Risk of bleeding complications and atrial fibrillation associated with ibrutinib treatment: A systematic review and meta-analysis.
The use of ibrutinib is hampered by major bleeding events and atrial fibrillation. Speculating whether randomized controlled trials might underestimate the risk of adverse events in clinical practice, we conducted a systematic review and meta-analysis studying patients treated in any setting and indication. We systematically searched the literature using MEDLINE and EMBASE databases for case series, cohort studies, or randomized controlled trials and retrieved all data in parallel. Proportions of patients with adverse events were pooled in relevant subgroups using the binominal distribution and Freeman-Tukey double arcsine transformation. Among 2'537 records screened, 85 were finally included, comprising 7'317 patients. Methodological quality according to the Newcastle-Ottawa Scale was rated as moderate to poor with regard to bleeding events and atrial fibrillation; 106 studies were excluded because of missing data at all. Reported events varied substantially between 0 % and 78 % (any bleedings), 0 % and 25 % (major bleedings), and 0 % and 38 % (new-onset atrial fibrillation). Pooled estimates were 28 % (95 % confidence interval 22 %, 34 %), 3 % (2 %, 4 %), and 8 % respectively (7 %, 10 %). The risk of events was higher in studies with an older population, high ibrutinib dosage, thrombocytopenia, antithrombotic treatment, and retrospective studies. In conclusions, reporting of bleeding events and atrial fibrillation varied substantially among studies. These observations, in combination with the estimates obtained, suggest a relevant risk in clinical practice.


[Assessment of regional microcirculatory changes by EPI perfusion studies in patients with multiple lacunar infarction].
The aim of this report is to assess regional cerebral microcirculatory changes by EPI perfusion study in patients with multiple lacunar infarction(MLI). Especially, we focused on the parameter(rCBV, MTT, rCBF) changes in the white matter and on the relationship between these changes in the gray and white matter. Twenty MLI patients(mean age 72 +/- 15 years) and 10 age-similar normal controls (mean age 65 +/- 12 years) were examined. As a result, the MLI patients demonstrated an insignificant rCBF reduction due to the rCBV elevation in the gray matter and a moderate rCBF reduction with less rCBV elevation in the white matter. These results show a difference in the vascular reserve between the gray and white matter, and insufficiency of the vascular reserve in MLI's white matter.


Hospitalizations realted to herpes zoster infection in the Canary Islands, Spain (2005-2014).
Herpes zoster is an important problem of public health especially among the elderly in Spain. A population-based retrospective epidemiological study to estimate the burden of herpes zoster requiring hospitalization in the Canary Islands, Spain was conducted by using data from the national surveillance system for hospital data, Conjunto Mínimo Básico de Datos. Records of all patients admitted to hospital with a diagnosis of herpes zoster in any position and cases of primary diagnosis (ICD-9-MC codes 053.0-053.9) during a 10-year period (2005-2014), were selected. A total of 1088 hospitalizations with a primary or secondary diagnosis of herpes zoster were identified during the study period. Annually there were 6.99 hospitalizations by herpes zoster per 100,000 population. It increases with age reaching a maximum in persons ≥85 years of age (43.98 admissions per 100,000). Average length of hospitalization was 16 days and 73 patients died, with a case-fatality rate of 4.03%. In 22% of the cases hospitalized, herpes zoster was the primary diagnosis. The hospitalization burden of herpes zoster in adults in the Canary Islands was still important during the last decade and justify the implementation of preventive measures, like vaccination in the elderly or other high risk groups to reduce the most severe cases of the disease.


Measurement of amino acid levels in the vitreous humor of rats after chronic intraocular pressure elevation or optic nerve transection.
To investigate whether the levels of free amino acids and protein in the vitreous of rat eyes are altered with chronic intraocular pressure (IOP) elevation or after optic nerve transection. The concentrations of 20 amino acids in the vitreous humor were measured by high-performance liquid chromatography in both eyes of 41 rats with unilateral IOP elevation induced by translimbal photocoagulation. Eyes were studied 1 day and 1, 2, 4, and 9 weeks after initial IOP elevation. The same amino acids were measured in 41 rats 1 day and 2, 4, and 9 weeks after unilateral transection of the orbital optic nerve. The intravitreal protein level was assayed in additional 22 rats with IOP elevation and 12 rats after nerve transection. Two masked observers evaluated the amount of optic nerve damage with a semiquantitative, light-microscopic technique. In rats with experimental glaucoma, amino acid concentrations were unchanged 1 day after treatment. At 1 week, 4 of 20 amino acids (aspartate, proline, alanine, and lysine) were higher than in control eyes ( < or = 0.01), but this difference was nonsignificant after Bonferroni correction for multiple simultaneous amino acid comparisons (none achieved < 0.0025). No amino acid was significantly different from control in the nerve transection groups (all > 0.05). Vitreous protein level was significantly higher in glaucomatous eyes than their paired controls at 1 day ( < 0.0001) and 1 week ( < 0.002). One day and 1 week after optic nerve transection, vitreal proteins were significantly elevated compared with control eyes from untreated animals ( < 0.0020 and < 0.0022, respectively), though not compared with their fellow eyes ( = 0.25 and 0.10). Chronic experimental glaucoma and transection of the optic nerve increase the amount of protein in the rat vitreous above control levels. In the vitreous of rats with experimental glaucoma, a number of free amino acids were transiently elevated to a modest degree, but no significant difference in vitreous glutamate concentration was detected ( > 0.01).


Human pegivirus infection after transplant: Is there an impact?
The microbiome's role in transplantation has received growing interest, but the role of virome remains understudied. Pegiviruses are single-stranded positive-sense RNA viruses, historically associated with liver disease, but their path-ogenicity is controversial. In the transplantation setting, pegivirus infection does not seem to have a negative impact on the outcomes of solid-organ and hematopoietic stem cell transplant recipients. However, the role of pegiviruses as proxies in immunosuppression monitoring brings novelty to the field of virome research in immunocompromised individuals. The possible immunomodulatory effect of pegivirus infections remains to be elucidated in further trials.


[Genetic analysis of one family with congenital limb malformations].
To detect potential mutation in a Chinese pedigree affected with congenital limb malformations. Clinical data was collected. Genomic DNA was extracted from peripheral blood samples of family members. The zone of polarizing activity regulatory sequence (ZRS) were amplified by PCR and subjected to direct sequencing. Among the 13 individuals in this pedigree, there were 4 PPD patients, who were characterized by varying degrees of deformity. The female patients suffered triphalangeal thumb and preaxial polydactyly, while the male patients only had preaxial polydactyly. Only one patient had foot involvement. TA heterogeneous mutations was discovered in the ZRS (105C>G) in all patients, the same mutation was not detected in 2 healthy family members. The inheritance pattern of PPD was autosomal dominant inheritance. There was a significant variability of symptoms among family patients. The heterozygous mutation of the ZRS (105C>G) probably underlie the disease.


Inability of refined CT to assess local extent of prostatic cancer.
A refined procedure for CT was evaluated as a staging procedure in 19 patients with localized prostatic carcinoma. The CT images were compared to histopathologic whole-mount step sections of the surgical specimens. Fourteen of the patients had pathologic stage T3 (pT3) and 5 had stage pT2 giving a prevalence of extracapsular growth of 0.74. The CT images were read by 2 radiologists independently with a diagnostic accuracy of 0.37 for both observers. This is no better than in previous studies using a routine CT procedure. We conclude that CT is of little value in the staging protocol for the local extent of prostatic carcinoma before radical prostatectomy.


Trace metals contamination potential and health risk assessment of commonly consumed fish of Perak River, Malaysia.
The rapid growth of industrial and agricultural activities in Malaysia are leading to the impairment of most of the rivers in recent years through realising various trace metals. This leads to toxicity, particularly when the toxic has entered the food chain. Perak River is one of the most dynamic rivers for the Malaysian population. Therefore, in consideration of the safety issue, this study was conducted to assess the concentration of such metals (Cd, Cu, Zn, Fe, and Pb) in the muscles of most widely consumed fish species (Barbonymus schwanenfeldii, Puntius bulum, Puntius daruphani, Hexanematichthys sagor, Channa striatus, Mystacoleucus marginatus, and Devario regina) from different locations of Perak River, Malaysia by employing inductively coupled plasma optical emission spectroscopy (ICP-OES). Among the trace metals, Fe and Cd were found to be the highest (29.33-148.01 μg/g) and lowest (0.16-0.49 μg/g) concentration in all of the studied species, respectively. Although the estimated daily intakes (μg/kg/day) of Cd (0.65-0.85), Fe (79.27-352.00) and Pb (0.95-12.17) were higher than their reference, the total target hazard quotients values suggested that the local residents would not experience any adverse health effects from its consumption. In contrast, the target cancer risk value suggested that all fish species posed a potential cancer risk due to Cd and cumulative cancer risk values, strongly implying that continuous consumption of studied fish species would cause cancer development to its consumers.


Assessment of drowsiness in epilepsy patients receiving chronic antiepileptic drug therapy.
Drowsiness is a common complaint among patients with epilepsy taking antiepileptic drugs (AEDs) and may be of particular importance because of the potential effects on cognitive abilities. We used a novel EEG-based measure (the Awake Maintenance Task, AMT) to determine objectively whether patients on chronic, stable AED therapy had impaired ability to maintain wakefulness. Thirty patients receiving AEDs [carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), valproate (VPA)] were compared to 35 healthy controls, 12 seizure patients not taking AEDs, and 16 patients with multiple sclerosis. A structured EEG recording was conducted under controlled conditions, and subjects were tested to determine their ability to maintain wakefulness during a 6-min unstimulated trial. Testing also included Digit Symbol, auditory reaction time, and subjective measures of fatigue or sleepiness [Profile of Mood States (POMS), Stanford Sleepiness Scale (SSS)]. Patients receiving AEDs had a mean total drowsiness score of 101 s compared with < or = 12 s for each of the three control groups (P < 0.001). One third of the AED-treated patients had > 120 s of drowsiness, in contrast to only 1 of 63 controls (p < 0.001). Among patients receiving AEDs, objective EEG drowsiness did not correlate with AED levels or performance measures. Untreated seizure patients had significantly greater complaints of lack of vigor despite a near absence of objective drowsiness on the AMT. These results suggest that epilepsy patients receiving chronic AED therapy have impaired ability to maintain wakefulness. Patient self-reports of AED-related sleepiness may not accurately represent this problem.


IR and UV spectroscopy of vapor-phase jet-cooled ionic liquid [emim]+ [Tf2N]-: ion pair structure and photodissociation dynamics.
Small gas-phase clusters (ion pairs) of the ionic liquid [emim](+)[Tf2N](-) have been generated in a supersonic expansion. Clusters are investigated via UV photofragmentation and time-of-flight mass spectrometry. Spectra between 42,000 and 45,000 cm(-1) reveal dynamical branching between direct dissociation of the ion pair to the cation and anion and to radical species. The IR spectrum between 2800 and 3200 cm(-1) was measured by action spectroscopy. Multiple conformations of the ion pair are found to be present in the molecular beam, leading to broad spectral features, further complicated by hydrogen bonding and Fermi resonances. The measured and theoretical spectra compare well, and the jet-cooled ion pair structures present in the molecular beam are strongly hydrogen bonded "stacked" conformers.


Recruitment of Family Child Care Homes for an Obesity Prevention Intervention Study.
Critical to the success of any intervention study is successful recruitment. The aim of this paper was to examine the recruitment process of a randomized controlled trial evaluating an intervention conducted with family child care home providers. Specifically, the recruitment challenges, the efforts employed to address the challenges, and their impact on participant recruitment are discussed. The study's original recruitment protocol was employed during waves 1 and 2 (out of 5). However, recruitment tracking showed a failure to meet enrollment targets, particularly in wave 2. Low enrollment prompted an all-day retreat to discuss potential revisions and enhancements to recruitment strategies. Four strategies to enhance the recruitment protocol emerged from the retreat: improving recruitment materials to enhance communication, increasing engagement with community partners, addressing provider concerns about participation and study burden, and facilitating parent engagement. The study successfully recruited 166 family child care home providers across the 5 waves. There was a significant impact on the recruitment of waves 3-5 versus waves 1-2 using the enhanced recruitment protocol. There was a dramatic increase in those who "consented" (43% vs. 60%, respectively) and a corresponding decrease in the percent of "interested and eligible" who then "failed to consent" (57% vs. 40%, respectively). Results of these enhanced recruitment strategies demonstrate the many lessons learned about successful recruitment of a difficult-to-reach population, family child care homes; specifically, the importance of building relationships, communicating clearly, and identifying key motivators.


An unusual case of sepsis due to Salmonella enterica serovar Weltevreden, an emerging pathogen of non-typhoidal salmonellosis.
Salmonella enterica serovar Weltevreden is identified as an emerging pathogen, especially in the South and Southeast Asian regions. A 45-year-old male presented with an acute febrile illness, disoriented and confused. Blood culture became positive for Salmonellae enterica serovar Weltevreden. The patient was started on intravenous Ceftriaxone. Despite aggressive management, he developed acute respiratory distress syndrome with septic shock, which required intubation and mechanical ventilation. On the 11th day of admission, he succumbed due to sepsis from peritonitis with bowel infarction. Severe sepsis due to S. Weltevreden is rare. Diabetes, malignancy, therapeutic immune suppression may predispose to invasive disease. Biochemical similarities to other Salmonella species may lead to S. Weltevreden being overlooked by clinicians. Isolates from around the world remain sensitive to most freely available antibiotics. Emergence of resistance to common antimicrobial agents could pose an obvious public health threat.


Reversible cerebral vasoconstriction syndrome (RCVS) caused by over-the-counter calcium supplement ingestion.
A 59-year-old woman was found unresponsive at home. Initial neurologic examination revealed aphasia and right-sided weakness. Laboratory results demonstrated a serum calcium level of 17.3 mg/dL (corrected serum calcium for albumin concentration was 16.8 mg/dL). Extensive workup for intrinsic aetiology of hypercalcemia was unrevealing. Further discussion with family members and investigation of the patient's home for over-the-counter medications and herbal supplements revealed chronic ingestion of calcium carbonate tablets. CT angiogram of the brain revealed multifocal intracranial vascular segmental narrowing, which resolved on a follow-up cerebral angiogram done 2 days later. These findings were consistent with reversible cerebral vasoconstriction syndrome.Appropriate blood pressure control with parenteral agents, calcium channel blockade with nimodipine and supportive care therapies resulted in significant improvement in neurologic status. By discharge, patient had near-complete resolution of neurologic symptoms.


[Transplantation with allogenic hematopoietic stem cells in adults].
Transplantation of allogeneic haematopoietic stem cells is an established curative treatment for certain severe, mainly malignant, bone marrow disorders. The method has a 10-40% treatment related mortality, but it is the best, and for some patients the only, curative option. The ten year survival probability in 214 Norwegian patients transplanted at Rikshospitalet, Oslo, between 1985 and 99 is 58% (65% for low-risk patients and 30% for high-risk patients). These results are similar to those of other centres. There is a need for better methods to prevent early mortality from complications and to prevent relapse of the bone marrow disorder.


[A review of the regulatory framework for personalized bacteriophages registration].
The increasing trend in antimicrobial resistance of pathogenic bacteria dictates the need for alternative solutions. Bacteriophages are bacterial viruses that kill their hosts during the lifecycle. The high specificity of phages makes the production of personalized cocktails the best option. Registration of drugs with variable composition lies beyond the current legal policies. In the present review, we studied the regulatory framework of the top 10 world economies from the point of personalized bacteriophages registration. We underlined procedures that countries can learn from each other.


Seed dormancy varies widely among Arabidopsis thaliana populations both between and within Fennoscandia and Italy.
The timing of germination is a key life-history trait in plants, which is strongly affected by the strength of seed dormancy. Continental-wide genetic variation in seed dormancy has been related to differences in climate and the timing of conditions suitable for seedling establishment. However, for predictions of adaptive potential and consequences of climatic change, information is needed regarding the extent to which seed dormancy varies within climatic regions and the factors driving such variation. We quantified dormancy of seeds produced by 17 Italian and 28 Fennoscandian populations of Arabidopsis thaliana when grown in the greenhouse and at two field sites in Italy and Sweden. To identify possible drivers of among-population variation in seed dormancy, we examined the relationship between seed dormancy and climate at the site of population origin, and between seed dormancy and flowering time. Seed dormancy was on average stronger in the Italian compared to the Fennoscandian populations, but also varied widely within both regions. Estimates of seed dormancy in the three maternal environments were positively correlated. Among Fennoscandian populations, seed dormancy tended to increase with increasing summer temperature and decreasing precipitation at the site of population origin. In the smaller sample of Italian populations, no significant association was detected between mean seed dormancy and climate at the site of origin. The correlation between population mean seed dormancy and flowering time was weak and not statistically significant within regions. The correlation between seed dormancy and climatic factors in Fennoscandia suggests that at least some of the among-population variation is adaptive and that climate change will affect selection on this trait. The weak correlation between population mean seed dormancy and flowering time indicates that the two traits can evolve independently.


CharID: a two-step model for universal prediction of interactions between chromatin accessible regions.
Open chromatin regions (OCRs) allow direct interaction between cis-regulatory elements and trans-acting factors. Therefore, predicting all potential OCR-mediated loops is essential for deciphering the regulation mechanism of gene expression. However, existing loop prediction tools are restricted to specific anchor types. Here, we present CharID (Chromatin Accessible Region Interaction Detector), a two-step model that combines neural network and ensemble learning to predict OCR-mediated loops. In the first step, CharID-Anchor, an attention-based hybrid CNN-BiGRU network is constructed to discriminate between the anchor and nonanchor OCRs. In the second step, CharID-Loop uses gradient boosting decision tree with chromosome-split strategy to predict the interactions between anchor OCRs. The performance was assessed in three human cell lines, and CharID showed superior prediction performance compared with other algorithms. In contrast to the methods designed to predict a particular type of loops, CharID can detect varieties of chromatin loops not limited to enhancer-promoter loops or architectural protein-mediated loops. We constructed the OCR-mediated interaction network using the predicted loops and identified hub anchors, which are highlighted by their proximity to housekeeping genes. By analyzing loops containing SNPs associated with cardiovascular disease, we identified an SNP-gene loop indicating the regulation mechanism of the GFOD1. Taken together, CharID universally predicts diverse chromatin loops beyond other state-of-the-art methods, which are limited by anchor types, and experimental techniques, which are limited by sensitivities drastically decaying with the genomic distance of anchors. Finally, we hosted Peaksniffer, a user-friendly web server that provides online prediction, query and visualization of OCRs and associated loops.


Artificial intelligence in sports on the example of weight training.
The overall goal of the present study was to illustrate the potential of artificial intelligence (AI) techniques in sports on the example of weight training. The research focused in particular on the implementation of pattern recognition methods for the evaluation of performed exercises on training machines. The data acquisition was carried out using way and cable force sensors attached to various weight machines, thereby enabling the measurement of essential displacement and force determinants during training. On the basis of the gathered data, it was consequently possible to deduce other significant characteristics like time periods or movement velocities. These parameters were applied for the development of intelligent methods adapted from conventional machine learning concepts, allowing an automatic assessment of the exercise technique and providing individuals with appropriate feedback. In practice, the implementation of such techniques could be crucial for the investigation of the quality of the execution, the assistance of athletes but also coaches, the training optimization and for prevention purposes. For the current study, the data was based on measurements from 15 rather inexperienced participants, performing 3-5 sets of 10-12 repetitions on a leg press machine. The initially preprocessed data was used for the extraction of significant features, on which supervised modeling methods were applied. Professional trainers were involved in the assessment and classification processes by analyzing the video recorded executions. The so far obtained modeling results showed good performance and prediction outcomes, indicating the feasibility and potency of AI techniques in assessing performances on weight training equipment automatically and providing sportsmen with prompt advice. Key pointsArtificial intelligence is a promising field for sport-related analysis.Implementations integrating pattern recognition techniques enable the automatic evaluation of data measurements.Artificial neural networks applied for the analysis of weight training data show good performance and high classification rates.


Relationships among milk yield, metabolism, and reproductive performance of primiparous Holstein cows treated with somatotropin.
Thirty-two primiparous Holsteins were assigned to receive 0, 5.15, 10.3, or 16.5 mg/d recombinant bST. Treatment began between 28 and 35 d postpartum and continued until 60 d prior to next expected calving or 400 d postpartum. Metabolic hormones and metabolites were measured in blood weekly during the first 10 wk of treatment, and progesterone was measured in milk twice weekly to assess ovarian activity until conception. Milk production (305 d, actual) was 8350 +/- 562, 8348 +/- 515, 9571 +/- 515, and 9070 +/- 515 for cows given 0, 5.15, 10.3, or 16.5 mg/d and did not differ statistically. Insulin, glucose, NEFA and blood urea nitrogen were not influenced by dose of bST. However, insulin-like growth factor-I increased linearly with dose of bST. Days from parturition to first detected estrus, days open, and services per conception did not differ among groups; however, days from parturition to first service increased with dose of bST. Rate of detection of estrus decreased with dose of bST, resulting in a longer interval to first insemination. The lower rate of detection of estrus in bST-treated cows may have been associated with reduced expression of estrus. Additional statistical analyses were conducted to determine the relationship between metabolism, milk production, and reproduction over all doses of bST. There was a negative correlation between 305-d milk yield and glucose (r = -.44) and insulin (r = -.46) concentrations during 30 to 100 d postpartum. In stepwise regression analyses, insulin accounted for 21% of the variance in 305-d milk yield. Glucose and NEFA accounted for 18% of the variance in days open, and there was a negative correlation (r = -.32) between glucose and days open. Days open and milk production were not correlated.


Theoretical study of H/D isotope effects on nuclear magnetic shieldings using an ab initio multi-component molecular orbital method.
We have theoretically analyzed the nuclear quantum effect on the nuclear magnetic shieldings for the intramolecular hydrogen-bonded systems of σ-hydroxy acyl aromatic species using the gauge-including atomic orbital technique combined with our multi-component density functional theory. The effect of H/D quantum nature for geometry and nuclear magnetic shielding changes are analyzed. Our study clearly demonstrated that the geometrical changes of hydrogen-bonds induced by H/D isotope effect (called geometrical isotope effect: GIE) is the dominant factor of deuterium isotope effect on ¹³C chemical shift.


Cuba's exiles: portrait of a refugee migration.
"This article provides a portrait of Cuba's exiles [in the United States] that encompasses all their waves of migration, while utilizing the Cuban exodus to shed light on the broader phenomenon of refugee migration. It argues that to understand the changing social characteristics of the exiles over twenty years of migration, we need to understand the changing phases of the Cuban revolution. Utilizing the Cuban exodus as data, the article uses Egon F. Kunz's...theoretical framework for refugee migration to shed light on the refugees' varying experiences, while also using the actual Cuban refugee experience to react to Kunz's abstract model."


Agreement Between Spatiotemporal Gait Parameters Measured by a Markerless Motion Capture System and Two Reference Systems-a Treadmill-Based Photoelectric Cell and High-Speed Video Analyses: Comparative Study.
Markerless systems to capture body motion require no markers to be attached to the body, thereby improving clinical feasibility and testing time. However, the lack of markers might affect the accuracy of measurements. This study aimed to determine the absolute reliability and concurrent validity of the Kinect system with MotionMetrix software for spatiotemporal variables during running at a comfortable velocity, by comparing data between the combination system and two widely used systems-OptoGait and high-speed video analysis at 1000 Hz. In total, 25 runners followed a running protocol on a treadmill at a speed of 12 km/h. The Kinect+MotionMetrix combination measured spatiotemporal parameters during running (ie, contact time, flight time, step frequency, and step length), which were compared to those obtained from two reference systems. Regardless of the system, flight time had the highest coefficients of variation (OptoGait: 16.4%; video analysis: 17.3%; Kinect+MotionMetrix: 23.2%). The rest of the coefficients of variation reported were lower than 8.1%. Correlation analysis showed very high correlations (r>0.8; P<.001) and almost perfect associations (intraclass correlation coefficient>0.81) between systems for all the spatiotemporal parameters except contact time, which had lower values. Bland-Altman plots revealed smaller systematic biases and random errors for step frequency and step length and larger systematic biases and random errors for temporal parameters with the Kinect+MotionMetrix system as compared to OptoGait (difference: contact time +3.0%, flight time -7.9%) and high-speed video analysis at 1000 Hz (difference: contact time +4.2%, flight time -11.3%). Accordingly, heteroscedasticity was found between systems for temporal parameters (r2>0.1). The results indicate that the Kinect+MotionMetrix combination slightly overestimates contact time and strongly underestimates flight time as compared to the OptoGait system and high-speed video analysis at 1000 Hz. However, it is a valid tool for measuring step frequency and step length when compared to reference systems. Future studies should determine the reliability of this system for determining temporal parameters.


The genus Broussonetia: a review of its phytochemistry and pharmacology.
Plants belonging to the genus Broussonetia (Moraceae), which grow naturally in Asian and Pacific countries, have long been used in traditional Chinese medicine to treat various conditions, particularly tinea, dysentery, hernia and oedema. Various parts of plants of this genus such as the fruits, bark, leaves, flowers and roots are used medicinally. According to Flora of China, the inner bark fibre is used in making paper, and the wood is used for furniture. Several active compounds including coumarins, polyphenols, alkaloids, flavonoids, glycosides, lignans and diterpenes have been isolated from the plants of this genus in the past few years, and some members of these constituents have been demonstrated to exert antioxidant, antiinflammatory, antiplatelet, antityrosinase, antimicrobial and antinociceptive effects. Antidiabetic and antitumoural properties seem possible, but need further support. Due to the lack of clinical trials, there are few published reports on target-organ toxicity or side effects. Currently, some East Asian nations such as China, South Korea and Japan have shown increased interest in these plants. This article reviews the phytochemical and potential beneficial therapeutic effects of plants of this genus reported since 2000.


Molecular characterization of the Dot/Icm-translocated AnkH and AnkJ eukaryotic-like effectors of Legionella pneumophila.
Although most Dot/Icm-translocated effectors of Legionella pneumophila are not required for intracellular proliferation, the eukaryotic-like ankyrin effectors, AnkH and AnkJ are required for intracellular proliferation. In this report, we show that the IcmSW chaperones are essential for translocation of AnkJ but not AnkH. The 10 C-terminal residues and the ANK domains of AnkH and AnkJ are required for translocation. Our data indicate that the two ANK domains of AnkH are critical domains required for the function of the effector in intracellular replication of L. pneumophila. The ankH and ankJ mutants are severely defective in intrapulmonary proliferation in mice. Expression of AnkH and AnkJ fusions within HEK293 cells show a punctuate distribution in the cytosol but no association with endocytic vesicles, the Golgi apparatus or the endoplasmic reticulum. Interestingly, the defect in intracellular proliferation of the ankH or ankJ mutants is rescued in HEK293 cells expressing the respective protein. We conclude that AnkH and AnkJ are effectors translocated by the Dot/Icm system by distinct mechanisms and modulate distinct cytosolic processes in the host cell.


Muscle-fiber conduction velocity during concentric and eccentric actions on a flywheel exercise device.
A gravity-independent flywheel exercise device (FWED) has been proven effective as a countermeasure to loss of strength and muscle atrophy induced by simulated microgravity. This study assessed muscle-fiber conduction velocity (CV) and surface EMG instantaneous mean power spectral frequency (iMNF) during brief bouts of fatiguing concentric (CON) and eccentric (ECC) exercise on a FWED in order to identify electromyographic (EMG) variables that can be used to provide objective indications of muscle status when exercising with a FWED. Multichannel surface EMG signals were recorded from vastus lateralis and medialis muscles of nine men during: (1) isometric, 60-s action at 50% of maximum voluntary action (MVC); (2) two isometric, linearly increasing force ramps (0-100% MVC); and (3) dynamic CON/ECC coupled actions on the FWED. Muscle-fiber CV and iMNF were computed over time during the three tasks. During ramps, CV, but not iMNF, increased with force (P < 0.001). Conduction velocity and iMNF decreased with the same normalized rate of change in constant-force actions. During CON/ECC actions, the normalized rate of change over time was larger for CV than iMNF (P < 0.05). These results suggest that, during fatiguing, dynamic, variable-force tasks, changes in CV cannot be indirectly inferred by EMG spectral analysis. This underlines the importance of measuring both CV and spectral variables for muscle assessment in dynamic tasks.


Impaired collateral development in mature rats.
The effect of maturation on collateral development of resistance arteries was investigated. Three to four sequential mesenteric arteries were ligated to create collateral pathways in anesthetized young (approximately 200 g) and mature (approximately 600 g) rats. Blood flow was similarly elevated in collaterals of young and mature animals. In vivo inner arterial diameter was increased only within young collaterals (33 +/- 7%, P < 0.001). Increases in number of intimal nuclei (57 +/- 10% vs. 52 +/- 14%) and cross-sectional medial area (33 +/- 13% vs. 38 +/- 5%) were similar between young and mature collaterals. Relative to the same animal controls, collateral endothelial nitric oxide synthase mRNA was increased as much in mature as in young rats. Proteomic analysis revealed significant differences in protein expression with maturation between control arteries as well as flow-loaded collateral vessels. The results indicate that, whereas intimal and medial remodeling events were similar in collaterals of young and mature rats, luminal expansion occurred only in young rats. Alteration in arterial protein expression with maturation and altered responses to stimuli for collateral development may contribute to this impairment.


Purification of carbonic anhydrase-II from sheep liver and inhibitory effects of some heavy metals on enzyme activity.
In this study; sheep carbonic anhydrase-II (SCA-II) (E.C: 188.8.131.52) was purified from sheep liver and in vitro effects of heavy metals on the enzyme was examined. SCA-II isozyme was purified with about 203 purification fold, a specific activity of 2320 EU/mg-protein and a yield of 72 by using Sepharose-4B-L tyrosine-sulfanilamide affinity gel chromatography. Purity of the SCA-II enzyme was verified by SDS-PAGE technique and subunit molecular mass of the enzyme was found as 29 kDa. In addition to this, inhibitory effects of some metal ions on the enzyme were examined. In this study, sheep liver tissue was chosen; because the liver is an organ in which metal wastes of air, water and food are collected and it is easy to obtain the liver tissue. Because of the very important duties of CA enzyme on living beings, the effect of metals on the CA enzyme was investigated.


Sequence comparisons among dispersed members of the Brassica S multigene family in an S9 genome.
Self-incompatibility (SI) systems prevent self-pollination and promote outbreeding. In Brassica, the SI genes SLG (for S-locus glycoprotein) and SRK (for S-receptor kinase) are members of the S multigene family, which share the SLG-like domain (S domain), which encodes a putative receptor. We have cloned members of the S multigene family from the S9 haplotype of B. campestris (syn. rapa). In addition, eight distinct genomic regions harboring 10 SLG/SRK-like genes were characterized in the present study. Sequence analysis revealed two novel SRK-like genes, BcRK3 and BcRK6 (for B. campestris receptor kinases 3 and 6, respectively). Other genes that were characterized included SFR2 (for S gene family receptor 2), SLR2 (for S locus related gene 2), and a pseudogene. Based on phylogenetic analysis of the nucleotide sequences of the S domain regions, SLG and SRK appear to be distinct from other members of the S multigene family. Linkage analysis showed that most members of the S multigene family are dispersed in the Brassica genome, and that SLR1 (S locus related gene 1) is not linked to the SLR2 in B. campestris.


L-type amino acid transporter 1 (LAT1) expression in malignant pleural mesothelioma.
L-Type amino acid transporter 1 (LAT1) is known to be highly expressed in various human neoplasms. However, little is known about how LAT1 is expressed in malignant pleural mesothelioma (MPM). Twenty-one patients were included in this study. Tumor sections were stained by immunohistochemistry for LAT1, glucose transporter 1 (GLUT1), GLUT3, hypoxia inducible factor-1α (HIF-1α), hexokinase I, vascular endothelial growth factor (VEGF), microvessel density (MVD) by determination of CD34, epidermal growth factor receptor (EGFR), phosphatase and tensin analog (PTEN), p-AKT, p-manmalian target of rapamycin (mTOR), p-S6K, p53 and BCL-2. LAT1 was overexpressed in approximately 50% of the patients with MPM. LAT1 expression was closely correlated with CD98, hypoxic markers, the mTOR pathway, Ki-67 and p53. The overexpression of LAT1 was closely associated with poor outcome in patients with MPM. LAT1 is closely associated with tumor development and progression in patients with MPM.


Response of preterm newborns to immunization with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio and Haemophilus influenzae type b vaccine: first experiences and solutions to a serious and sensitive issue.
Preterm infants are at increased risk from infections and should be vaccinated at the usual chronological age. The aim of the study was to evaluate the immunogenicity and reactogenicity of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio and Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) vaccine in preterm infants. In a comparative trial, 94 preterm infants between 24 and 36 weeks (mean +/- SD gestational age: 31.05 +/- 3.45 weeks; mean birth weight: 1420 +/- 600 g) and a control group of 92 full-term infants were enrolled to receive 3 doses of a DTPa-HBV-IPV/Hib vaccine at 2, 4, and 6 months. Immunogenicity was assessed in serum samples that were taken before and 4 weeks after primary vaccination. Evaluation of reactogenicity was based on diary cards. All preterm (n = 93) and full-term (n = 89) infants who were included in the immunogenicity analysis had seroprotective titers to diphtheria; tetanus; and polio virus types 1, 2, and 3. The immune response to the Hib and hepatitis B components was lower in preterm than in full-term infants: 92.5% versus 97.8% and 93.4% versus 95.2%, respectively. Vaccine response rates for pertussis antigens were >98.9% in both study groups. Although most geometric mean titers were lower in preterm infants, titers were similar for pertussis, a major threat for premature infants. The vaccine was well tolerated, and there were no differences in reactogenicity between groups. Some extremely immature infants experienced transient cardiorespiratory events within the 72 hours after the first vaccination with no clinical repercussion. Preterm infants who were immunized with the hexavalent DTPa-HBV-IPV/Hib vaccine at 2, 4, and 6 months displayed good immune response to all antigens. The availability of this vaccine greatly facilitates the vaccination of premature infants.


Commentary on model systems of care in neurotrauma: clinical perspectives and future directions.
The first section of this article discusses the principal clinical components of a model system of care for traumatic brain injury (TBI) or spinal cord injury (SCI). The next section, "The Future of Model Systems", addresses the advantages of such a system, as related to the changing health care climate and predicted future directions of health care in the United States. The need for innovative approaches to rehabilitation is upon us. In addressing this need, the last section, "Recommendations for Change", outlines cost-effective measures for providing rehabilitation services to our clientele.


Increased regional myocardial blood flows and oxygen deliveries during hypoxemia in lambs.
Newborn humans may develop myocardial dysfunction in conjunction with severe birth asphyxia. Subendocardial or papillary muscle ischemia appears to be the basis for the myocardial dysfunction, yet patent coronary arteries have been demonstrated in the nonsurvivors. The asphyxiated newborns also have experienced hypoxemia, which has been suggested as the cause of myocardial ischemia. This study was designed to determine the relationship between reduced aortic blood oxygen content and blood flow as well as oxygen delivery within different regions of the heart. Three days after surgery, we measured blood flow and oxygen delivery to the free walls and papillary muscles of the right and left ventricles, the ventricular septum, and the atria in 10 lambs, during 20-min periods in 8-10% and 5-6% environmental oxygen concentrations. In each region of myocardium, blood flow increased linearly as the aortic blood oxygen content decreased. The slopes of the regression lines were similar for each region of ventricular myocardium. Atrial myocardial blood flow also increased as a linear function of the reductions in aortic blood oxygen content, but at a slower rate than in the ventricular regions. Hypoxemia was associated with increased oxygen delivery in each region of myocardium, but the two variables were not related in a linear or quadratic fashion. The results demonstrate that isolated hypoxemia is associated with increased blood flow and oxygen delivery in the free walls and papillary muscles of the right and left ventricles, the ventricular septum, and the atria.


Central administration of kisspeptin-10 inhibits water and sodium excretion of anesthetized male rats and the involvement of arginine vasopressin.
To investigate the effect of hypothalamus kisspeptin on water and sodium excretion and the possible mechanism. The intracerebroventricular (icv) administration and radioimmunoassay were used to observe the effect of kisspeptin-10 on urine flow, sodium and potassium excretion, plasma arginine vasopressin (AVP), and atrial natriuretic peptide (ANP) concentrations in anesthetized male rats. The mediation of renal sympathetic nerve was also investigated by studies conducted on rats with bilateral renal sympathetic denervation. The urine flow, sodium excretion, and free water clearance decreased significantly by icv injection of 5 nmol kisspeptin-10 (p < 0.05) from 30 to 60 min post-injection. Meanwhile, plasma AVP concentrations increased significantly 30 min after the icv injection of 5 nmol kisspeptin-10 (p < 0.05), whereas the equal dose of kisspeptin-10 did not significantly change plasma ANP concentrations. The mean arterial blood pressure, heart rate, and potassium excretion did not significantly change during the experiment. Furthermore, pretreatment with 5 nmol kisspeptin-10 could still significantly decrease urine flow and sodium excretion in renal sympathetic denervated rats. Central administration of kisspeptin-10 could inhibit sodium excretion and urine flow in anesthetized male rats, which is probably mediated by increasing the plasma AVP concentration and is independent of plasma ANP concentration and renal sympathetic nerve activity.


Ligands influence Zn transport into cultured endothelial cells.
Experimental results were obtained that demonstrate the importance of the relative concentrations of Zn ligands and their affinities for Zn to the rate of Zn transport across a biological membrane. The transport rate into cultured endothelial cells became saturated near a Zn concentration of 30 microM in the presence or absence of 14% serum. However, the maximum transport rate identified by the saturation plateau was nearly twice as fast from serum-free medium. The addition of histidine or picolinic acid to the medium with serum resulted in the coincidental shift of Zn from high molecular weight ligands to low molecular weight ligands and increased the overall transport rate. In serum-free medium, adding histidine or picolinic acid slowed the transport rate. This indicates that the rate of Zn transport is influenced by the ligand to which it is associated and that altering the relative proportions of specific ligands influences the Zn transport rate. The rate of Zn transport decreased in a stepwise fashion as the albumin to Zn ratio increased from 0 to 4:1, with further increases having little effect. This suggests that albumin has a special role as modulator of Zn transport into endothelial cells. These studies underscore the importance of controlling the relative concentrations of Zn and its ligands in Zn transport kinetic research and suggest that varying their concentrations in a physiological range may be a method of regulating the distribution of Zn into specific cells and tissues.


Evaluating the Implementation of Mexico's Health Reform: The Case of Seguro Popular.
Abstract-In 2012, the Mexican government declared that Seguro Popular had reached the goal of providing health insurance to nearly 53 million individuals previously not enrolled with social security. This major achievement was reached in only nine years of operation of the new system. However, enormous challenges remain to guarantee that Seguro Popular will provide adequate services to the newly enrolled population. This article uses information collected by four external evaluations of Seguro Popular carried out between 2007 and 2012 to analyze how financial resources are transferred from the federal level to the states and how these resources are used to purchase services on behalf of the affiliated population. We focus on three topics: the financial transfer mechanisms, the purchasing of medicines, and the contracting of health workers. The analysis shows that the implementation of Seguro Popular has confronted major challenges due to limited institutional capacity at the federal and state levels, tension in federal-state relations, limited information systems, the influence of political interests, and the use of financial resources for unauthorized expenditures at the state level. Various legal, normative, and technical changes have been introduced during implementation of Seguro Popular to improve performance, with mixed results. Mexico's experiences with the implementation of health reform may offer important lessons for other countries seeking to expand health coverage.


Extracting input-line position from Hough transform data.
The Hough transform (HT) detects lines in an input but not their location. We describe a new way to determine the position of a line from HT data. The line position information is extracted from the shape of the HT pattern around the HT peak. Results are shown illustrating this algorithm on single- and multiple-line input images.


Stage-Specific Risk of Recurrence and Death From Melanoma in Denmark, 2008-2021: A National Observational Cohort Study of 25 720 Patients With Stage IA to IV Melanoma.
To ensure optimal treatment and surveillance of patients with melanoma, knowledge of the clinical stage-specific risk of recurrence, mortality, and recurrence patterns across the American Joint Committee on Cancer Eighth Edition (AJCC8) substages is needed. To estimate stage-specific recurrence and melanoma-specific mortality rates, assess absolute stage-specific risks of recurrence and mortality, and describe stage-specific recurrence patterns, including conditional rates. Retrospective cohort study of prospectively collected nationwide population-based registry data. Nationwide, population-based cohort study. The 25 720 Danish patients, 18 years or older, diagnosed with first-time stage IA to IV cutaneous melanoma between January 1, 2008, and December 31, 2019, were included and followed up from time of primary treatment until December 31, 2021. First diagnosis of stage IA to IV cutaneous melanoma. Stage-specific cumulative incidence of recurrence and melanoma-specific mortality, melanoma-specific recurrence-free survival, and assessed absolute stage-specific risks of recurrence and melanoma-specific mortality. Secondary outcomes were stage-specific recurrence patterns, including conditional rates, and melanoma-specific survival. We followed up 25 720 patients for a median of 5.9 years (95% CI, 58.9-59.3 years). Mean age was 59.1 years (95% CI, 58.9-59.3 years). Patients with stage IIB to IIC melanoma were older, had more comorbidities at diagnosis, and had the lowest rate of pathologic staging by sentinel node biopsy (81.6%-87.4%). A total of 10.6% of patients developed recurrence; first recurrence included distant recurrence, alone or with synchronous locoregional recurrence, in 56.6% of patients. We found a comparable risk of recurrence in stages IIIA and IIB (29.7% vs 33.2%) and in stages IIIB and IIC (35.9% vs 36.8%), respectively. Melanoma-specific mortality was comparable between stages IIIA and IIA (13.0% vs 13.6%) and between stages IIIB and IIB (18.4% vs 22.0%), respectively. These risk patterns persisted in cause-specific hazards models. This nationwide, population-based cohort study found that the increasing stages of the current AJCC8 staging system do not accurately reflect an increasing risk of recurrence and mortality in melanoma. The high proportion of distant recurrences suggests that hematogenous spread is a more common metastatic pathway than previously assumed, and surveillance with routine functional/cross-sectional imaging should be considered for stages IIB to IV. Future efforts should be put toward developing new tools for risk stratification and determining the survival effect of routine imaging in surveillance.


Challenges and Opportunities in Protease-Activated Receptor Drug Development.
Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the generation of a tethered ligand that cannot diffuse away. Despite the fact that GPCRs have proved to be the most successful class of druggable targets, the development of agents that target PARs specifically has been challenging. As a consequence, researchers have taken a remarkable diversity of approaches to develop pharmacological entities that modulate PAR function. Here, we present an overview of the diversity of therapeutic agents that have been developed against PARs. We further discuss PAR biased signaling and the influence of receptor compartmentalization, posttranslational modifications, and dimerization, which are important considerations for drug development.


Hybrid Radiobioconjugated Superparamagnetic Iron Oxide-Based Nanoparticles for Multimodal Cancer Therapy.
Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used for biomedical applications for their outstanding properties such as facile functionalization and doping with different metals, high surface-to-volume ratio, superparamagnetism, and biocompatibility. This study was designed to synthesize and investigate multifunctional nanoparticle conjugate to act as both a magnetic agent, anticancer immunological drug, and radiopharmaceutic for anticancer therapy. The carrier, 166Ho doped iron oxide, was coated with an Au layer, creating core-shell nanoparticles ([166Ho] Fe3O4@Au. These nanoparticles were subsequently modified with monoclonal antibody trastuzumab (Tmab) to target HER2+ receptors. We describe the radiobioconjugate preparation involving doping of a radioactive agent and attachment of the organic linker and drug to the SPIONs' surface. The size of the SPIONs coated with an Au shell measured by transmission electron microscopy was about 15 nm. The bioconjugation of trastuzumab onto SPIONs was confirmed by thermogravimetric analysis, and the amount of two molecules per one nanoparticle was estimated with the use of radioiodinated [131I]Tmab. The synthesized bioconjugates showed that they are efficient heat mediators and also exhibit a cytotoxic effect toward SKOV-3 ovarian cancer cells expressing HER2 receptors. Prepared radiobioconjugates reveal the high potential for in vivo application of the proposed multimodal hybrid system, combined with magnetic hyperthermia and immunotherapy against cancer tissues.


How nano-wollastonite can change the fundamental properties of a wood fibre and rice straw composites?
The potential of using rice straw (RS) in combination with wood fibre in the production of medium density fibreboard was investigated. Nano-wollastonite (NW) was added to some of the panels to determine if it would enhance the physical and mechanical properties. It was found that satisfactory composite boards could be made with the addition of 10% RS to the wood fibre. Furthermore, the mechanical and physical properties of the composite were enhanced when NW was added.


Application of Carbon Fiber Cement-Based Composites in Improving Construction Durability.
In order to improve the durability of building construction, this study proposes a construction method based on carbon fiber and cement-based composites. Analyze the mechanical properties of carbon fiber cement-based composites, combined with experiments to further analyze its advantages in building construction, to achieve the purpose of building durability construction. The experimental results show that the elastic modulus of CFRC samples with a 0.6% carbon fiber volume percentage is the largest. When the content of carbon fiber increases within a certain range, the elastic modulus of CFRC samples will also increase. Conclusion. The application of carbon fiber cement-based composites in building construction can effectively improve the durability of buildings and further improve the quality of buildings.


IS6110 restriction fragment length polymorphism of Mycobacterium tuberculosis isolates from an area of Casablanca, Morocco.
Using IS6110 RFLP, 61 isolates recovered from new cases of pulmonary tuberculosis (TB) were compared from September to December 1999 in Casablanca, Morocco, a city with a high incidence of TB. The majority of the isolates (92%) harboured 6-14 copies of IS6110. The minimal fraction of patients in groups of recently acquired infection is 13.1%. This preliminary study showed that IS6110 RFLP is a suitable method for finger-printing Mycobacterium tuberculosis in Casablanca. The unexpectedly low level of recent transmission of TB found in this study deserves further studies involving higher numbers of isolates recovered during a longer recruitment period.


Use of the ICHD-II criteria in the diagnosis of pediatric migraine.
To evaluate the sensitivity of the new International Classification of Headache Disorders-2nd edition (ICHD-II) criteria in the diagnosis of childhood migraine and to propose specific criteria for the diagnosis of childhood migraine. In 2004, ICHD-II was adopted by the International Headache Society. The prior version had been criticized for its lack of sensitivity in diagnosing childhood headaches. ICHD-II is felt to be an improvement as it provides for some differences between pediatric and adult migraine diagnosis in its footnotes, however, has yet to be validated. Clinically, it is the impression of many pediatric headache specialists that children's migraines are of shorter duration, tend to be bilateral rather than unilateral, and that children more often report either photophobia or phonophobia, rather than both. The characteristics of headache in 260 patients, ages 18 and under, clinically diagnosed with migraine at two large pediatric headache centers were compiled using standard intake questionnaires. Inter-rater reliability in clinical diagnosis was determined by consensus of the clinical diagnosis. These data were analyzed applying the International Classification of Headache Disorders-1st edition (ICHD-I) and ICHD-II criteria for migraine to determine sensitivity of migraine diagnosis in comparison with clinical impression. Each headache characteristic in ICHD-II was analyzed individually to determine its effect on sensitivity of diagnosis. 183/260 patients (70.4%) met ICHD-I criteria. 161/260 patients (61.9%) met the ICHD-II criteria with a 4- to 72-hour range. When the footnoted allowance of ICHD-II for short duration (2 hours) was utilized, 187/260 patients (71.9%) met criteria, while this improved to 192/260 patients (73.9%) with 1-hour duration. If duration was excluded, 210/260 patients (80.8%) met criteria. The most common reasons for patients not meeting the standard criteria were the requirement of unilateral location, headache duration and number of associated symptoms. Based on these observations, modified criteria were empirically derived and the sensitivity increased to 84.4%. Data were reanalyzed using the criteria of focal head pain, either bilateral or unilateral, shortened duration, and modified associated symptoms, which resulted in an improved sensitivity in migraine diagnosis of 84.4%. Modification of ICHD-II criteria to include bilateral headache, headache duration of 1 to 72 hours, and nausea and/or vomiting plus two of five other associated symptoms (photophobia, phonophobia, difficulty thinking, lightheadedness, or fatigue), in addition to the usual description of moderate to severe pain of a throbbing or pulsating nature worsening or limiting physical activity, improved sensitivity of migraine diagnosis to 84.4%.


Influence of Electron Beam Irradiation on Electrical Insulating Properties of PLA with Soft Resin Added †.
Polylactic acid (PLA), a bioplastic, is a hard resin, and requires softening in order to be used in electric wire sheaths. A soft resin was added to PLA in order to soften it, but this caused the electric breakdown strength (EB) to decrease. In this study, PLA with soft resin added was irradiated with an electron beam and the influence of the electron beam irradiation on EB was examined. The irradiation dose was set at 100 kGy. At 25 °C, the EB of PLA with no soft resin added decreased due to the irradiation. On the other hand, the EB of PLA with soft resin added showed almost no change due to the irradiation. At 80 °C, the EB of PLA with no soft resin added decreased due to the irradiation, as was the case at 25 °C. On the other hand, the EB of PLA with soft resin added increased due to the irradiation.


A handheld device for magnetically inserting a neural interface into a peripheral nervous system.
This paper proposes a compact handheld device for magnetically inserting a neural interface into a peripheral nervous system (PNS). Users can pull and hold a flexible peripheral nerve (e.g., sciatic nerve) at the front of the device for the accurate and stable targeting process. The device automatically inserts a neural interface using magnetic impacts that are generated by a miniature motor and a pair of magnets. We investigate the characteristics of the employed mechanism, and present the preliminary experimental results.


ELF3 Is a Target That Promotes Therapeutic Efficiency in EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer Cells via Inhibiting PKCί.
(1) Background: Mutations in epidermal growth factor receptor (EGFR) proteins account for many non-small cell lung cancers (NSCLCs), and EGFR tyrosine kinase inhibitors (TKIs) are being used as targeted therapeutics. However, resistance to TKIs continues to increase owing to additional mutations in more than half of the patients receiving EGFR TKI therapy. In addition to targeting new mutations with next-generation therapeutics, it is necessary to find an alternative target to overcome the challenges associated with resistance. (2) Methods: To identify potential alternative targets in patients with NSCLC undergoing targeted therapy, putative targets were identified by transcriptome profiling and validated for their biological and therapeutic effects in vitro and in vivo. (3) Results: ELF3 was found to be differentially expressed in NSCLC, and ELF3 knockdown significantly increased cell death in K-Ras mutant as well as in EGFR L858R/T790M mutation harboring lung cancer cells. We also found that auranofin, an inhibitor of protein kinase C iota (PKCί), a protein upstream of ELF3, effectively induced cell death. (4) Conclusions: Our study suggests that blocking ELF3 is an effective way to induce cell death in NSCLC with K-Ras and EGFR T790M/L858R mutations and thus advocates the use of auranofin as an effective alternative drug to overcome EGFR TKI resistance.


MDReg-Net: Multi-resolution diffeomorphic image registration using fully convolutional networks with deep self-supervision.
We present a diffeomorphic image registration algorithm to learn spatial transformations between pairs of images to be registered using fully convolutional networks (FCNs) under a self-supervised learning setting. Particularly, a deep neural network is trained to estimate diffeomorphic spatial transformations between pairs of images by maximizing an image-wise similarity metric between fixed and warped moving images, similar to those adopted in conventional image registration algorithms. The network is implemented in a multi-resolution image registration framework to optimize and learn spatial transformations at different image resolutions jointly and incrementally with deep self-supervision in order to better handle large deformation between images. A spatial Gaussian smoothing kernel is integrated with the FCNs to yield sufficiently smooth deformation fields for diffeomorphic image registration. The spatial transformations learned at coarser resolutions are utilized to warp the moving image, which is subsequently used as input to the network for learning incremental transformations at finer resolutions. This procedure proceeds recursively to the full image resolution and the accumulated transformations serve as the final transformation to warp the moving image at the finest resolution. Experimental results for registering high-resolution 3D structural brain magnetic resonance (MR) images have demonstrated that image registration networks trained by our method obtain robust, diffeomorphic image registration results within seconds with improved accuracy compared with state-of-the-art image registration algorithms.


Monomeric and trimeric forms of photosystem I reaction center of Mastigocladus laminosus: crystallization and preliminary characterization.
Photosystem I (PSI) reaction centers (RCs) of the thermophilic cyanobacterium Mastigocladus laminosus were purified and characterized. The PSI RC was obtained in two forms, monomeric and trimeric. The two forms contained the same number of pigments per P700 and displayed similar photochemical activities. The two forms had nearly identical polypeptide subunit compositions; the only observed difference was an additional subunit of about 12 kDa observed in the trimeric form. The purified preparations of both the monomeric and the trimeric forms were used for crystallization and preliminary crystallographic analysis. The trimeric PSI RC preparations produced several three-dimensional crystal forms, one of which, the "hexagonal needle" form (THN), had a hexagonal unit cell with dimensions of 300 x 300 x 160 A, containing four PSI RC trimers. The monomeric preparations also produced single crystals of several forms under various crystallization conditions. One of these crystal forms, the "hexagonal plate" (MHP), diffracted to a resolution of about 5.5 A. It had a hexagonal unit cell with dimensions of 192 x 192 x 163 A, containing six PSI RC monomers. Comparison of the PSI RCs in the crystals with those in the precrystallization preparations demonstrated that neither the monomeric nor the trimeric form of PSI RC was altered by the crystallization process. Both forms retained their original polypeptide subunit composition and their pigment content.


Progressive multifocal leukoencephalopathy: lessons from AIDS and natalizumab.
The dramatic increase in the incidence of progressive multifocal leukoencephalopathy (PML) that occurred as a consequence of the AIDS pandemic and the recent association of PML with the administration of natalizumab, a monoclonal antibody to alpha4 integrin that blocks inflammatory cell entry into the brain, has stimulated a great deal of interest in this previously obscure viral demyelinating disease. The etiology of this disorder is JC virus (JCV), a polyoma virus, observed in 80% of the population worldwide. Seroepidemiological studies indicate that infection with this virus typically occurs before the age of 20 years. No primary illness owing to JCV infection has been recognized and the means of spread from person to person remains obscure. Following infection, the virus becomes latent in bone marrow, spleen, tonsils and other tissues. Periodically the virus reactivates during which time it can be demonstrated in circulating peripheral lymphocytes. The latter is significantly more commonly observed in immunosuppressed populations than that in normal subjects. Despite the large pool of people infected with JCV, PML remains a relatively rare disease. It is seldom observed in the absence of an underlying predisposing illness, typically one that results in impaired cellular immunity. A variety of factors are likely responsible for the unique increase in frequency of PML in HIV infection relative to other underling immunosuppressive disorders. Preliminary data suggests that natalizumab appears to distinctively predispose recipients to PML relative to other infectious complications. Studies in these populations will be invaluable in understanding the mechanisms of disease pathogenesis.


Bone Transport for Limb Reconstruction Following Severe Tibial Fractures.
A common treatment of tibial defects especially after infections is bone transport via external fixation. We compare complications and outcomes of 25 patients treated with a typical Ilizarov frame or a hybrid system for bone reconstruction of the tibia. Average follow up was 5.1 years. Particular interest was paid to the following criteria: injury type, comorbidities, development of osteitis and outcome of the different therapies. The reason for segmental resection was a second or third grade open tibia fractures in 24 cases and in one case an infection after plate osteosynthesis. Average age of the patients was 41 years (range 19 to 65 years) and average defect size 6.6 cm (range 3.0 to 13.4 cm). After a mean time of 113 days 23 tibial defects were reconstructed, so we calculated an average healing index of 44.2 days/cm. Two patients with major comorbidities needed a below knee amputation. The presence of osteitis led to a more complicated course of therapy. In the follow up patients with an Ilizarov frame had better results than patients with hybrid systems. Bone transport using external fixation is suitable for larger defect reconstruction. With significant comorbidities, however, a primary amputation or other methods must be considered.


Biological activity of 4-hydroxyisophthalic acid derivatives. Hydrazones with antimicrobial activity.
The following hydrazono derivatives (I-XIX) of type (A) (sequence in text) where Rn = (sequence in text ) (I-XVII); (sequence in text) (XVIII); -CCl3 (XIX); and Xn = H (I); 2-Cl (II); 3-Cl (III); 4-Cl (IV); 2-NO2 (V); 3-NO2 (VI); 4-NO2 (VII); 2-OH (VIII); 3-OH (IX); 4-OH (X); 4-F (XI); 3,4-OCH3,OH (XII); 3,4,5-OCH3,OH,J (XIII); 3,4-OCH3,OCH3 (XIV); 2,4-Cl2 (XV); 3,4-Cl2 (XVI); 2,6-Cl2 (XVII); were prepared and characterized in an attempt to make available for testing a representative selection of hitherto unreported 4-hydroxyisophthalic acid derivatives. The new compounds in question were obtained in satisfactory yield by condensation of 4-hydroxyisophthalic acid hydrazide with the appropriate aldehydes. The prepared compounds were tested for their possible activity against Gram-positive (S. epidermidis, B. subtilis, B. anthracis) and Gram-negative bacteria (P. aeruginosa, B. melitensis, S. typhi O, S. typhi H, S. infantis, S. paratyphi B, E. coli Bb, E. coli 7075), and fungi (C. albicans, A. niger, S. cerevisiae). The "in vitro" antimicrobial assays were carried out using the paper disk technique (Kirby-Bauer modified). The influence of certain structural modifications on the antimicrobial activity was evaluated.


Estradiol inhibits transcription of the human glycoprotein hormone alpha-subunit gene despite the absence of a high affinity binding site for estrogen receptor.
Chronic administration of estradiol inhibits transcription of the gene encoding the alpha-subunit of pituitary glycoprotein hormones. Here, we show, using transfection analyses and a filter binding assay, that 1500 basepairs of proximal 5' flanking sequence of the human alpha-subunit gene lack a functional estrogen response element when transfected into heterologous cell lines, and fail to bind estrogen receptor purified from calf uterus. Yet, this same region of the alpha-subunit gene confers estradiol responsiveness (transcriptional suppression) to the bacterial chloramphenicol acetyltransferase gene in transgenic mice. A smaller promoter fragment of the bovine alpha-subunit gene also confers responsiveness to estradiol in transgenic mice, suggesting that the same element may mediate the steroid responsiveness of both promoters. Furthermore, regulation by estradiol of the chimeric human or bovine alpha-chloramphenicol acetyltransferase genes is pituitary specific, underscoring the physiological significance of these studies. Based on these results, we conclude that estradiol regulates expression of the alpha-subunit gene in vivo through a mechanism that does not involve high affinity binding of estrogen receptor to the alpha-subunit gene. Whether this mechanism is manifest at the level of the pituitary or hypothalamus remains to be determined.


Acute haemodynamic effects of the atrial natriuretic hormone in rats.
Haemodynamic effects of atriopeptin II (AP II) were determined in conscious and anaesthetized rats chronically instrumented with a Doppler flow probe on the ascending aorta. Intravenous injection of AP II (7 micrograms/kg) produced a decrease in mean arterial pressure within 5 min; however, a biphasic change occurred in total peripheral resistance (TPR). At 1 min in the anaesthetized rats, TPR decreased while cardiac output tended to increase, and similar changes occurred in the conscious rats. By 5-8 min the haemodynamic profile had reversed: cardiac output had decreased in both anaesthetized and conscious rats and TPR had increased in anaesthetized rats. Mean circulatory filling pressure (MCFP) was measured during brief circulatory arrest by inflating an intracardiac balloon. Blood volume was measured with 51Cr-erythrocytes and organ blood volume by whole-animal freezing in liquid nitrogen. There were no changes in MCFP in the conscious and the anaesthetized rats, nor in the blood volume or cardiopulmonary blood volume in the anaesthetized rats, at 5-7 min after AP II. Atriopeptin III (10 micrograms/kg intravenously) had no effects on MCFP and the blood volume in the conscious rats at 5 and 15 min after injection. These results suggest multiple mechanisms of action for the acute haemodynamic effects of atrial peptides.


[Curative and preventive treatment of NSAID-associated gastroduodenal ulcers].
The use of treatments to heal or to prevent nonsteroidal anti-inflammatory drugs (NSAIDs) associated gastroduodenal lesions is based on replacement of mucosal prostaglandin deficiency or inhibition of acid secretion. Four-week acid suppression by proton pump inhibitors (PPI) with 7-day eradication triple therapy in Helicobacter pylori positive patients is effective in healing gastric and duodenal ulcer upon discontinuation of NSAIDs. In the event NSAIDs must be continued, PPIs (omeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg) are more effective than H2-blockers and cytoprotective agents (sucralfate, misoprostol) to heal mucosal lesions. In long-term prevention studies, omeprazole 20 mg, lansoprazole 15 mg, and pantoprazole 20 mg significantly reduce gastric and duodenal ulcer rates. Misoprostol 800 microg is as effective as PPIs for preventing symptomatic and complicated gastric ulcers, but less effective to prevent duodenal ulcer, with a high rate of adverse effects such as diarrhea. Helicobacter pylori eradication in infected patients decrease the risk of NSAIDs-associated lesions but is less effective than concomitant antisecretory treatment. Current data from comparative studies of PPIs vs ranitidine or misoprostol are in favor of the PPIs as well tolerated and effective drugs in the prophylaxis of NSAIDs-related gastroduodenal lesions in high-risk patients.


Apoptotic Activities of Sanguinaria canadensis: Primary Human Keratinocytes, C-33A, and Human Papillomavirus HeLa Cervical Cancer Lines.
Sanguinarine is a benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis. Multiple published, preclinical studies have demonstrated that sanguinarine causes apoptosis in human cancer cells. An expert panel of naturopathic doctors identified sanguinarine as a component for consideration in cervical atypia management protocols. Clinical studies have identified positive outcomes when Sanguinaria is a constituent of escharotic treatment in cervical atypia management protocols. Therefore, further investigation and development of sanguinarine as a potential cancer treatment is recommended. Thus, the aim of this study is to further elucidate the signaling pathways of sanguinarine-induced cell death. Cell cultures of cervical cancer line C-33A (human papillomavirus [HPV] negative), HeLa (HPV positive), and normal primary human keratinocytes were established. Microscopic plate inspection, cell viability, initiator and effector caspase assays were completed in triplicate on C-33A (HPV negative), HeLa (HPV positive), and normal primary human keratinocytes cells exposed to incremental doses of sanguinarine. Sanguinarine induced dose-dependent cell death in cervical cancer lines as well as in normal human keratinocytes. Microscopic plate inspection confirmed morphologic changes of cell death in normal keratinocytes, C-33A, and HeLa including cell shrinkage, round up, and detachment from plate surface. Caspase assays demonstrated that sanguinarine treatment of C-33A cells resulted in an induction of caspase-3/7 when compared with vehicle-treated controls. Sanguinarine demonstrates potential as an agent with therapeutic impact because of the capacity to eliminate cancerous cells through apoptosis, the process of programed cell death. Further elucidation of signaling pathways of sanguinarine-induced cell death is necessary when considering sanguinarine as a treatment for cervical cancer.


Suppression of experimental colitis by intestinal mononuclear phagocytes.
The contribution of innate immunity to inflammatory bowel disease (IBD) remains an area of intense interest. Macrophages (MØ) and dendritic cells (DC) are considered important factors in regulating the onset of IBD. The goal of this study was to determine if intestinal mononuclear phagocytes (iMNP) serve a pathological or protective role in dextran sulfate sodium (DSS)-induced colitis in mice. Using a conditional MØ/DC depletion transgenic mouse line--MØ Fas-induced apoptosis--to systemically deplete iMNP, DSS colitis histopathology was shown to be more severe in MØ/DC-depleted compared with MØ/DC-intact mice. Similarly, localized iMNP depletion by clodronate-encapsulated liposomes into C57BL/6, BALB/c, and CB.17/SCID mice also increased DSS colitis severity, as indicated by increased histopathology, weight loss, rectal bleeding, decreased stool consistency, and colon length compared with MØ/DC-intact, DSS-treated mice. Histology revealed that iMNP depletion during DSS treatment led to increased neutrophilic inflammation, increased epithelial injury, and enhanced mucin depletion from Goblet cells. iMNP depletion did not further elevate DSS-induced expression of TNF-alpha and IFN-gamma mRNA but significantly increased expression of CXCL1 chemokine mRNA. Myeloperoxidase activity was increased in colons of MØ/DC-depleted, DSS-treated mice, compared with DSS alone, coincident with increased neutrophil infiltration in diseased colons. Neutrophil depletion combined with MØ/DC depletion prevented the increase in DSS colitis severity compared with MØ/DC depletion alone. This study demonstrates that iMNP can serve a protective role during development of acute colitis and that protection is associated with MØ/DC-mediated down-regulation of neutrophil infiltration.


Impact of Diet Consistency on the Mandibular Morphology: A Systematic Review of Studies on Rat Models.
Apart from genetics, environmental factors, such as food consistency, may affect craniofacial morphology and development. The present systematic review aims to systematically investigate and appraise the available evidence regarding the effect of diet consistency on the anatomical structures of the basal bone of the rat mandible. The search was performed without restrictions in five databases (PubMed, Scopus, Web of Science, ProQuest Dissertations and Theses Global, including grey literature) and hand searching through January 2022. A total of 14,904 references were initially identified, and 16 articles were finally included in the systematic review. Rats that consumed hard diets were found to exhibit an increase inbigonial width, corpus height, condylar depth, condylar base inclination, condylar process inclination, mandibular plane inclination, height and length of angular process, mandibular body height, depth of antegonial notch, growth rate in the gonial angle, angular process convexity and height of condylar process. It was also noted that mandibular depth, mandibular height, ramus angle and angle between the angular process and mandibular plane were decreased in rats that were fed with a hard diet. On the other hand, there were conflicting results about the growth of mandibular length and width, corpus length, mandibular body length, ramus height, condylar length and width, gonial angle and height of coronoid process. From the abovementioned results, it can be concluded that food consistency may affect the morphology of anatomical structures and the overall growth and development of rat mandibles in various ways.


High expression of microRNA-454 is associated with poor prognosis in triple-negative breast cancer.
MicroRNA-454 (miR-454) has been reported to play an oncogenic or tumor suppressor role in most cancers. However, the clinical relevance of miR-454 in breast cancer remains unclear. We examined the expression of miR-454 in a tissue microarray containing 534 breast cancer specimens from female patients at Fudan University Shanghai Cancer Center using in situ hybridization (ISH). Of these, 250 patients formed the training set and the other 284 were the validation set. The relationship between miR-454 and clinical outcome was analyzed by the Kaplan-Meier method. High expression of miR-454 indicated worse disease-free survival (DFS) in both cohorts (P = 0.006 for training set; P = 0.010 for validation set). Furthermore, in the triple-negative breast cancer (TNBC) subtype, miR-454 was positively correlated with worse clinical outcome (P = 0.013 for training set, P = 0.014 for validation set). In addition, patients in the low miR-454 expression cohort had better response to anthracycline compared to non-anthracycline chemotherapy (P = 0.056), but this difference was not observed in the high miR-454 expression cohort. Our findings indicated that miR-454 is a potential predictor of prognosis and chemotherapy response in TNBC.


Health and network centrality in a continuing care retirement community.
The overlap between social networks and health represents a key area of research in social gerontology. Set in a continuing care retirement community, this research focuses on how health is related to outgoing and incoming reports of social interaction among residents. Study participants (n = 123) were given the RAND 36-item Health Survey and asked about their social interaction with other people living at the retirement community. Negative binomial and linear regression analysis was used to assess associations between measures of network centrality and health. Retirement community residents in better health received more nominations from their peers about general socializing, net of how many ties they themselves reported. The ties received by healthier people, moreover, tended to come from others who were central in the network. Conversely, those in better health reported fewer close ties with their coresidents, net of the alter reports. Results are interpreted in light of status processes, which emerge in bounded social settings.


How important are economic factors in choice of medical specialty?
An ongoing debate exists among health care researchers about the mechanism that allocates physicians across medical specialties, and appropriate policy measures to correct imbalances that may arise from time to time. Most researchers believe that choice of residency program by medical school graduates is key to understanding how physicians are distributed across specialties, but there is much disagreement about whether economic or non-economic factors are most influential in determining this choice. We undertake an empirical investigation of two potentially important economic factors: income and leisure. To do so, we specify a two way error component regression model to estimate the effects of expected earnings and available leisure time, and uncertainty of earnings and leisure, on specialty choices of medical residents. Our findings indicate that economic factors are an important influence in the specialty choice process; in particular, medical residents are attracted to specialties that offer the prospect of longer and more certain annual vacations, higher earnings, shorter residency programs, and more certain work schedules. Our results suggest that employment contracts that provide generous annual vacation time and promise regular weekly work schedules may be more effective than increased earnings in correcting the current perceived shortage of primary care physicians.


Role of Anatomic and Salivary Factors in Dental Calculus Formation in Primary and Mixed Dentition Stages.
Clinical experience shows that formation of calculus is a very rare phenomenon in primary teeth, but it increases as the permanent teeth erupt. The purpose of this study was to assess the relationship between dental calculus, dental anatomy, and salivary factors in primary and mixed dentition stages. A cross-sectional study was carried out to determine the buccolingual dimensions of the most concave and the most convex surfaces of the lingual aspect of mandibular central incisor crowns in a sample group of 120 three- to five-old children and 120 eight- to 10-year old children. Saliva samples were collected from 20 in each group. Data were analyzed using t tests. Significant differences were found between the ratio of the buccolingual dimensions of the most convex to the most concave areas of the lingual surfaces in primary and permanent incisors (P=0.028). Saliva analysis revealed significant differences in total protein (P=0.002), sodium (P=0.037), bicarbonate (P=0.003), and ammonia (P=0.025) between the two age groups. Anatomic and salivary factors may be important reasons for the differences in calculus formation.


Feasibility and Acceptability of a Counseling- and mHealth-Based Physical Activity Intervention for Pregnant Women With Diabetes: The Fit for Two Pilot Study.
Diabetes during pregnancy poses serious health risks to both mother and child. Regular physical activity can reduce these risks, yet few clinic-based interventions of physical activity for pregnant women with diabetes have been attempted. The purpose of this single-arm pilot trial is to assess the feasibility and acceptability, and explore the potential efficacy of a counseling- and mobile health-based physical activity intervention for pregnant women with diabetes. Participants (N=17) who had type 2 or gestational diabetes, could read and speak in English or Spanish, and were between 10 and 27 weeks of gestation were recruited from the University of California San Diego Diabetes and Pregnancy Program. Participants engaged in a one-on-one counseling and goal-setting session immediately following a clinic visit with their physician. They were given a Fitbit and shown how to use the Fitbit app, including entering personalized step goals, and were encouraged to build up to 10,000 daily steps. Daily steps were recorded for 12 weeks, until they were 36 weeks' gestation, or until 1 week before they gave birth, whichever came first. Feasibility was measured by recruitment, retention, and adherence, and acceptability was measured using consumer satisfaction questionnaires and follow-up interviews. Potential efficacy was explored by examining changes in daily steps over time. The participants were primarily Hispanic (13/17, 76%), had public insurance (15/17, 88%), and had type 2 diabetes (12/17, 71%). Of the 17 patients who began the intervention, 76% (13/17) completed a follow-up visit, and 71% (12/17) continued wearing the Fitbit regularly after 8 weeks in the intervention. Adherence in wearing the Fitbit was relatively high, with a median wear adherence of 90% of days. The intervention was generally well accepted, with 85% (11/13) indicating that they were motivated to exercise more following the counseling session, 85% (11/13) indicating that the Fitbit helped increase their activity, and 92% (12/13) recommending the program overall. Mean daily steps increased from baseline (mean 6122, SD 2439) to week 3 (mean 6269, SD 2166) and then decreased through week 12 (mean 4191, SD 2228). High acceptability, retention, and adherence suggest that this may be a promising approach to delivering a simple, low-burden intervention in a clinical setting to a high-risk, underserved population. A randomized controlled trial is needed to determine whether this approach is effective in slowing the reduction in activity typically seen throughout pregnancy. ClinicalTrials.gov NCT03302377; https://clinicaltrials.gov/ct2/show/NCT03302377.


Nuclear localization is essential for the activity of p53 protein.
p53 appears to be a growth regulator, the perturbation of which induces changes in normal cell proliferation. Wild-type p53 protein is thought to function as a growth arrest gene, whereas mutant p53, which accumulates in transformed cells, has been shown to enhance malignant transformation. Both wild-type and mutant p53 migrate into the cell nucleus by means of identical nuclear localization signals (NLS) inherent in their primary sequences. Results presented here show that the suppressive activity of wild-type p53 measured as the reduction of transformation of primary rat fibroblasts induced by co-transfection with ras and either E1A or mutant p53, as well as the transformation enhancement of mutant p53 estimated by cooperation with ras in transformation of primary rat fibroblasts, is dependent upon nuclear localization signals in p53 protein. While transfection of unmodified wild-type p53 significantly reduces the number of rat embryonic fibroblast-transformed foci induced by E1A and ras or mutant p53 and ras, the wild-type p53 protein without NLS has completely lost this suppressive activity. Partially defective NLS wild-type p53, with a reduced nuclear accumulation ability, still exhibits some suppressive activity. In addition, we found that plasmids coding for intact mutant p53 protein efficiently cooperate with the ras oncogene, whereas the corresponding plasmids without NLS are totally inert. On this basis we conclude that nuclear localization of both wild-type and mutant p53 is a fundamental feature for manifesting the activities of these proteins. Both the suppressor activity mediated by the wild-type p53 and enhancement of transformation mediated by the mutant p53 require nuclear localization of the proteins to function.


Pancreatic fat accumulation and its relationship with liver fat content and other fat depots in obese individuals.
We assessed the associations between pancreatic fat accumulation and other fat compartments, including liver fat and visceral adipose tissue as well as insulin resistance and other metabolic abnormalities in obese individuals. We studied 42 Caucasian adults with obesity [20 men and 22 women; mean body mass index (BMI) 35.2±4 kg/m(2)], who had no history of liver diseases or excessive alcohol consumption, in which subcutaneous, visceral, liver, and pancreatic fat contents were quantified by an in-opposed-phase magnetic resonance imaging (MRI) technique. Compared with patients in the lower tertile (<5.6%, no.=15), those in the upper tertile of liver fat content had more visceral adipose tissue, greater insulin resistance and had higher values of BMI, blood pressure, triglycerides and lower HDL-cholesterol and adiponectin. Notably, pancreatic fat accumulation also significantly increased across tertiles of liver fat content. In univariate analysis, the strongest correlates of pancreatic fat were visceral and liver fat contents (r=0.80 and r=0.54, p<0.001- 0.0001, respectively). Pancreatic fat accumulation was also moderately associated with insulin resistance and other metabolic syndrome features. However, when adjusted for age, gender and visceral adipose tissue, the associations of pancreatic fat accumulation with liver fat and other metabolic abnormalities were no longer significant. There are significant associations between pancreatic fat accumulation and liver fat content as well as insulin resistance and other metabolic abnormalities in obese, but otherwise healthy, individuals. However, these associations are largely mediated by the amount of visceral adipose tissue.


Comparison of L- and D-Amino Acids for Bacterial Imaging in Lung Infection Mouse Model.
The effectiveness of L- and D-amino acids for detecting the early stage of infection in bacterial imaging was compared. We evaluated the accumulation of 3H-L-methionine (Met), 3H-D-Met, 3H-L-alanine (Ala), and 3H-D-Ala in E. coli EC-14 and HaCaT cells. Biological distribution was assessed in control and lung-infection-model mice with EC-14 using 3H-L- and D-Met, and 18F-FDG. A maximum accumulation of 3H-L- and D-Met, and 3H-L- and D-Ala occurred in the growth phase of EC-14 in vitro. The accumulation of 3H-L-Met and L-Ala was greater than that of 3H-D-Met and D-Ala in both EC-14 and HaCaT cells. For all radiotracers, the accumulation was greater in EC-14 than in HaCaT cells at early time points. The accumulation was identified at 5 min after injection in EC-14, whereas the accumulation gradually increased in HaCaT cells over time. There was little difference in biodistribution between 3H-L-and D-Met except in the brain. 3H-L- and D-Met were sensitive for detecting areas of infection after the spread of bacteria throughout the body, whereas 18F-FDG mainly detected primary infection areas. Therefore, 11C-L- and D-Met, radioisotopes that differ only in terms of 3H labeling, could be superior to 18F-FDG for detecting bacterial infection in lung-infection-model mice.


Treatment of isolated ulnar shaft fractures with functional bracing.
A prospective study was initiated using functional bracing to treat isolated ulnar shaft fractures. Forty-seven consecutive patients with 48 fractures were treated from July 1987 to January 1989. Twenty-eight patients with 29 fractures were available for follow up. Three of these fractures were subsequently excluded, as they had open reduction and internal fixation, leaving a group of 26 fractures. The mean time to union was 45 days (6.4 weeks). Fractures of the middle third of the ulnar diaphysis had the highest mean time to union, as did those with an oblique fracture pattern of 26% to 50% initial displacement. For union time, there was no significant difference for fracture location (P > .05 via t-test) or for fracture pattern (P > .05 via analysis of variance).


Comparison of group and individual cognitive-behavioral therapy in reducing fear of negative evaluation.
Previous studies have established the efficacy of group and individual formats of cognitive-behavioral therapy in reducing fear of negative evaluation in social anxiety disorder, but the effectiveness of the group and individual therapies has not been widely assessed. This study was conducted to compare the effectiveness of cognitive-behavior group therapy to individual cognitive-behavioral therapy in social anxiety disorder. 28 patients were randomly allocated to two groups of 14. Each group participated in 12 weekly sessions. The final sample was 22 participants after drop-out. Pretest and posttest data were collected using the Brief Fear of Negative Evaluation Scale and the Beck Depression Inventory-II. Controlling for pretest fear of negative evaluation and depression, cognitive-behavioral group therapy was more effective than individual cognitive-behavioral therapy in reducing fear of negative evaluation, but the clinical significance and improvement rates of the two treatment formats were equivalent.


Natural triterpenoid avicins selectively induce tumor cell death.
Avicins, a family of plant-derived triterpenoids, have been shown to possess pro-apoptotic, anti-mutagenic and anti-inflammatory properties in mammalian cells. Through thiol binding, avicins can also mediate antioxidant defense. Accumulating evidence uncovered during the past several years suggests that avicins induce tumor cell death via multiple mechanisms. This review will focus on recent studies that provide insights into the cellular and molecular processes and pathways by which avicins induce tumor cell death, including the canonical intrinsic mitochondrial and the Fas-mediated apoptosis cascades as well as autophagy-associated non-apoptotic programmed cell death.


Do breast cancer patients adapt CAM methods according to the therapeutic situation?
and purpose: Complementary and alternative medicine (CAM) is frequently used among cancer patients. It is unclear whether and how far patients adapt CAM to the treatment situation. The objective is to assess the changes of CAM use between radiotherapy for breast cancer and the follow-up. 107 patients who participated in a study assessing the possible effects of vitamin D and selenium on radiation-induced skin toxicity completed the CAM-PRIO (Working Group for Prevention and Integrative Oncology of the German Cancer Society) questionnaire during and after radiotherapy. The results were compared. Overall, 79.8% of the patients used at least one CAM method. Supplementation with vitamin D (49.4%) and selenium (28.7%) and prayer (37.1%) were the methods most used. After completing radiotherapy, many patients started using selenium, vitamin D, relaxation techniques, and yoga to a greater extent. Prior chemotherapy or concurrent endocrine treatments were not associated with the changes in CAM use. CAM use is mainly reported to be a static phenomenon. However, this study shows that this is not the case and that after the end of radiotherapy patients started using new CAM methods or increased the number of methods used.


Third distant recurrence of benign thymoma in a patient with myasthenia gravis.
Myasthenia gravis (MG) is an autoimmune disease where antibodies attack the presynaptic terminals at the neuromuscular junction causing progressive weakness. Associated with thymomas, resection can improve symptoms. A 29-year-old woman with MG who underwent two previous thymectomies, at ages 11 and 15 presented 14 years later with recurrent MG symptoms and an anterior mediastinal mass. Robotic-assisted thoracoscopic excision of the mediastinal mass was performed without complications. She recovered well and had improvement of her MG symptoms. Thymectomy can significantly improve symptoms in MG even for patients who do not have a thymoma. Reports of distant benign thymoma recurrence are rare. MG patients require continued monitoring and vigilance, even after thymectomy. Benign thymomas can recur even after significant time intervals, and utilisation of the robotic platform for recurrent thymoma excision is safe, even following two sternotomies. Patient symptoms improve with redo thymectomy.