between the plasma SLI and kidney function as estimated by the 51Cr-EDTA-clearance rate. In uraemic patients a significant inverse correlation was found between plasma SLI and plasma gastrin.


Nitric oxide in the failing myocardium.
It is now apparent that NO is produced in the myocardium. There it plays a central role in normal myocardial physiology. In addition, NO has the ability to exert whether beneficial or deleterious effects on the structure and function of the myocardium. At low, "physiologic" concentrations, NO may protect from deleterious stimuli such as mechanical stress and norepinephrine. At higher, "pathologic" concentrations, NO may cause the loss of myocytes. The mechanisms by which NO exerts these contrasting effects may involve decreases and increases in oxidative stress, respectively. A better understanding of the role NO plays in the development and progression of myocardial failure may lead to new treatment strategies.


Spatiotemporal patterns and drivers of methane uptake across a climate transect in Inner Mongolia Steppe.
Steppe soils are important biological sinks for atmospheric methane (CH4), but the strength of CH4 uptake remains uncertain due to large spatiotemporal variation and the lack of in situ measurements at regional scale. Here, we report the seasonal and spatial patterns of CH4 uptake across a 1200 km transect in arid and semi-arid steppe ecosystems in Inner Mongolia, ranging from meadow steppe in the east plain to typical and desert steppes on the west plateau. In general, seasonal patterns of CH4 uptake were site specific, with unimodal seasonal curves in meadow and typical steppes and a decreasing seasonal trend in desert steppe. Soil moisture was the dominant factor explaining the seasonal patterns of CH4 uptake, and CH4 uptake rate decreased with an increase in soil moisture. Across the transect, CH4 uptake showed a skewed unimodal spatial pattern, with the peak rate observed in the typical steppe sites and with generally higher uptake rates in the west plateau than in the east plain. Soil moisture, together with soil temperature, soil total carbon, and aboveground plant biomass, were the main drivers of the regional patterns of CH4 uptake rate. These findings are important for model development to more precisely estimate the soil CH4 sink capacity in arid and semi-arid regions.


Lindane binding to sections of human skin: skin capacity and isotherm determinations.
Human autopsy skin was sliced into three sections; an outer epidermis-rich layer, a middle dermis layer, and an inner dermis and subcutaneous fat layer. Each slice was bathed in lindane solutions over a 50-fold concentration range for 48 h at 37 degrees C. Lindane uptake by the skin was extensive (less than 90%) for all concentrations and all skin slices. Equilibrium dialysis with lindane at 37 degrees C for 24 h showed binding affinities by the skin sections to exceed 98%. The binding constants of the outer skin section (epidermis-rich) were higher than those of the middle and inner sections. The binding attraction for lindane by United States Pharmacopeia (USP) human plasma protein fraction (mean 90.5% bound) resulted in its competitive extraction from the skin slices in a three-compartment dialytic procedure. Since the least binding constants were in the middle and inner layers, and since lindane has a preference for plasma over skin, the two (inner skin and plasma) may combine to create the sink conditions necessary for lindane percutaneous absorption into the body. This plus the high epidermis capacity for lindane explains why in some instances (such as occlusion) high levels of lindane can be percutaneously absorbed.


Aerial oxidation of the glucocorticoid side-chain under pH control.
The outcome of aerial oxidation of the glucocortico-steroid side-chain (as exemplified by dexamethasone) has been shown to be subject to strict pH control. At pH 7.4 the glyoxal is the only product; at pH values of 8 and 9.2 the etioacid is formed, and at pH values of 13 or above the epimeric glycolic acids are produced. The glycolic acid epimer that predominates by a factor of 2 and is more stable has been shown by an X-ray crystal structural analysis to be the 20R compound. The presence of arsenite changes the course of the reaction and only the glycolic acids are yielded at pH values of 8 and above.


Personality factors and vulnerability to post-traumatic stress responses after childbirth.
To investigate whether levels of perfectionism, organization, and intolerance of uncertainty predispose women to more negative birth experiences and post-partum post-traumatic stress symptoms (PTSS). Birth experience was also examined as a potential moderator of the relationship between levels of the personality traits and post-natal PTSS. Prospective survey. First-time expectant mothers (N = 10,000) were contacted via Emma's Diary during the perinatal period. At 32-42 weeks' gestation, participants completed measures examining the three personality traits and prenatal mood. At 6-12 weeks' post-partum, instruments assessing childbirth experience, birth trauma, PTSS, and post-natal mood were completed. Data from 418 women were analysed. Higher perfectionism and intolerance of uncertainty were associated with more negative birth appraisals and PTSS. Organization was unrelated to birth experience or PTSS. In a regression, higher intolerance of uncertainty and perfectionism statistically predicted more negative birth appraisals. Only perfectionism predicted PTSS. Birth experience did not moderate the relationship between perfectionism or intolerance of uncertainty and PTSS. Personality risk factors for negative birth experiences and post-natal PTSS are identifiable prenatally. Maternity care providers could educate women about the unique roles of high perfectionism and intolerance of uncertainty during antenatal birth preparation. Women who expect themselves to be more perfect or who find it more difficult to cope with uncertainty had more negative experiences of childbirth. Women with higher levels of perfectionism were more likely to experience more symptoms of post-traumatic stress during the early post-natal period. Being more perfectionistic continued to have a more negative effect on women's well-being after birth, regardless of whether they had a positive or negative experience of birth. Integrating these findings into antenatal discussion around birth preferences would increase women's awareness of predisposing and obstetric risk factors that partially explain experiences of unsatisfactory births and post-partum post-traumatic stress.


Clinical characteristics of young-onset ischemic colitis.
Ischemic colitis (IC) typically develops in the elderly, where hypertension, cerebrocardiovascular disease, and past history of abdominal surgery are regarded as risk factors. Although there have been reports of younger patients with IC, its clinical features remain unclear. The aim of this study was to clarify the clinical characteristics of IC in young adults. Three hundred fifty-nine patients were diagnosed as having IC at five hospitals across Nagano prefecture, Japan. Clinical data were compared between the young patient group [20-45 years, n = 53 (15%)] and the elderly patient group [>45 years, n = 306 (85%)], as well as with age- and gender-matched healthy individuals (n = 156). The presence of a smoking habit and hyperuricemia were significantly higher in the young patient group compared with the elderly patient group (42 vs. 19%, P = 0.001 and 8 vs. 1%, P = 0.019, respectively), which was confirmed by multiple logistic regression analysis (P = 0.001, odds ratio 3.239 and P = 0.028, odds ratio 16.907, respectively). Additionally, multiple logistic regression analysis of the young IC patient group and age- and gender-matched healthy individuals demonstrated that these two factors were strongly associated with IC development (P = 0.008, odds ratio 2.49 for smoking habit and P = 0.039, odds ratio 6.37 for hyperuricemia). High prevalences of a smoking habit and hyperuricemia are characteristic features of IC in the young adult population.


Atg39 selectively captures inner nuclear membrane into lumenal vesicles for delivery to the autophagosome.
Mechanisms that turn over components of the nucleus and inner nuclear membrane (INM) remain to be fully defined. We explore how components of the INM are selected by a cytosolic autophagy apparatus through a transmembrane nuclear envelope-localized cargo adaptor, Atg39. A split-GFP reporter showed that Atg39 localizes to the outer nuclear membrane (ONM) and thus targets the INM across the nuclear envelope lumen. Consistent with this, sequence elements that confer both nuclear envelope localization and a membrane remodeling activity are mapped to the Atg39 lumenal domain; these lumenal motifs are required for the autophagy-mediated degradation of integral INM proteins. Interestingly, correlative light and electron microscopy shows that the overexpression of Atg39 leads to the expansion of the ONM and the enclosure of a network of INM-derived vesicles in the nuclear envelope lumen. Thus, we propose an outside-in model of nucleophagy where INM is delivered into vesicles in the nuclear envelope lumen, which can be targeted by the autophagosome.


Cardiovascular effects of Boophone disticha aqueous ethanolic extract on early maternally separated BALB/C mice.
There are a number of reports from traditional medical practice in Zimbabwe and neighboring countries and few in vitro studies suggesting an effect with extracts of Boophone disticha in some forms of anxiety disorder. In order to validate the use of Boophone disticha in treatment of anxiety, this study was set to determine the effects of the plant extracts on blood pressure (BP) and heart rate (HR) in adult BALB/c mice subjected to repeated early maternal separation (MS) stress. To test whether early life stress increases anxiety in mice, non-invasive tail cuff method was used to examine the autonomic nervous system activity by assessing cardiovascular reactivity and response to acute mixing stress (AMS) and restraint stress (RS) in adult mice subjected to early postnatal stress as compared to control. AMS-induced cardiovascular response was then evaluated in adult MS mice treated with Boophone disticha as compared to vehicle and diazepam. Comparisons of the BP and HR measurements indicated that MS significantly reduced AMS-induced HR responses in BALB/c mice when compared with control. Boophone disticha treatment significantly reduced AMS-induced BP response in BALB/c MS mice as compared to vehicle and diazepam treatments. Our findings demonstrate for the first time that postnatal stress can induce short-term changes in the sensitivity of the cardiovascular system to subsequent stress which can be reduced by treatment with a freeze dried aqueous ethanolic extract of Boophone disticha.


Episomal Reprogramming of Human Peripheral Blood Mononuclear Cells into Pluripotency.
Peripheral blood is an easily accessible cell resource for reprogramming into pluripotency by episomal vectors. Here, we describe an approach for efficient generation of integration-free induced pluripotent stem cells (iPSCs) under feeder or feeder-free conditions. Additionally, in combination with the CRISPR-Cas9 genome-editing system, we can directly generate edited iPSCs from blood cells. With this protocol, one can easily generate either integration-free iPSCs or genetically edited iPSCs from peripheral blood at high efficiency.


Temperature control after cardiac arrest: friend or foe.
Most patients who are successfully resuscitated after cardiac arrest are initially comatose and require mechanical ventilation and other organ support in an ICU. Best practice has been to cool these patients and control their temperature at a constant value in the range of 32-36 oC for at least 24 h. But the certainty of the evidence for this practice is increasingly being challenged. This review will summarize the evidence on key aspects of temperature control in comatose postcardiac arrest patients. The Targeted Temperature Management 2 (TTM-2) trial documented no difference in 6-month mortality among comatose postcardiac arrest patients managed at 33 oC vs. targeted normothermia. A systematic review and meta-analysis completed by the Advanced Life Support (ALS) Task Force of the International Liaison Committee on Resuscitation (ILCOR) concluded that temperature control with a target of 32-34 °C did not improve survival or favourable functional outcome after cardiac arrest. Two observational studies have documented an association between predicted moderate hypoxic-ischaemic brain injury and better outcome with temperature control at 33-34 oC compared with 35-36 oC. We suggest actively preventing fever by targeting a temperature 37.5 oC or less for those patients who remain comatose following return of spontaneous circulation (ROSC) after cardiac arrest.


The incidence of type 1 diabetes in children under 15 years of age is rising again-a nationwide study.
International incidence rates (IRs) and trends of childhood type 1 diabetes (T1D) vary. Recent data from Ireland and other high incidence countries suggested a stabilisation in IRs of T1D in children aged under 15 years. Our primary objective was to report the IR of T1D in children in Ireland from 2019 to 2021 and evaluate if age, sex and season of diagnosis had changed. Incident cases of T1D in those aged under 15 years were identified prospectively by clinicians nationally and reported to the Irish Childhood Diabetes National Register (ICDNR). Following case verification, capture-recapture methodology was applied, and IRs calculated. Numbers of children including age, sex and season of diagnosis per year were evaluated. There were 1027 cases, 542 males (53%). The direct standardised incidence rates (SIRs) increased by 21% overall and were 31.1, 32.2 and 37.6/100,000/year, respectively, with no significant sex difference. The highest IRs were in the 10-14-year category until 2021, then changed to the 5-9-year category (40% of cases). Whilst autumn and winter remain dominant diagnostic seasons, seasonality differed in 2021 with a greater number presenting in spring. The incidence of childhood T1D in Ireland is increasing, observed prior to the COVID-19 pandemic, and shifting to an earlier age at diagnosis for the first time. The pattern of seasonality also appears to have changed. This may reflect an increased severity of diabetes with important implications for healthcare providers. • Ireland has a very high incidence of T1D in childhood, which had stabilised following a rapid rise, similar to other high incidence countries. • The incidence rate is consistently highest in older children (10-14 years). • Irish IR is no longer stable and has increased again, with the highest incidence occurring in the younger 5-9 age category for the first time. • The seasonality of diagnosis has changed during the COVID-19 pandemic years of 2020-2021.


Purification of very high density lipoproteins by differential density gradient ultracentrifugation.
Differential density gradient ultracentrifugation procedures, utilizing a vertical rotor, were developed for the preparative purification of very high density lipoproteins (VHDL, density greater than 1.21 g/ml). The VHDLs of several insect species were purified as follows. An initial density gradient ultracentrifugation step removed lipoproteins of lower density from the VHDL-fraction, which partially separated from the nonlipoproteins present in the infranatant. A complete separation was achieved by a second centrifugation step employing a modified gradient system. The use of a vertical rotor and specially designed discontinuous gradients allows a relatively fast, efficient, and economical isolation of the class of very high density lipoproteins. Similar gradient systems should be useful for the detection and purification of VHDLs from other sources.


Analysis of amadori-glycated phosphatidylethanolamine in the plasma of healthy subjects and diabetic patients by liquid chromatography-tandem mass spectrometry.
Peroxidized phospholipid-mediated cytotoxity, the abnormal increase in the levels of phosphatidylcholine hydroperoxide (PCOOH) found in the plasma of type 2 diabetic patients, is involved in the pathophysiology of many diseases. PCOOH accumulation may be related to Amadori-glycated phosphatidylethanolamine (deoxy-D-fructosyl PE, or Amadori-PE) because Amadori-PE causes oxidative stress. However, the occurrence of lipid glycation products, including Amadori-PE, in vivo remains unclear. We developed a method to analyze Amadori-PE by using quadrupole/linear ion-trap mass spectrometry, the Applied Biosystems 4000 Q TRAP. We found that pyridoxals could easily be condensed with PE before the glucose-PE reaction occurred. The PE-pyridoxal 5'-phosphate adduct was detectable in human red blood cells, and the increased plasma Amadori-PE concentration in streptozotocin-induced diabetic rats was decreased by dietary supplementation with pyridoxal 5'-phosphate. Therefore, it is likely that pyridoxal 5'-phosphate acts as a lipid glycation inhibitor in vivo, and this may contribute to diabetes prevention.


Chemical and antigenic alterations of Candida albicans cell walls related to the action of amphotericin B sub-inhibitory doses.
Sub-inhibitory doses of amphotericin B led to Candida albicans cell wall modifications which involved peptidomannans. The amount of this product was reduced by a third, the decrease being due to mannans whose absolute and relative values fell whereas the amount of amino-acids increased. Concomitantly, the treated cells exhibited a loss in their immunological reactivity.


The hypothalamo-hypophysial system in Acipenseridae. IX. Formation of monoaminergic neurosecretory cells in the preoptic nucleus region during early ontogeny.
"Falck-positive" monoaminergic neurosecretory cells (M-NSC) are found in stage I-II sturgeon larvae in the dorsal zone of the preoptic nucleus (PN) by means of fluorescence and electron microscopy. Single poorly differentiated M-NSC are located mostly among the ependymal cells. At this stage the M-NSC have very short dendrites protruding into the third ventricle. In the process of differentiation the M-NSC move subependymally and their dendrites become longer. Axons of the M-NSC can be clearly traced only in stage IV larvae. Perikarya and dendrites of M-NSC contain little rough endoplasmic reticulum and numerous neurosecretory granules (NSG) 60-150 nm in diameter. Ventricular dendrites of the "Gomori-positive" peptidergic neurosecretory cells (P-NSC) containing NSG 110-200 nm in diameter are observed within the PN in stage III larvae. Thus the M-NSC differentiate earlier than the P-NSC. The intraventricular terminals have kinocilia and show typical macroapocrine secretion. This fact supports the view of a receptory as well as a secretory function of the M-NSC and P-NSC. It is proposed that in early ontogeny monoamine as well as peptide neurohormones are secreted into the cerebrospinal fluid. This transventricular pathway is considered phylogenetically ancient.


Bovine lactoferrin suppresses inflammatory cytokine expression in endometrial stromal cells in chronic endometritis.
Chronic endometritis (CE) is a type of chronic inflammation in the endometrium that is associated with infertility, which is primarily due to implantation failure. Antibiotics are the most common treatment for CE. However, some patients with CE are resistant to antibiotic treatment, while others refuse this treatment. Therefore, we focused on lactoferrin (Lf), which exhibits antimicrobial and anti-inflammatory properties, and studied its effect on inflammation in endometrial stromal cells (ESCs) from patients with CE. Endometrial tissue was collected from patients with CE, and ESCs were isolated and cultured. When ESCs were cultured with bovine lactoferrin (bLf: 1 mg/mL), the mRNA expression of TNF-α (p < 0.05) and IL-1β (p < 0.01) was significantly decreased compared with that in cells cultured without bLf. The level of TNF-α protein in the culture medium was significantly decreased (p < 0.01), while that of IL-1β was also decreased, but not significantly (p < 0.10), when 1 mg/mL of bLf was added to the culture medium. When more inflammation was induced artificially by adding 0.1 ng/mL of TNF-αto ESCs, the addition of bLf (1 mg/mL) to ESCs decreased IL-6 and IL-1β mRNA expression to levels similar to those in ESCs without TNF-α treatment. Furthermore, it was revealed that the actions of bLf are mediated by the AKT and MAPK intracellular signaling pathways, which are mechanisms by which the increase in TNF-α-induced cytokine expression is suppressed in ESCs. bLf suppresses the expression of inflammatory cytokines in human ESCs and may be a new therapeutic candidate for CE.


Ubiquitin-mediated regulation of sterol homeostasis.
Cholesterol is an essential component of mammalian membranes, and its homeostasis is strictly regulated, with imbalances causing atherosclerosis, Niemann Pick disease, and familial hypercholesterolemia. Cellular cholesterol supply is mediated by LDL-cholesterol import and de novo cholesterol biosynthesis, and both pathways are adjusted to cellular demand by the cholesterol-sensitive SREBP2 transcription factor. Cholesterol homeostasis is modulated by a wide variety of metabolic pathways and the ubiquitination machinery, in particular E3 ubiquitin ligases. In this article, we review recent progress in understanding the role of E3 ubiquitin ligases in the metabolic control of cellular sterol homeostasis.


[The lateral tension band--a method of osteosynthesis of patella fractures for immediate carrying capacity (author's transl)].
The tensions caused by means of flexors and tensors on the intact and by various procedures operated fractured patella have been determined. The disadvantages of the cerclage and the eccentric ventral tension band, both of them mainly usual, are exposed. Interfragmentary measurements of pression power in a corpse knee as well as breaking tests with a model patella and first experiences by operation with a new method confirm the reflexions. Principles for a modus of osteosynthesis for fractures of the patella are realized by the lateral tension-band. All loading inclined fragment distractive powers thereby are taken up by production a high-level interfragmentary compression, so that immediate postoperative loading is possible.


Mechanistic target of rapamycin (mTOR) signaling in status epilepticus.
The mechanistic target of rapamycin (mTOR) pathway plays a critical role in brain development, neuronal shape and size, and synaptic plasticity, as well as learning and memory. Mutations in mTOR pathway genes (MPG) cause malformations of cortical development (MCDs) that are highly associated with often intractable epilepsy, thus highlighting an association between the mTOR pathway and establishment of the epileptic network. A growing body of preclinical evidence in in vitro and rodent model systems suggests that mTOR signaling may be altered in status epilepticus (SE) and that modulation of mTOR activation with mTOR inhibitors such as rapamycin (sirolimus) could provide new therapeutic avenues for treatment of both refractory epilepsy and SE. Rapamycin may have ubiquitous effects on all neuronal subtypes as well as astrocytes and seems to prevent the development of seizures following experimentally induced SE. To date, there have been no human studies focused on mTOR signaling in SE, but clearly, preclinical data support investigation into this pivotal cell signaling pathway. Thus, modulation of the mTOR pathway may provide a new strategy for treatment of SE and could have implications for the prevention of epilepsy in patients with SE. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".


Interferon beta neutralizing antibodies in multiple sclerosis: neutralizing activity and cross-reactivity with three different preparations.
The presence and titer of neutralizing antibodies (NABs) was evaluated by an antiviral biological assay in 387 samples of 111 multiple sclerosis (MS) patients treated with one of the three commercial preparations of interferon beta (IFNbeta). Fifty NAB positive samples were found in 19 patients: 11 treated with IFNbeta-1b (Betaferon(R)) and eight with IFNbeta-1a (five with Avonex(R) and three with Rebif(R)). All the 38 NABs+ samples of patients treated with IFNbeta-1b cross-reacted with IFNbeta-1a of both commercial types. The median level of neutralizing units (NUs) of the sera was higher when tested against IFNbeta-1a than against IFNbeta-1b (p=0.000 vs. Avonexr(R) and p=0.003 vs. Rebif(R)). In line with these data, the NABs+ sera of patients treated with IFNbeta-1a cross-reacted with IFNbeta-1b and the level of NUs were lower when tested against IFNbeta-1b than against IFNbeta-1a (p=0.003). The different amount of NUs against IFNbeta types 1a and 1b could be due to the presence of aggregates in the IFNbeta-1b preparation. The different levels of cross-reactivity of NABs could reduce the bioavailability and therapeutic efficacy of IFNbeta in NABs+ patients switching from IFNbeta-1b to IFNbeta-1a.


Fragment-based approaches to enzyme inhibition.
Fragment-based approaches have provided a new paradigm for small-molecule drug discovery. The methodology is complementary to high-throughput screening approaches, starting from fragments of low molecular complexity and high ligand efficiency, and building up to more potent inhibitors. The approach, which depends heavily on a number of biophysical techniques, is now being taken up by more groups in both industry and academia. This article describes key aspects of the process and highlights recent developments and applications.


Effect of protein, fat, carbohydrate and fibre on gastrointestinal peptide release in humans.
Short-term regulation of food intake controls what, when and how much we eat within a single day or a meal. This regulation results from an integrated response to neural and humoral signals that originate from the brain, gastrointestinal (GI) tract and adipose tissue. In the GI tract, multiple sites including the stomach, duodenum, distal small intestine, colon, and pancreas are involved in this process. Ingested food evokes satiety by mechanical stimulation and by release of peptides in the GI tract. The intestine in particular plays a key role in satiety through various peptides secreted in response to food. Many of the intestinal peptides inhibit also gastric emptying thus enhancing gastric mechanoreceptor stimulation. In this review, the current knowledge about the effects of different macronutrients and fibre on the release of GI satiety-related peptides in humans is discussed.


The evidence base for community-based rehabilitation: a literature review.
Literature on community-based rehabilitation (CBR) published between 1978 and 2002 is reviewed to assess the evidence base for CBR. There were 128 articles found that met the criteria set by the authors. The articles have been classified according to the methodology used and the key aspects studied. The review showed an ever-increasing number of publications on CBR. Theory papers and descriptive studies are the most common types of papers in CBR literature. Intervention studies and case reports are relatively rare. No systematic review has yet been carried out although reviews on specific aspects of CBR have become available. The key aspects of 'implementation' and 'stakeholders' are relatively well presented but the numbers of articles on 'participation' and 'use of local resources' are noticeably low. This study reveals that there is no real focus of research in CBR and therefore the evidence base for CBR is fragmented and incoherent on almost all aspects of CBR. It is recommended that comprehensive review studies should be carried out on key aspects of CBR projects. This should be supported by systematic research in CBR projects in order to establish evidence-based practices.


[Metastasis to the lateral skull base].
Tumours and metastases of the lateral skull base are rare findings. Clinically, the progressive involvement of ipsilateral cranial nerves is important. A 69-year-old man presented with headache and palsies of the facial nerve and nerve VI. Furthermore, he had hearing loss and hypaesthesia of the trigeminal nerve (V3). Four months previously, laser therapy for carcinoma of the trachea (cT4 cN3 cM0) had been done. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed an intrapetrosal mass with destruction of the lateral skull base. The findings suggested a metastasis of the tracheal carcinoma. We performed a mastoidectomy with specimen collection, and the pathological analysis revealed infiltration of a squamous cell carcinoma. The patient died within 3 weeks after radiotherapy with palliative intention despite malignant progression. The diagnosis and therapy of metastases to the lateral skull base is an interdisciplinary challenge. CT and MRI scans are essential for planning further procedures. In cases of headache and cranial nerve palsies, a metastasis to the lateral skull base must be considered in the differential diagnosis.


Chlorido-(4'-chloro-2,2':6',2''-terpyridine-κ3 N,N',N'')(tri-fluoro-methane-sulfonato-κO)zinc(II) aceto-nitrile monosolvate.
In the title complex, [Zn(CF3O3S)Cl(C15H10ClN3)]·CH3CN, the zinc(II) core is fivefold coordinated by one chloride, one tri-fluoro-methane-sulfonate O atom and three terpyridine N atoms in a slightly distorted square-pyramidal geometry. The structure provides a distinct example amongst other zinc(II) 4-chloro-terpyridine complexes because of the unusual planarity of the coordinated chloride, the short length of the Zn-N bond opposite to the chloride ligand [1.9572 (15) Å], and the presence of an elongated Zn-O bond [2.3911 (14) Å] in the coordinated tri-fluoro-methane-sulfonate ion. A molecule of acetonitrile is also found in the asymmetric unit of the title complex.


PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation.
IKKbeta serves as a central intermediate signaling molecule in the activation of the NF-kappaB pathway. However, the precise mechanism for the termination of IKKbeta activity is still not fully understood. Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, PPM1A and PPM1B, as IKKbeta phosphatases. Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. PPM1A and PPM1B associate with the phosphorylated form of IKKbeta, and the interaction between PPM1A/PPM1B and IKKbeta is induced by TNFalpha in a transient fashion in the cells. Furthermore, knockdown of PPM1A and PPM1B expression enhances TNFalpha-induced IKKbeta phosphorylation, NF-kappaB nuclear translocation and NF-kappaB-dependent gene expression. These data suggest that PPM1A and PPM1B play an important role in the termination of TNFalpha-mediated NF-kappaB activation through dephosphorylating and inactivating IKKbeta.


"Think aloud": a program for developing self-control in young aggressive boys.
"Think Aloud" was designed as a training program to improve self-control in 6- to 8-year-old boys. It involved modeling and verbalization of cognitive activity to foster use of verbal mediation skills in dealing with both cognitive and interpersonal problems. It was hypothesized that this training would lead to improvement in test performance and teacher ratings of classroom behavior in hyperaggressive boys. Twelve aggressive second grade boys participated in daily, 30-minute, individual sessions for 6 weeks. Normal and aggressive control subjects received no intervention. Teachers rated both trained and untrained aggressive boys as improving in aggressive behaviors but they rated the experimental group as showing improvement on a significantly larger number of prosocial behaviors. The pattern of performance on cognitive tests also changed significantly in the experimental group. On pretest, their pattern differed from normals and resembled the aggressive control group, while on posttest their pattern resembled normals and differed from agressive controls. Suggestions were made concerning additional refinements needed in the program, but overall results indicated potential value in the present approach for providing assistance to aggressive boys in the early grades.


Inhibition of xanthine oxidase by uric acid and its influence on superoxide radical production.
The inhibition of xanthine oxidase by its reaction product, uric acid, was studied by steady state kinetic analysis. Uric acid behaved as an uncompetitive inhibitor of xanthine oxidase with respect to the reducing substrate, xanthine. Under 50 microM xanthine and 210 microM oxygen, the apparent K(i) for uric acid was 70 microM. Uric acid-mediated xanthine oxidase inhibition also caused an increase in the percentage of univalent reoxidation of the enzyme (superoxide radical production). Steady-state rate equations derived by the King-Altman method support the formation of an abortive-inhibitory enzyme-uric acid complex (dead-end product inhibition). Alternatively, inhibition could also depend on the reversibility of the classical ping-pong mechanism present in xanthine oxidase-catalyzed reactions.