Supervisory power and its influence on staff members and their customers.
The authors examined supervisors' selective use of legitimate, reward, coercive, referent, and expert powers and these power bases' influence on two outcomes: (a) employee perception of organizational support and (b) employee willingness to engage in service recovery activities with the customer. The authors found that the supervisor's use of expert, referent, and reward powers were positively related to perceived organizational support and that the use of coercive power was important in contributing to service recovery initiatives, particularly with regard to the employee's empathetic presentation to the customer.


Imaging of pediatric ovarian masses.
Ultrasonography is generally the initial diagnostic study of choice for evaluating suspected or known genital masses in young girls and adolescents. The authors reviewed the sonographic anatomy of the normal ovary and the sonographic spectrum in 88 pediatric patients with a variety of ovarian masses: simple and hemorrhagic cyst, teratoma, malignant tumor, tuboovarian abscess, torsion, and ectopic pregnancy. Among the various sonographic patterns observed, those of cystic ovarian masses and complex masses with mural nodules were the most specific, representing simple cysts and benign teratomas, respectively. Sonographic features of the remaining conditions were often similar, and diagnosis required correlation with clinical data and computed tomographic or magnetic resonance imaging findings.


Compression of the right atrium due to coexistence of diaphragmatic eventration and Chilaiditi's syndrome.
We report on a 70-year-old male who was admitted to hospital due to progressive onset of dyspnea and fever. Diagnostic work-up revealed a high diaphragmatic position, compression of the right heart and supraventricular tachycardia. A simultaneous incidental finding was hepatodiaphragmatic colonic interposition (Chilaiditi's syndrome). Diaphragmatic plication through a right thoracotomy with bowel reduction was effective to treat the patient.This is the second reported case in the literature of a simultaneous occurrence of diaphragmatic eventration and Chilaiditi's syndrome.


Effects of Baduanjin on glucose and lipid metabolism in diabetic patients: A protocol for systematic review and meta-analysis.
Baduanjin is an ancient technique of physical and breathing exercises (Dao Yin). This technique is divided into eight sections and each section is a motion, so it is called "Baduanjin". It is practice without equipment, simple and easy to learn, whose effect is significant leading to good fitness effect. Diabetes mellitus is a chronic metabolic disease. Clinical studies have reported that Baduanjin can affect the metabolism of blood glucose and blood lipid in diabetic patients, but the reported efficacy is different among different studies. Therefore, the study is aimed to systematically evaluate the size and differences of the impact of Baduanjin on the metabolism of glucose and lipid in diabetic patients. Retrieved randomized controlled trials(RCTs) on effects of Baduanjin on glucose and lipid metabolism in diabetic patients from PubMed, Web of Science, the Cochrane Library, Embase, CNKI with computer while mutually retrieved the same things from Chinese Clinical Trial Registry(ChiCTR), Google Academic and Baidu Academic. The retrieval time was from their establishment to October 2020. Then 2 researchers independently extracted relevant data and evaluated the quality of the included literatures, and meta-analysis was conducted on the included literatures using RevMan5.3. This research used outcome indicators like fasting blood glucose, postprandial blood glucose, glycosylated hemoglobin, total cholesterol content and triglyceride content to explore the effect of Baduanjin on glucose and lipid metabolism in diabetic patients specifically. The research will provide reliable evidence-based proof for Baduanjin improving glucose and lipid metabolism of diabetic patients. Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval was not required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences. DOI 10.17605/ OSF.IO/AGJHQ.


Impact of Outpatient Rehabilitation Service in Preventing the Deterioration of the Care-Needs Level Among Japanese Older Adults Availing Long-Term Care Insurance: A Propensity Score Matched Retrospective Study.
Outpatient rehabilitation (OR) and outpatient day long-term care (ODLC) services are frequently used by older adult patients in Japan. However, there is a need to clarify that OR service, which has more rehabilitation professionals than ODLC, has the role of providing rehabilitation. This retrospective study examined the impact of OR services by comparing the two services based on City A data from the care-needs certification survey conducted between 2015 to 2017. We performed a propensity score matched analysis to compare the changes in the care level and function of OR and ODLC users after two years. The results showed that OR users showed a lower deterioration in care levels and less decline in the activities of daily living (ADL) in dementia and adaptation to social life. In the analysis of older adults requiring support, OR users had a lower deterioration in care levels and less decline in the ADL in dementia and behavioral and psychological symptoms than ODLC users did. There was no difference between the two services with respect to older adults requiring long-term care. The OR service has had an increasingly preventive effect on the deterioration of care levels compared to the ODLC service, which was particularly evident in older adults requiring support.


Structure of the pilus assembly protein TadZ from Eubacterium rectale: implications for polar localization.
The tad (tight adherence) locus encodes a protein translocation system that produces a novel variant of type IV pili. The pilus assembly protein TadZ (called CpaE in Caulobacter crescentus) is ubiquitous in tad loci, but is absent in other type IV pilus biogenesis systems. The crystal structure of TadZ from Eubacterium rectale (ErTadZ), in complex with ATP and Mg(2+) , was determined to 2.1 Å resolution. ErTadZ contains an atypical ATPase domain with a variant of a deviant Walker-A motif that retains ATP binding capacity while displaying only low intrinsic ATPase activity. The bound ATP plays an important role in dimerization of ErTadZ. The N-terminal atypical receiver domain resembles the canonical receiver domain of response regulators, but has a degenerate, stripped-down 'active site'. Homology modelling of the N-terminal atypical receiver domain of CpaE indicates that it has a conserved protein-protein binding surface similar to that of the polar localization module of the social mobility protein FrzS, suggesting a similar function. Our structural results also suggest that TadZ localizes to the pole through the atypical receiver domain during an early stage of pili biogenesis, and functions as a hub for recruiting other pili components, thus providing insights into the Tad pilus assembly process.


Acetylcholinesterase histochemistry and functional characterization of the muscarinic receptor mediating the contraction of the bovine oesophageal groove.
1. By using acetylcholinesterase (AChE) histochemistry and in vitro isometric techniques, we have studied the presence and distribution of AChE-positive nerves, as well as the effects of muscarinic cholinoceptor agonists and selective antagonists, in the bovine oesophageal groove. 2. AChE-positive nerves and cells were distributed widely on the oesophageal groove floor. These fibres originated from adventitial ganglia containing bodies with high AChE activity and were shown grouped as large adventitial nerve bundles. 3. Both in the presence and absence of physostigmine, acetylcholine (ACh) induced concentration dependent contractions of bovine oesophageal groove strips. The rank order of the pD2 values for muscarinic agonists was: oxotremorine-M (7.37) = carbachol (7.14) > acetylcholine plus physostigmine (6.46) > bethanechol (5.42) > McN-A-343 (4.45) > acetylcholine (4.06). 4. Hexamethonium (10(-6)-10(-4) M), a nicotine receptor blocker, did not affect the carbachol concentration-response curve, which was significantly inhibited by the muscarinic antagonist, atropine (10(-9)-10(-8) M). 5. The preferential muscarinic antagonists pirenzepine (M1), 11-(2(diethyl-amino)methyl)-1- piperidinylacetyl)-5,-11-dihydro-6H-pyrido(2,3-b)-(1,4)-benzodiaze pine-6-one (AF-DX 116) and methoctramine (M2), 4-diphenyl-acetoxy-N-methyl-piperidine methiodide (4-DAMP) and p-fluorohexahydrosiladiphenidol (p-F-HHSiD) (M3) evoked rightwards displacements in a parallel manner of the carbachol control curve, and there was no decrease of the maximum response with the highest concentration of antagonist utilized. The muscarinic antagonist affinities, expressed in terms of pA2, values, were: atropine (9.51) = 4-DAMP (9.32) > p-F-HHSiD (7.78) > tropicamide (7.40) > pirenzepine (6.91) = AF-DX 116 (6.88) = methoctramine (6.71). This muscarinic antagonist profile suggests that an M3 receptor is involved in the carbachol induced contraction. 6. The present results suggest that a rich network of AChE- positive fibres is present in the oesophageal groove floor, where they form a nerve trunk and thinner branches accompanying blood vessels and sometimes around ganglia. The muscarinic cholinergic contraction of the bovine oesophageal groove seems to be mediated via activation of an M3 postsynaptic muscarinic receptor.


Kinetics of indium-111-labeled leukemic cells in patients with acute nonlymphocytic leukemia.
The distribution within the body of autologous leukemic cells labeled with indium-111 oxine was studied in seven patients with acute nonlymphocytic leukemia. The leukemic blood cells initially entered the spleen and liver, and the major site of localization was the former rather than the latter. The majority of the leukemic cells had not left the spleen and liver within 48 hr. Liver radioactivity fell transitorily up to the third hr after the initial rise. The clearance curve of radioactivity from the blood showed a plateau or the appearance of a "hump" from 1 to 5 hr after injection of labeled leukemic cells. These results might reflect recirculation of a portion of the leukemic cells between these organs and the bloodstream. In a patient with acute monoblastic leukemia. OKM1 monoclonal-antibody-treated monoblasts showed the lowest recovery into the blood and a greater increase of liver than splenic radioactivity at 30 min after injection. These results suggest the removal of damaged cells by the cytotoxic effects of antibody mediated by reticuloendothelial clearance mainly of the liver and others. In one patient with acute promyelocytic leukemia, leukemic cells accumulated in both kidneys, indicating the possible infiltration of these cells. Since indium-111 oxine stays firmly attached to the cells in spite of the possibility of radiation damaged in a long-term survey, it seems an ideal label for studying leukemic cell kinetics.


Stretching of the Mueller muscle results in involuntary contraction of the levator muscle.
Since the levator muscle involuntarily and tonically contracts against the weight and elastic resistance of the upper eyelid to maintain an adequate visual field, a mechanoreceptor such as a muscle spindle or a periodontal mechanoreceptor is thought to be essential for its functioning. It was surmised that the Mueller muscle might act as a serial kind of muscle spindle of the levator muscle. The response of the bilateral levator muscles evoked by stretching the Mueller muscle of each eyelid of 87 patients with dermatochalasis or aponeurotic blepharoptosis was electromyographically and photographically recorded. Stretching of the unilateral Mueller muscle evoked contraction of the ipsilateral levator muscle in 18 and of the bilateral levator muscle in 69 of the 87 patients. The Mueller muscle can be thought of as a large, serial kind of muscle spindle, so that stretching by voluntary phasic contraction of the levator muscle for initial eye opening may evoke an afferent impulse to the mesencephalic trigeminal nucleus. Subsequently, this nucleus may stimulate the central caudal nucleus of the oculomotor nuclear complex, leading to involuntary tonic contraction of the ipsilateral or bilateral levator muscles, in the form of a continuous stretch reflex, to maintain an adequate visual field.


EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1.
Curcumin, the yellow pigment of the spice turmeric, has emerged as a promising anticancer agent due to its antiproliferative and antiangiogenic properties. However, the molecular mechanism of action of this compound remains a subject of debate. In addition, curcumin's low bioavailability and efficacy profile in vivo further hinders its clinical development. This study focuses on the mechanism of action of EF24, a novel curcumin analog with greater than curcumin biological activity and bioavailability, but no increased toxicity. Treatment of MDA-MB231 breast and PC3 prostate cancer cells with EF24 or curcumin led to inhibition of HIF-1alpha protein levels and, consequently, inhibition of HIF transcriptional activity. This drug-induced HIF inhibition occurred in a VHL-dependent but proteasome-independent manner. We found that, while curcumin inhibited HIF-1alpha gene transcription, EF24 exerted its activity by inhibiting HIF-1alpha posttranscriptionally. This result suggested that the two compounds are structurally similar but mechanistically distinct. Another cellular effect that further differentiated the two compounds was the ability of EF24, but not curcumin, to induce microtubule stabilization in cells. EF24 had no stabilizing effect on tubulin polymerization in an in vitro assay using purified bovine brain tubulin, suggesting that the EF24-induced cytoskeletal disruption in cells may be the result of upstream signaling events rather than EF24 direct binding to tubulin. In summary, our study identifies EF24 as a novel curcumin-related compound possessing a distinct mechanism of action, which we believe contributes to the potent anticancer activity of this agent and can be further exploited to investigate the therapeutic potential of EF24.


The effect of tamoxifen and two of its non-isomerizable fixed-ring analogs on multistage rat hepatocarcinogenesis.
Long-term treatment of breast cancer patients with tamoxifen has prompted concern over potential toxicity of this drug with chronic administration. Since tamoxifen has estrogenic action in the rat liver and estrogenic agents can increase hepatoma incidence in rats, tamoxifen and two non-isomerizable, fixed-ring analogs (FRT1 and FRT2) were evaluated as promoting agents in a two-stage model of hepatocarcinogenesis in female Fischer F344 rats. The rats were subjected to 70% partial hepatectomy and half of the animals were administered the initiating agent, diethylnitrosamine (DEN; 10 mg/kg body wt), while the other half were not initiated. Groups of initiated and uninitiated animals were allowed to recover for 2 weeks and were then administered tamoxifen or one of the fixed-ring analogs admixed into AIN-76A diet at 25, 100 or 250 mg/kg diet. After 6 months of anti-estrogen administration the rats were sacrificed and uterine weights, blood levels of anti-estrogen, and liver histopathology were assessed. Uterine weights were decreased 2- to 3-fold by each of the agents, consistent with an anti-estrogenic action in the rat. The serum levels in rats administered 250 mg anti-estrogen/kg diet for 6 months were 320+/-20 ng/ml for tamoxifen, 320+/-10 for FRT1 and 350+/-20 for FRT2. The liver levels after a 6 month administration of 250 mg anti-estrogen/kg diet were 13 870+/-860 ng/g for tamoxifen, 13 300 +/-860 for FRT1 and 26 900+/-1900 for FRT2. A dose-dependent increase in serum and liver level of each compound was noted when measured at the 6 month time period. The number and percentage of the liver occupied by altered hepatic foci (AHF) were determined by quantitative stereology. A dose-dependent increase above initiated controls was observed in the initiated, tamoxifen-treated rats. Both fixed-ring analogs also increased the number and size of AHF compared with initiated controls, but were less potent than tamoxifen, suggesting that tamoxifen has an intrinsic promoting action in the liver that is independent of its ability to isomerize to more potent estrogenic compounds. In addition, the fixed-ring analogs have a weaker promoting activity in the rat liver than does tamoxifen. This may be due to pharmacokinetic differences at the lower two doses, but it is independent of achieved serum level at the highest dose and hence may reflect differences in intrinsic activity of these compounds. Thus tamoxifen and the two fixed-ring analogs promote the development of rat hepatocarcinogenesis.


Kinetic Inhibition of Clathrate Hydrate by Copolymers Based on N-Vinylcaprolactam and N-Acryloylpyrrolidine: Optimization Effect of Interfacial Nonfreezable Water of Polymers.
Amphiphilic polymers have now been designed to achieve an icephobic performance and have been used for ice adhesion prevention. They may function by forming a strongly bonded but nonfreezable water shell which serves as a self-lubricating interfacial layer that weakens the adhesion strength between ice and the surface. Here, an analogous concept is built to prevent the formation of clathrate hydrate compounds during oil and natural gas production, in which amphiphilic water-soluble polymers act as efficient kinetic hydrate inhibitors (KHIs). A novel group of copolymers with N-vinylcaprolactam and N-acryloylpyrrolidine structural units are investigated in this study. The relationships among the amphiphilicity, lower critical solution temperature, nonfreezable bound water, and kinetic hydrate inhibition time are analyzed in terms of the copolymer compositions. Low-field NMR relaxometry revealed the crucial interfacial water in tightly bound dynamic states which led to crystal growth rates changing with the copolymer compositions, in accord with the rotational rheometric analysis results. The nonfreezable bound water layer confirmed by a calorimetry analysis also changes with the polymer amphiphilicity. Therefore, in the interface between the KHI polymers and hydrate, water surrounding the polymers plays a critical role by helping to delay the nucleation and growth of embryonic ice/hydrates. Appropriate amphiphilicity of the copolymers can achieve the optimal interfacial properties for slowing down hydrate crystal growth.


The cost of a hospital ward in Europe: is there a methodology available to accurately measure the costs?
Costing health care services has become a major requirement due to an increase in demand for health care and technological advances. Several studies have been published describing the computation of the costs of hospital wards. The objective of this article is to examine the methodologies utilised to try to describe the basic components of a standardised method, which could be applied throughout Europe. Cost measurement however is a complex matter and a lack of clarity exists in the terminology and the cost concepts utilised. The methods discussed in this review make it evident that there is a lack of standardized methodologies for the determination of accurate costs of hospital wards. A standardized costing methodology would facilitate comparisons, encourage economic evaluation within the ward and hence assist in the decision-making process with regard to the efficient allocation of resources.


Microcosmus anchylodeirus (Ascidiacea, Pyuridae) introduced in the Mediterranean Sea.
Several specimens of Microcosmus anchylodeirus Traustedt, 1883 were successively collected by dives along the shore of southern Corsica. With a corrugated tunic covered with all kinds of epibionts they are difficult to notice on the rocks and are recorded for the first time from Mediterranean Sea. These ascidians correspond well internally and externally to Atlantic specimens from the Caribbean islands and also to those described from Brazil. Pacific specimens identified as Microcosmus multitentaculatus Tokioka, 1953 from Japan and Korea have been examined and are now considered as junior synonyms of Microcosmus anchylodeirus, a species whose origin is not known.


Abdominal wound dehiscence: a review of 60 cases at the University College Hospital, Ibadan.
A total of 212 cases of abdominal wound dehiscence requiring secondary closure occurred in 8632 surgical obstetric and gynaecological laparotomies over a 7-year period ending in December 1981. The incidence of abdominal wound dehiscence at Ibadan was 2.5%. Contaminated wounds were the most susceptible with an incidence of 19%. A detailed review of 60 cases revealed a mean age of 29 years. Wound infection was the most prominent contributory factor. Tension sutures appeared to be ineffective in preventing wound dehiscence. Following secondary closure, 53% of the patients developed further wound complications, mainly wound infection, incisional hernia and repeat dehiscence. The average duration of hospitalization was 35 days and 7% of the patients died post-operatively.


Applications to medical and surgical specialist training in the UK National Health Service, 2021-2022: a cross-sectional observational study to characterise the diversity of successful applicants.
To compare success of applicants to specialty training posts in the UK by gender, ethnicity and disability status. Cross-sectional observational study. National Health Service, UK. All specialty training post applications to Health Education England, UK, during the 2021-2022 recruitment cycle. Nil. Comparison of success at application to specialty training posts by gender, ethnicity, country of qualification (UK vs non-UK) and disability. The influence of ethnicity on success was investigated using a logistic regression model, where country of qualification was included as a covariate. 12 419/37 971 (32.7%) of applicants to specialty training posts were successful, representing 58 specialties. The difference in percentage of successful females (6480/17 523, 37.0%) and males (5625/19 340, 29.1%) was 7.9% (95% CI 6.93% to 8.86%), in favour of females. Segregation of applications to specialties by gender was observed; surgical specialties had the highest proportion of male applicants, while obstetrics and gynaecology had the highest proportion of female applicants. The proportion of successful recruits to specialties largely reflected the number of applications. 11/15 minority ethnic groups (excluding 'not stated') had significantly lower adjusted ORs for success compared with white-British applicants. 'Mixed white and black African' (OR 0.52, 95% CI 0.44 to 0.61, p≤0.001) were the least successful minority group in our study, while non-UK graduates had an adjusted ORs for success of 0.43 (95% CI 0.41 to 0.46, p≤0.001) compared with UK graduates. The difference in percentage of success by disabled applicants (179/464, 38.6%) and non-disabled applicants (11 940/36 418, 32.8%) was 5.79% (95% CI 1.23% to 10.4%), in favour of disabled applicants. No disabled applicants were accepted to 21/58 (36.2%) of specialties. Despite greater success by female applicants overall, there is an attraction issue to specialties by gender. Further, most ethnic minority groups are less successful at application when compared with white-British applicants. This requires continuous monitoring and evaluation of the reasons behind observed differences. Not applicable.


[The expression stathmin gene in laryngeal squamous cell carcinoma].
To observe expression of stathmin gene in laryngeal squamous cell carcinoma (LSCC) and relation between expression of stathmin gene and occurrence and development of LSCC. The expression of the stathmin gene was determined in 35 LSCC of specimens and 18 normal laryngeal tissues (NLT) of specimens by in situ hybridization with Digoxigenin labeled probe of stathmin mRNA. Expression of stathmin gene was observed in 35 cases of laryngeal squamous cell carcinoma tissue (positive rate, 69%) and positive signal was observed in both cytoplasm and nuclear. Among 18 cases of normal tissue, only 6 showed weak positive signal. There was significant difference in expression of stathmin gene between laryngeal squamous cell carcinoma tissue and normal tissue. Expression of stathmin gene may play a key role in the pathogenesis and development of laryngeal squamous cell carcinoma. It may be a very important biotherapy target in the treatment of laryngeal squamous cell carcinoma.


Two distinct subunits of hemerythrin from the brachiopod Lingula reevii: an apparent requirement for cooperativity in O2 binding.
Reported are results on the subunit composition of octameric hemerythrin (Hr) from the brachiopod Lingula reevii. Unlike most other Hrs, L. reevii Hr shows cooperativity in O2 binding. Purified L. reevii Hr was found to consist of two different subunits in approximately equimolar proportions. These two subunits differ in molecular weight by approximately 1000. Amino acid sequence data for the first 24 residues of the two subunits, labeled alpha and beta, show 70% identity with each other. Comparisons to amino acid sequences of other Hrs show approximately 50% identity in the first 24 residues and that both the alpha and beta subunits of L. reevii Hr have one residue deleted at their amino termini. Very recently, one other Hr, that from the brachiopod Lingula unguis, was also shown to contain equimolar proportions of two different subunits [Satake, K., Yugi, M., Kamo, M., Kihara, H., & Tsugita, A. (1990) Protein Seq. Data Anal. 3, 1-5], and this Hr also shows cooperativity in O2 binding. An alpha 4 beta 4 octamer is, therefore, proposed to be a common feature of those Hrs that show such cooperativity. Likely arrangements of alpha and beta subunits within an alpha 4 beta 4 octamer having the same configuration of subunits as that in other octameric Hrs are proposed. The most probable arrangements can be readily derived from physically reasonable restrictions on the types of intersubunit interactions and on transmission of allosteric effects.


The relationship between weight stigma, weight bias internalization, and physical health in military personnel with or at high-risk of overweight/obesity.
Perceived weight stigma is associated with adverse health indices, such as elevated cortisol, lipid/glucose dysregulation, and poorer self-rated health. This relationship may be particularly relevant for military personnel, given the cultural emphasis on fitness and weight/shape. Therefore, we investigated the relationship between weight stigma and physical health in 117 active duty personnel (66.7% male; 56.4% non-Hispanic White; age: 30.8 ± 7.4 years; BMI: 29.5 ± 2.5 kg/m2). Participants reported weight stigma (general and military-specific), weight bias internalization, and the presence (≥1; n = 55) or absence (n = 62) of medical conditions. Logistic regressions were conducted examining the ability of weight stigma (general or military-specific) and weight bias internalization to predict the presence or absence of medical conditions. General weight stigma was not significantly associated with the presence of a medical condition (p > .05). However, individuals with military-specific weight stigma scores twice that of their peers were over three times more likely (p = .04) to report a medical condition. Weight bias internalization was not significant in any model (ps > .20). Longitudinal studies should prospectively examine the relationship between weight stigma in the military setting and health among service members.


Marital adjustment in families of young children with disabilities: associations with daily hassles and problem-focused coping.
A family systems framework was used to examine associations between stressors/hassles, problem-focused coping, and marital adjustment in 67 families of young children with disabilities. Most of the couples were experiencing average to above average marital adjustment. When daily stressors/hassles were higher, husbands and wives viewed their marriages more negatively. After variance contributed by stressors/hassles was statistically controlled, fathers who employed more problem-focused coping strategies were more positive about their marriages. For wives (but not husbands), a cross-spousal partner effect was found; women reported higher marital adjustment when their husbands employed more problem-focused coping strategies. We reaffirmed the systemic nature of family processes and highlighted the role of parent gender in understanding the relationships among stressors, coping, and marital well-being.


Viral ecology and the maintenance of novel host use.
Viruses can occasionally emerge by infecting new host species. However, the early phases of emergence can hinge upon ecological sustainability of the virus population, which is a product of both within-host population growth and between-host transmission. Insufficient growth or transmission can force virus extinction before the latter phases of emergence, where genetic adaptations that improve host use may occur. We examined the early phase of emergence by studying the population dynamics of RNA phages in replicated laboratory environments containing native and novel host bacteria. To predict the breadth of transmission rates allowing viral persistence on each species, we developed a simple model based on in vitro data for phage growth rate over a range of initial population densities on both hosts. Validation of these predictions using serial passage experiments revealed a range of transmission rates for which the native host was a source and the novel host was a sink. In this critical range of transmission rates, periodic exposure to the native host was sufficient for the maintenance of the viral population on the novel host. We argue that this effect should facilitate adaptation by the virus to utilize the novel host--often crucial in subsequent phases of emergence.


Antibody-based proteomics: fast-tracking molecular diagnostics in oncology.
The effective implementation of personalized cancer therapeutic regimens depends on the successful identification and translation of informative biomarkers to aid clinical decision making. Antibody-based proteomics occupies a pivotal space in the cancer biomarker discovery and validation pipeline, facilitating the high-throughput evaluation of candidate markers. Although the clinical utility of these emerging technologies remains to be established, the traditional use of antibodies as affinity reagents in clinical diagnostic and predictive assays suggests that the rapid translation of such approaches is an achievable goal. Furthermore, in combination with, or as alternatives to, genomic and transcriptomic methods for patient stratification, antibody-based proteomics approaches offer the promise of additional insight into cancer disease states. In this Review, we discuss the current status of antibody-based proteomics and its contribution to the development of new assays that are crucial for the realization of individualized cancer therapy.


Endogenous growth hormone secretion and clearance rates in normal boys, as determined by deconvolution analysis: relationship to age, pubertal status, and body mass.
Mean plasma GH concentrations increase in normal boys during mid- to late-puberty. To investigate the nature of the pituitary secretory events and/or altered metabolic clearance responsible for these serum GH concentration changes, we performed multiple-parameter deconvolution analysis of 46 24-h serum GH concentration-time series obtained from normal boys at various stages of puberty and young adulthood. The subjects ranged in chronological age from 7-27 yr. The height and weight of each subject were between the 5th and 95th percentile for age. The calculated daily mass of GH secreted was greatest (P less than 0.001) in late pubertal boys (mean +/- SE, 1810 +/- 250 micrograms/24 h) and was triple the value in prepubertal boys (610 +/- 65 micrograms/24 h). When the values were normalized and expressed as mass of GH secreted per unit (m2) body surface area or per L distribution volume, GH secretion in late pubertal boys was still significantly greater than that in any other group (P less than 0.05). These values for late pubertal boys were nearly double the corresponding values for prepubertal boys (1160 +/- 160 vs. 600 +/- 58 micrograms GH/m2.24 h and 440 +/- 63 vs. 270 +/- 25 micrograms GH/L vol.24 h, respectively). When the effect of clearance mechanics on serum GH concentrations was removed mathematically, the primary change in predicted GH secretory burst parameters during pubertal development was an increase in GH mass released per burst resulting from an increase in the maximal rate of GH secretion attained within the bursts. These changes in the amplitude of GH release events were specific, in that they were largely independent of any accompanying alterations in duration or frequency of the GH secretory bursts or in serum GH half-life. Correlation analysis revealed that the 24-h GH secretion rate varied inversely with the subjects' body mass index SD score (r = -0.65; P less than 0.01), suggesting that differences in body mass, even within the normal range, contribute to the wide variability in daily GH secretion rates among normally growing children. The plasma insulin-like growth factor-I concentrations of all subjects correlated positively with the calculated 24-h GH secretion rate (r = 0.51; P less than 0.001). In summary, the primary neuroendocrine alteration responsible for the augmented serum GH concentrations characterizing mid- to late-puberty in boys is an increased mass of GH released per pituitary secretory episode resulting from an increased maximal rate of GH secretion within each burst.(ABSTRACT TRUNCATED AT 400 WORDS)


Atherosclerosis in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease that has a late mortality phase owing mainly to cardiovascular manifestations. Atherosclerosis itself is characterized by inflammatory components, fulfilling the criteria of Witebsky and Rose for an autoimmune disease. SLE patients have increased risk for cardiovascular events, and these are the result of both atherosclerosis and thromboembolic events. Risk factors for atherosclerosis in SLE include "traditional" risk factors (mainly the Framingham risk factors), as well as disease-related factors including disease duration, steroid therapy, and renal disease, and inflammatory mechanisms that specifically contribute to enhanced atherosclerosis in SLE. These include specific antibodies to beta2GPI; anticardiolipin antibodies; anti-oxidized low-density lipoprotein; and antibodies to heat shock proteins, complement activation, impaired ability to activate TGF-beta1, and elevated levels of CRP. These findings stress the importance of surveillance and preventive strategies to control atherosclerosis in SLE.


Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive).
The LEOPARD syndrome is a complex of multisystemic congenital abnormalities characterized by lentiginosis, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness (sensorineural). Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located on chromosome 12q24.1, have been identified in 88% of patients with LEOPARD syndrome. A missense mutation (836-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in this patient and his mother with LEOPARD syndrome. This mutation is one of the two recurrent mutations most often associated with the syndrome. Leukemia has not previously been reported in patients with LEOPARD syndrome. The authors describe a 13-year-old boy diagnosed with both LEOPARD syndrome and acute myelomonocytic leukemia (AML-M4).


Immune reconstitution inflammatory syndrome associated with pulmonary sarcoidosis in an HIV-infected patient: an immunohistochemical study.
Sarcoidosis has been rarely described in literature as a cause of interstitial pulmonary disease associated with AIDS. This study reports a case of immune reconstitution inflammatory syndrome associated with pulmonary sarcoidosis in a patient with a history of previous pulmonary tuberculosis concomitant with HIV infection. Results of the immunohistochemical study of samples from the resected right lower lobe are described. Pathological findings suggest a role of Th1, Th2 and Th17 response in IRIS associated sarcoidosis.


[Gamma-knife radiosurgery for brainstem arteriovenous malformations. Preliminary results].
Microsurgical resection have the advantage to be immediately effective according to bleeding risk and is the reference treatment for cerebral arteriovenous malformations. For cerebral arteriovenous malformations located in the brainstem gamma-knife radiosurgery due to its low invasivity is classically a first line treatment. We reviewed the Marseilles experience to assess the efficacy and safety of gamma-knife radiosurgery for brain stem arteriovenous malformations. We analyzed retrospectively data of 45 patients with an arteriovenous malformation located in the brain stem treated in Marseilles by gamma-knife radiosurgery by between 07/92 and 12/99. Mean age was 42 years, there were 5 children. Arteriovenous malformations were located in the pons or midbrain for the majority of the patients. Intraaxial lesion was found in 82% of patients. Hemorrhage prior to radiosurgery occurred in 75% of the patients. Gamma-knife procedure was the first treatment of the arteriovenous malformations for 29 patients (65%); previous surgery was performed in 34 patients (15%). Mean nidus volume was 550 mm(3) (32-14 196 mm(3)). Mean margin dose was of 23 Gy (range 15-30 Gy). Follow up was available for 25 patients (mean 18 months). One patient presented a transient worsening of his neurological status, and 2 patients developed a fixed deficit. Two patients underwent rebleeding at an interval of 12 to 36 months after the gamma-knife procedure. At last angiographic follow-up (13 patients), the obliteration rate was 82% of the arteriovenous malformations. A second procedure was proposed to a patient with only partial occlusion at 3 years. Gamma-knife radiosurgery can achieve good obliteration rate of brain stem arteriovenous malformations with low morbidity and may be a valuable first-choice therapy for such arteriovenous malformations. A larger population and longer follow up are mandatory in order to confirm these preliminary results.


Morphological Properties of Methacrylate-Based Polymer Monoliths: From Gel Porosity to Macroscopic Inhomogeneities.
Shaping chemical interfaces of hard and soft matter materials into physical morphologies that guarantee excellent transport properties is of central importance for technologies relying on adsorption, separation, and reaction at the interface. Polymer monoliths with a hierarchically structured pore space, for example, are widely used in flow-driven processes, whose efficiency depends on the morphology of the support material over several length scales. Compared with alternative support structures, particularly silica monoliths, polymer monoliths yield lower efficiency, which suggests a suboptimal morphology. Based on physical reconstruction by serial block-face scanning electron microscopy we evaluate the structural features of a methacrylate-based polymer monolith from the pore scale to the column scale. The morphological data reveal a homogeneous polymer skeleton with a solute-impenetrable core-porous shell architecture and a heterogeneous macropore space that suffers from inhomogeneities at the short-range and the transcolumn scale. Although the morphology of the polymer phase is favorable to efficient mass transport, the performance of the polymer monolith is limited by severe transcolumn gradients in macroporosity and macropore size. We propose to overcome these morphological limitations by pursuing a preparation strategy that involves active rather than passive shaping of the macropore space, for example, by using silica monoliths as templating structures for polymer monolith preparation.


Orexin-A stimulates 3β-hydroxysteroid dehydrogenase expression and cortisol production in H295R human adrenocortical cells through the AKT pathway.
Orexin-A is a regulatory peptide involved in the regulation of food intake, sleep-wakefulness, and it has various endocrine and metabolic functions. It orchestrates diverse central and peripheral processes through the stimulation of two G-protein coupled receptors, orexin receptor type 1 (OX1 receptor) and orexin receptor type 2 (OX2 receptor). In this study, human adrenocortical cells (NCI-H295R cells) were incubated with various concentrations of orexin-A (10-10 to 10-6 M) in vitro, and the mRNA and protein expression of OX1 receptor was determined in the cells. In addition, NCI-H295R cells treated with 10-6 M orexin-A were then treated with or without OX1 receptor specific antagonist (SB334867), AKT antagonist (PF-04691502), or a combination of both. Subsequently, cell proliferation, the cortisol content in the medium and the mRNA and protein expression expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) were analyzed. The activity of the AKT signaling pathway was also determined in the NCI-H295R cells. We observed that the increase in the mRNA and protein expression of OX1 receptor was orexin-A concentration-dependent, with 10-6 M orexin-A exerting the most potent effect. Orexin-A enhanced cell proliferation and cortisol production, and increased the mRNA and protein expression of 3β-HSD in the NCI-H295R cells; however, these effects were partly blocked by the OX1 receptor antagonist, the AKT antagonist and the combination of both. Furthermore, orexin-A significantly increased the phosphorylation of AKT, with the levels of total AKT protein remaining unaltered. This effect was blocked in the presence of PF-04691502 (10-6 M), SB334867 (10-6 M) and the combination of both. On the whole, our data demonstrate that the effects of orexin-A on the survival and function of human adrenocortical cells are mediated through the AKT signaling pathway.


Overlooked dislocation of C6/C7 vertebra with minimal neurologic deficit.
The beginning of 21 century was marked by an enormous increase in the number of traffic accidents, which led to an increasing number of multiple injured patients with associated injuries, especially injuries of cervical spine, because of its anatomical features. Even in the era of modern diagnostic procedures, cervical spine injuries are still often overlooked, especially in multiple injured patients and unconscious patients, and the consequences of undiagnosed injuries can be fatal. Very often there are ligamentous lesions, which can be detected only by using NMR, while the osteoarticular lesions can be diagnosed through careful clinical examination, X-rays and CT scan. This paper presents the case of female in the middle age with initially missed injury of the lower cervical spine segments, sustained in a car accident as a driver, with excellent results of treatment and complete recovery.


Differences in brain changes between adults with childhood-onset epilepsy and controls: A prospective population-based study.
To determine the impact of childhood-onset uncomplicated epilepsy (COE) on brain aging over 50-year prospective follow-up. A population-based cohort of 41 aging subjects with COE and their 46 matched controls participated in a detailed in-person prospective assessment in 2012 and 2017 to characterize ongoing changes in the aging brain. The mean age of the COE participants was 63.2 years (SD 4.14, median 63.2, range 55.8-70.6) and 63.0 years (mean, SD 4.13, median 63.3, range 56.0-69.9) years for controls. Neurologic signs were significantly more common in COE participants not in remission (p = .015), and the most frequent abnormalities were cerebellar signs (p < .001). Neurologic signs in general (p = .008) and cerebellar signs in particular (p = .018) were significantly more common in focal than in generalized epilepsies. MRI white matter abnormalities were significantly associated with absence of vocational education (p = .011), and MRI hippocampal atrophy in COE subjects was associated with arterial hypertension versus normal blood pressure (p = .017). In the combined study cohort of COE subjects and controls, presenting neurologic signs increased both in the subjects and in the controls from the 2012 to 2017 study. At ultra-long-term follow-up, clinical and neuroimaging findings show tendencies to brain aging that is more accelerated in COE participants with active adult childhood-onset epilepsy, and particularly in focal epilepsy.


[Management of infections from cardiac implantable electronic devices: recommendations from a study panel].
Cardiac Implantable Electronic Device (CIED) infections are an emerging clinical issue. There are no national recommendations on the management of these infections, also due to the limited number of dedicated and high quality clinical studies. Therefore, researchers from southern Italian centres have decided to share the clinical experience gathered so far in this field and report practical recommendations for the diagnosis and treatment of adult patients with CIED infection or endocarditis. Here we review the risk factors, diagnostic issues (microbiological and echocardiographic) and aetiology, and describe extensively the best therapeutic approach. We also address the management of complications, follow-up after discharge and the prevention of CIED infections. In this regard, a multidisciplinary approach is fundamental to appropriately manage the initial diagnostic process and the comorbidities, to plan proper antimicrobial treatment and complete percutaneous hardware removal, with the key support of microbiology and echocardiography.


A novel SRD5A2 mutation in an Iranian family with sex development disorder.
Disorders of sex development (DSD) are different types of conditions that their accurate diagnosis by using conventional phenotypic and biochemical approaches is a challenging issue. Precise determination of DSD is critical due to the detection of possible life-threatening associated disorders. It may also assist parents in choosing the most suitable management for their affected child. In this study, two affected kids born from consanguineous families who were clinically diagnosed for sex development disorder were investigated for the main cause of the disease. Biochemical analysis failed to make an accurate diagnosis. Karyotype analysis showed an abnormal sex chromosome pattern. Whole exome sequencing was sequentially applied to precisely ascertain the genetic cause of the disease. A novel deletion, g.40936_53878del12943insTG (NG_008365.1), and one known mutation, c.586G>A (p.Gly196Ser), were detected in SRD5A2 gene in case I and case II respectively. Further analysis was performed using polymerase chain reaction, primer walking and Sanger sequencing to detect the nucleotides changes accurately. Segregation analysis in the families confirmed 13kb novel homozygous deletion of SRD5A2 in case I and c.586G>A in case II. The present study confirms the diagnostic value of whole exome sequencing in the detection of DSD aetiology, especially when several differential diagnoses are possible.


[Multiple Aspergillus brain abscesses complicated by bronchial asthma].
A 35-year-old man was hospitalized for the treatment of severe asthma attack. His condition improved with intensive steroid chemotherapy under artificial ventilation. On the 12th hospital day, he was taken off respirator support but lost consciousness afterward. Computed tomography of the brain disclosed multiple hypodense lesions with bleeding. T1-weighted magnetic resonance imaging disclosed low-intensity lesions containing high-intensity areas. T2-weighted images showed heterogeneous high-intensity lesions. The autopsy specimen demonstrated multiple brain abscesses. Histologic examination revealed branching fungal hyphae in abscess walls and also extending through arterial walls with emboli. These findings yielded a diagnosis of multiple Aspergillus infarct abscesses of the brain.


Sensing and Liquid-Liquid Extraction of Dicarboxylates Using Dicopper Cryptates.
We report the investigation of dicopper(II) bistren cryptate, containing naphthyl spacers between the tren subunits, as a receptor for polycarboxylates in neutral aqueous solution. An indicator displacement assay for dicarboxylates was also developed by mixing the azacryptate with the fluorescent indicator 5-carboxyfluorescein in a 50:1 molar ratio. Fluorimetric studies showed a significant restoration of fluorophore emission upon addition of fumarate anions followed by succinate and isophthalate. The introduction of hexyl chains on the naphthalene groups created a novel hydrophobic cage; the corresponding dicopper complex was investigated as an extractant for dicarboxylates from neutral water into dichloromethane. The liquid-liquid extraction of succinate-as a model anion-was successfully achieved by exploiting the high affinity of this anionic guest for the azacryptate cavity. Extraction was monitored through the changes in the UV-visible spectrum of the dicopper complex in dichloromethane and by measuring the residual concentration of succinate in the aqueous phase by HPLC-UV. The successful extraction was also confirmed by 1H-NMR spectroscopy. Considering the relevance of polycarboxylates in biochemistry and in the environmental field, e.g., as waste products of industrial processes, our results open new perspectives for research in all contexts where recognition, sensing, or extraction of polycarboxylates is required.


The MsK family of alfalfa protein kinase genes encodes homologues of shaggy/glycogen synthase kinase-3 and shows differential expression patterns in plant organs and development.
This paper reports on the isolation of a novel class of plant serine/threonine protein kinase genes, MsK-1, MsK-2 and MsK-3. They belong to the superfamily of cdc2-like genes, but show highest identity to the Drosophila shaggy and rat GSK-3 proteins (65-70%). All of these kinases share a highly conserved catalytic protein kinase domain. Different amino-terminal extensions distinguish the different proteins. The different plant kinases do not originate from differential processing of the same gene as is found for shaggy, but are encoded by different members of a gene family. Similarly to the shaggy kinases, the plant kinases show different organ-specific and stage-specific developmental expression patterns. Since the shaggy kinases play an important role in intercellular communication in Drosophila development, the MsK kinases are expected to perform a similar function in plants.


Characteristics of sports-related dermatoses for different types of sports: a cross-sectional study.
Skin lesions are common in athletes. Athletic activities may lead to new skin lesions or aggravate existing ones. We aimed to determine the effects of sport type and participation length on the occurrence of sports-related dermatoses and to identify the localization characteristics of these lesions. A total of 121 licensed athletes (42 swimmers, 23 handball players, 33 soccer players and 23 wrestlers) and 121 sedentary controls were included in the study. A consultant dermatologist examined all subjects. Lesion types, duration, and localization characteristics were noted. The lesions were categorized as viral, bacterial, traumatic, and non-traumatic. Traumatic lesions were frequently seen in soccer players and wrestlers; fungal infections were more commonly seen in swimmers and in soccer players. Lesion types and localizations varied by sport type. There were no significant relationships between sport type and the incidence of viral and bacterial lesions. The results suggest that athletic activity seems to be a predisposing factor, especially for fungal infections and acute or chronic traumatic lesions. Thus, regular dermatological screening of athletes is critical for rapid identification and treatment of dermatoses disrupting sport performance.


Hemopoietic inhibition in hairy cell leukemia.
Leukopenia, thrombocytopenia, and anemia are important features of hairy cell leukemia (HCL). They are generally considered to be due to hypersplenism and to inadequate production by bone marrow which is heavily infiltrated by the neoplastic hairy cells (HC). However, the cytopenias may also be caused by hemopoietic inhibition by cytokines derived from the mononuclear cells (MNC) of HCL. We studied the MNC of HCL with an in vitro assay for granulocyte-macrophage progenitors (CFU-GM) to search for this hemopoietic inhibitor(s) and to determine the cell source and mechanism of its production/release. We found that MNC conditioned media from 7 of 9 HCL cases exerted substantial inhibitory effect (23% to 66%) on normal marrow cells. Peak inhibitory activity was obtained in media conditioned with 10(6) MNC/ml for 90 minutes to 24 hours. Both HC and lymphocytes could release inhibitor(s) through mutually synergistic cell interactions. HC alone were inactive and lymphocytes alone were only weakly active. Mixtures of conditioned media of HC and of lymphocytes were not synergistic. The lymphocytes responsible for the inhibition were present in preparations depleted of cells bearing the cluster designation 4 antigen (CD4+) and B cells and were most likely the CD8+ T-cells. In one patient so examined, a partial reversal of inhibition was achieved by treating MNC-CM with antibodies to tumor necrosis factor (TNF)-alpha suggesting that TNF-alpha was at least partly involved in the inhibition of CFU-GM. This mechanism of cytokine release may be operative in vivo to account for the cytopenias in HCL and, if so, could alter the concept of hypersplenism in this disease.


[Therapeutic endoscopic ultrasound: current indications and future perspectives.]
Endoscopic ultrasound (EUS) is rapidly evolving from a diagnostic into a mainly therapeutic procedure, similarly to what previously occurred to endoscopic retrograde cholangio-pancreatography (ERCP). The capability to easily access adjacent organs and structures with a minimally invasive approach as well as the availability of dedicated devices are driving this process. Several therapeutic procedures can be performed under EUS-guidance, such as drainage of pancreatic fluid collections, of the biliary system after ERCP failure, of the gallbladder for acute cholecystitis in high-risk surgical patients, as well as endoscopic gastroenteral-anastomosis creation. The introduction of dedicated lumen-apposing metal stents in the latest years has made these procedures technically easier. However, further improvements of stent design will be required in the next future. Moreover, data on long-term efficacy and safety coming from well-designed randomized multicenter controlled trials are still needed to bring EUS-guided procedures to the next level.


Enhanced macrophage delivery to the colon using magnetic lipoplexes with a magnetic field.
Magnetically guided cell delivery systems would be valuable to achieve effective macrophage-based cell therapy for colonic inflammatory diseases. In the current study, we developed a method for the efficient and simultaneous introduction of superparamagnetic iron oxide nanoparticles (SPIONs) and plasmid DNA (pDNA) into RAW264 murine macrophage-like cells using SPION-incorporated cationic liposome/pDNA complexes (magnetic lipoplexes). SPIONs and pDNA were introduced for magnetization and functionalization of the macrophages, respectively. We also evaluated the adhesive properties of magnetized RAW264 cells using magnetic lipoplexes in the murine colon under a magnetic field. Significant cellular association and gene expression without cytotoxicity were observed when magnetic cationic liposomes and pDNA were mixed at a weight ratio of 10:1, and SPION concentration and magnetic field exposure time was 0.1 mg/mL and 10 min, respectively. We also observed that cytokine production in magnetized RAW264 cells was similar to that in non-treated RAW264 cells, whereas nitric oxide production was significantly increased in magnetized RAW264 cells. Furthermore, magnetized RAW264 cells highly adhered to a Caco-2 cell monolayer and colon in mice, under a magnetic field. These results suggest that this magnetic cell delivery system can improve the colonic delivery of macrophages and its therapeutic efficacy against colonic inflammatory diseases.


"Enteric Tears": Chloride Secretion and Its Neural Regulation.
Neural reflex circuits within the submucosal plexus and axon reflexes via extrinsic primary afferents control chloride secretion by intestinal epithelial cells. The regulation of chloride secretion is a complex interplay between excitatory and inhibitory influences from neurotransmitters and chemical messengers released from epithelial, endocrine, and immune cells.


Nuclear factor (erythroid-derived 2)-like 2 activation-induced hepatic very-low-density lipoprotein receptor overexpression in response to oxidative stress contributes to alcoholic liver disease in mice.
Chronic alcohol consumption leads to hypertriglyceridemia, which is positively associated with alcoholic liver disease (ALD). However, whether and how it contributes to the development of fatty liver and liver injury are largely unknown. In this study we demonstrate that chronic alcohol exposure differently regulates the expression of very-low-density lipoprotein receptor (VLDLR) in adipose tissue and the liver. Whereas adipose tissue VLDLR is significantly down-regulated, its hepatic expression is dramatically increased after chronic alcohol feeding. While HepG2 cells stably overexpressing VLDLR manifests increased intracellular triglyceride accumulation, VLDLR-deficient mice are protective against fatty liver and liver injury after chronic alcohol exposure. Mechanistic investigations using both in vitro and in vivo systems reveal that oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation plays a critical role in alcohol-induced VLDLR up-regulation in hepatocytes, but not in adipocytes. Oxidative stress enhances VLDLR gene expression and protein abundance in primary hepatocytes, concomitant with the Nrf2 activation. Conversely, Nrf2 gene silencing abrogates oxidative stress-induced VLDLR up-regulation in the liver, but not in adipose tissue. In mice, alcohol exposure induces hepatic oxidative stress and Nrf2 activation. Supplementation of N-acetylcysteine alleviates fatty liver and liver injury induced by chronic alcohol exposure, which is associated with suppressed Nrf2 activation and attenuated VLDLR increase in the liver. Furthermore, in comparison to wild-type counterparts, Nrf2-deficient mice demonstrate attenuated hepatic VLDLR expression increase in response to chronic alcohol exposure. Chronic alcohol consumption differently alters VLDLR expression in adipose tissue and the liver. Oxidative stress-induced Nrf2 activation is mechanistically involved in VLDLR overexpression in hepatocytes in response to chronic alcohol consumption. Hepatic VLDLR overexpression plays an important role in the pathogenesis of ALD.


Non-phospholipid fusogenic liposomes.
We have demonstrated the capacity of non-phospholipid liposomes composed primarily of dioxyethylene acyl ethers and cholesterol to fuse with membranes composed primarily of phospholipid. Phase-contrast microscopy, freeze-fracture electron microscopy and a macromolecular probe indicate that these non-phospholipid liposomes can fuse with the plasma membranes of erythrocytes and fibroblasts. Furthermore, fluorescence probe experiments have demonstrated fusion between phosphatidylcholine liposomes and non-phospholipid liposomes. Mixing of internal contents was shown by a terbium/dipicolinate assay. Mixing of membrane lipid components was demonstrated by measuring (i) fluorescence resonance energy transfer between N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)phosphatidylethanolamine and N-(lissamine rhodamine B sulfonyl)phosphatidylethanolamine, after phosphatidylcholine liposomes were mixed with non-phospholipid liposomes, and (ii) reduced concentration quenching of rhodaminephosphatidylethanolamine and octadecylrhodamine incorporated into phosphatidylcholine liposomes after mixing with the non-phospholipid liposomes. The degree of apparent fusion reported by the different probe techniques ranged from 25% to 64%.


[Intestinal spirochetosis in HIV infection: prevalence, isolation and morphology of spirochetes].
The prevalence of intestinal spirochaetosis was investigated in 39 HIV-positive homosexual males (mean age 39 [24-65] years) in different stages of HIV infection (3 with the lymphadenopathy syndrome, 8 with AIDS-related complex and 28 with AIDS). Biopsies for cultural and histological demonstration of spirochaetes were obtained during routine ileoscopies. At the time of examination 35 of the 39 patients had intestinal symptoms. 27 patients had had no previous antimicrobial treatment. In 12 of the 27 previously untreated patients with intestinal symptoms spirochaetes were demonstrated, to different extent, from the terminal ileum to the rectum, while the treated group of eight and the control group of four were negative. There were no significant inflammatory changes histologically. Treatment with metronidazole in most cases improved symptoms. In their ultrastructure the microorganisms showed several complete convolutions, cone-shaped cell endings, cell length of 4-18 microns, cell diameter of 0.21-0.35 microns and five subterminal flagella. Morphological considerations favour the inclusion of these microorganisms in the genus Treponema rather than Brachyspira.


An Australasian model license reassessment procedure for identifying potentially unsafe drivers.
Most licensing jurisdictions in Australia currently employ age-based assessment programs as a means to manage older driver safety, yet available evidence suggests that these programs have no safety benefits. This paper describes a community referral-based model license re assessment procedure for identifying and assessing potentially unsafe drivers. While the model was primarily developed for assessing older driver fitness to drive, it could be applicable to other forms of driver impairment associated with increased crash risk. It includes a three-tier process of assessment, involving the use of validated and relevant assessment instruments. A case is argued that this process is a more systematic, transparent and effective process for managing older driver safety and thus more likely to be widely acceptable to the target community and licensing authorities than age-based practices.


Measuring muscle blood flow: a key link between systemic and regional metabolism.
To provide a brief overview of the main techniques to measure muscle blood flow in humans and highlight some of the strengths and weaknesses associated with each technique. Peak muscle blood flow values of 300 ml/min per 100 g are possible in humans during heavy exercise performed with small muscle mass. This value is far higher than that which appears in most textbooks. Accurate and reliable techniques are therefore essential in measuring muscle blood flow. Current invasive techniques commonly used include indicator dilution (thermodilution and dye dilution) and radiolabel tracer washout (e.g. 133Xe washout) methods. Although invasive techniques have provided valuable insight into tissue blood flow, noninvasive techniques such as venous occlusion plethysmography and Doppler ultrasound are frequently used and provide accurate measurements of blood flow. Newer imaging techniques (MRI, positron emission tomography, and contrast-enhanced ultrasonography) promise increased resolution of measurements of local blood flow, including in discrete tissues in which more classical techniques are not able to be used. Muscle blood flow is a key link in the interplay and regulation of systemic and local muscle metabolism. Recognizing the advantages and limitations of each technique is essential to translational researchers studying the effects of nutrition and metabolism on muscle blood flow.


Morphometric characteristics and reproductive capacity of nuclear transplants derived from embryonic cells of loach, Misgurnus anguillicaudatus.
Nuclear transplants of loach were produced by transplantating blastula cell nuclei into nonenucleated unfertilized eggs, using recipient eggs and donor cells distinguished by different polymorphic microsatellites. Of the total of 2,847 operated eggs, 143 hatched and 119 developed to the feeding larval stage. For 15 nuclear transplants (i.e., 11.1-year-old fish and 4.2-year-old fish) that survived up to the adulthood, DNA analysis and karyotype analysis were performed. Results showed that, of the 15 fish, 14 had only a nucleus derived from the donor; moreover, 12 were diploids, 1 was a triploid, 1 was a tetraploid, and 1 was a diploid-tetraploid mosaic with both donor and recipient nuclei. For the 12 fish with only a 2n donor nucleus, morphometric analysis was performed, and two female fish and two male fish were mated with normal fish. The fish with only a 2n donor nucleus were determined to be morphometrically identical to normal fish: they had normal gametogenesis and were able to reproduce. Currently, nuclear transplantation technology is beginning to be adopted in fisheries. Biological information on nuclear transplants obtained in this study can be used in the development of nuclear transplantation technology.


Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families.
Hereditary nonpolyposis colorectal cancer is caused by germline mutations in DNA mismatch repair genes. Mutation carriers have a 60 to 85 percent risk of developing colorectal cancer. In the Netherlands hereditary nonpolyposis colorectal cancer families are monitored in an intensive surveillance program. The aim of this study was to examine the stage of the screening-detected tumors in relation to the surveillance interval and to assess the risk of developing colorectal cancer while on the program. The Dutch hereditary nonpolyposis colorectal cancer family registry was used. A total of 114 families had a mismatch repair gene defect and/or met the clinical criteria for hereditary nonpolyposis colorectal cancer. The interval between surveillance and colorectal cancer was investigated in initially healthy family members who underwent at least one surveillance examination without showing evidence for colorectal cancer (surveillance group) and in family members who previously underwent partial or subtotal colectomy for colorectal cancer. The risk of colorectal cancer was calculated for proven mutation carriers (surveillance group) and for putative carriers after partial or subtotal colectomy. A total of 35 cancers were detected while on the program. With intervals between colorectal cancer and the preceding surveillance examination of two years or less, tumors were at Dukes Stage A (n = 4), B (n = 11), and C (1). With intervals of more than two years, tumors were at Dukes Stage A (n = 3), B (n = 10), and C (n = 6). The 10-year cumulative risk of developing colorectal cancer was 10.5 (95 percent confidence interval, 3.8-17.2) percent in proven mutation carriers, 15.7 (95 percent confidence interval, 4.1-27.3) percent after partial colectomy, and 3.4 percent after subtotal colectomy. There is a substantial risk of developing colorectal cancer while on the program. However, all tumors but one of subjects who underwent a surveillance examination two years or less before detection were at a local stage. We recommend surveillance for hereditary nonpolyposis colorectal cancer with an interval of two years or less.


Specificity for in vivo graft prolongation in gamma delta T cell receptor+ hybridomas derived from mice given portal vein donor-specific preimmunization and skin allografts.
gamma delta TCR+ hybridoma cells prepared from mesenteric lymph node cells of animals receiving donor-specific immunization via the portal vein can adoptively transfer this increased graft survival to naive animals. Analysis of TCR gamma-chain junctional sequence diversity suggested that some 40 to 50% of the hybridomas expressed gamma-chain junctional sequence diversity and were stimulated to produce cytokines both by heat shock proteins and by minor histocompatibility Ag-specific irradiated peritoneal cells. The remaining gamma delta TCR+ hybridoma cells expressed TCR with a common gamma-chain junctional sequence and were stimulated to cytokine production by MHC-matched, but minor histocompatibility Ag-mismatched (as well as matched), peritoneal cells, but not by heat shock proteins. We have compared the effectiveness of representative hybridomas expressing unique gamma-chain junctional sequences or common gamma-chain junctional sequences for prolongation of donor-specific or third-party (MHC-matched or MHC-mismatched) skin grafts. Our data show a good correlation between the specificity for stimulation for cytokine production in vitro and efficacy in graft prolongation assays in vivo. Hybridoma cells expressing unique gamma-chain junctional sequences that showed Ag-specific stimulation of cytokine production in vitro and skin graft survival in vivo augmented survival of third-party skin grafts if simultaneously transplanted with both Ag-specific and third-party skin grafts. Graft prolongation in vivo using cells from either population of gamma delta TCR+ hybridomas was decreased by infusion of anti-IL-10 mAb and abolished when both anti-IL-10 and anti-TGF-beta Abs were used together.


Early growth response 1 (EGR1): a gene with as many names as biological functions.
Although most researchers in biology tend to focus on very specific issues and questions about their preferred gene or pathway, sometimes we face situations in which nature presents us with a remarkable example of a gene with multiple functions. Since the discovery of the early growth response 1 (EGR1) gene in the mid eighties, several independent groups attributed its activation as an immediate early response gene to extracellular stimuli such as environmental cues, growth factors, irradiation and small molecules. Even twenty-plus years after its initial cloning and characterization, EGR1 continues to attract considerable attention among biological circles. Recently, work by Wagers and colleagues reported yet another novel and rather promising function for EGR1. They demonstrated that EGR1 is involved in regulating homeostasis of hematopoietic stem cells (HSC) by coordinating proliferation and migration. Importantly, this finding allows a conduit by which manipulation of this pathway will elucidate further understanding of the biology driving HSC mobilization and transplantation in a clinical setting.


Effect of increasing dietary vitamin A on bone density in adult dogs.
There has been an increase in vitamin A fortification of livestock feeds resulting in increased residual vitamin A in organ meats, which are often used in canned dog foods. The effect on bone density of feeding various concentrations of vitamin A in a canned dog food product was investigated. Thirty-two random-source dogs were assigned to four treatments in a randomized complete block design. The diets contained 15,000, 50,000, 116,000, or 225,000 IU vitamin A/1,000 kcal ME. Diets were fed up to 1 yr. Computed tomography was used to determine bone density of the right tibia at 0, 3, 6, 9, and 12 mo. Computed tomography is a more sensitive technique for determining bone density in vivo than conventional x-rays. There were no differences (P > .10) in tibia bone or marrow density in any of the dogs fed the various concentrations of vitamin A. There was no interaction of time x diet on bone density (P > .05) or bone marrow density (P > .05). In addition, there were no changes in serum alkaline phosphatase, calcium, or phosphorus. These results indicate that concentrations of vitamin A three times the recommended maximum safe amount (71,429 IU/1,000 kcal ME) are not detrimental to normal bone health in dogs. Therefore, these data support the hypothesis that canines are less sensitive to excess vitamin A in the diet than some other mammals.


Saving the ground beneath our feet: Establishing priorities and criteria for governing soil use and protection.
The continual loss and impairment of soil ecosystem services (SES) across the globe calls for a fundamental reconsideration of soil governance mechanisms. This critical synthesis charts the history and evolution of national and international soil law and seeks to unravel certain challenges that have contributed to this failure in governance. It describes and categorizes law and policy responses to different soil threats, and identifies a worrying widespread absence of legislation for oversight and protection of agricultural soils from urbanization, as well as a lack of clear legal mechanisms to determine national priorities for soil protection. A reduction in the world's prime farmland threatens SES, including food security, carbon storage and biodiversity. Falling between the stalls of agricultural and environmental law, the fate of farmland is often left to planners who do not see themselves as responsible for soils. Consequently, legal instruments with the greatest power to affect soil, sometimes irreversibly, are often framed and worded with little or no reference to the soil. Nevertheless, emerging conceptual frameworks might offer positive outcomes. The authors advocate robust holistic policies of soil governance and land use planning that place SES and natural capital at the heart of decision making.


Bone marrow cells other than stem cells seed the bone marrow after rescue transfusion of fatally irradiated mice.
In a previous publication, iodinated deoxyuridine (125IUdR) incorporation data were interpreted as indicating that spleen colony-forming units (CFU-S) in DNA synthesis preferentially seeded bone marrow. In the present studies, the CFU-S content of marrow from irradiated, bone-marrow transfused mice was directly determined. Pretreatment of the transfused cells with cytocidal tritiated thymidine resulted in an insignificant diminution in CFU-S content when compared with nontritiated thymidine pretreatment, implying that there is no preferential seeding. The 125IUdR incorporation data have been reinterpreted as being a result of the proliferation of other progenitor cells present that have seeded the bone marrow.


The effect of treadmill training pre-exercise on glutamate receptor expression in rats after cerebral ischemia.
Physical exercise has been demonstrated to be neuroprotective in both clinical and laboratory settings. However, the exact mechanism underlying this effect is unclear. Our study aimed to investigate whether pre-ischemic treadmill training could serve as a form of ischemic preconditioning in a rat model undergoing middle cerebral artery occlusion (MCAO). Thirty-six rats were divided into three groups: a sham control group, a non-exercise with operation group and an exercise with operation group. After treadmill training, ischemia was induced by occluding the MCA for 2 h, followed by reperfusion. Half of the rats in each group were sacrificed for mRNA detection of mGluR5 and NR2B 80 min after occlusion. The remaining animals were evaluated for neurological deficits by behavioral scoring and then decapitated to assess the infarct volume. The mRNA expression of mGluR5 and NR2B was detected by real-time PCR. The results suggest that pre-ischemic treadmill training may induce brain ischemic tolerance by reducing the mRNA levels of mGluR5 and NR2B, and thus, the results indicate that physical exercise might be an effective method to establish ischemic preconditioning.


CO(2) capture properties of alkaline earth metal oxides and hydroxides: A combined density functional theory and lattice phonon dynamics study.
By combining density functional theory and lattice phonon dynamics, the thermodynamic properties of CO(2) absorption/desorption reactions with alkaline earth metal oxides MO and hydroxides M(OH)(2) (where M=Be,Mg,Ca,Sr,Ba) are analyzed. The heats of reaction and the chemical potential changes of these solids upon CO(2) capture reactions have been calculated and used to evaluate the energy costs. Relative to CaO, a widely used system in practical applications, MgO and Mg(OH)(2) systems were found to be better candidates for CO(2) sorbent applications due to their lower operating temperatures (600-700 K). In the presence of H(2)O, MgCO(3) can be regenerated into Mg(OH)(2) at low temperatures or into MgO at high temperatures. This transition temperature depends not only on the CO(2) pressure but also on the H(2)O pressure. Based on our calculated results and by comparing with available experimental data, we propose a general computational search methodology which can be used as a general scheme for screening a large number of solids for use as CO(2) sorbents.


Prevention of infective endocarditis: a review of the American Heart Association guidelines.
Ever since the last American Heart Association (AHA) publication on prevention of infective endocarditis (IE) many medical societies and physicians have questioned the efficacy of prophylaxis in patients that undergo a dental, genitourinary (GU) or gastrointestinal (GI) procedures. In 1997 AHA recognize that most cases of IE were not related to invasive procedures but as a result of arbitrarily occurring bacteremia from routine daily activities as well as recognition of the possibility of IE prophylaxis failure. This assumptions as well as review of numerous published studies over the past two decades caused that AHA to revise the guidelines of 1997. Based on published series this new guidelines identify the following underlying cardiac conditions with an increase risk of IE and are the ones in which prophylaxis is recommended. They include (1) prosthetic cardiac valve or prosthetic material used for cardiac valve repair, (2) previous IE, (3) Congenital Heart Disease (CHD) including unrepaired cyanotic as well as palliative shunts and conduits, completely repaired congenital heart defect with prosthetic material or device during the first six months after the procedure, repaired CHD with residual defects and (4) cardiac transplantation recipients who develop cardiac valvulopathy. All dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa will require IE prophylaxis. Patients that undergo respiratory tract procedure that involves incision or biopsy of the respiratory mucosa will also required IE prophylaxis. In contrast to previous AHA guidelines, antibiotic prophylaxis to prevent IE is not recommended for GU or GI procedures. First line therapy recommended includes amoxicillin or ampicillin and if allergic to penicillin, clindamycin 600 mg or azithromycin 500 mg. Antibiotics should be administered in a single dose before the procedure, but the dosage may be administered up to two hours after procedure. This new AHA recommendation are more clear for healthcare providers regarding to which patient should undergo prophylaxis in comparison with previous ones and are expected to reduce antibiotic resistance that increased during the past years as a result of previous antibiotic prophylaxis for IE.


Integrative physiological study of adaptations induced by aerobic physical training in hypertensive hearts.
Aerobic physical training reduces arterial pressure in patients with hypertension owing to integrative systemic adaptations. One of the key factors is the decrease in cardiac sympathetic influence. Thus, we hypothesized that among other causes, cardiac sympathetic influence reduction might be associated with intrinsic cardiac adaptations that provide greater efficiency. Therefore, 14 spontaneously hypertensive rats (SHR group) and 14 normotensive Wistar Kyoto rats (WKY group) were used in this study. Half of the rats in each group were trained to swim for 12 weeks. All animals underwent the following experimental protocols: double blockade of cardiac autonomic receptors with atropine and propranolol; echocardiography; and analysis of coronary bed reactivity and left ventricle contractility using the Langendorff technique. The untrained SHR group had a higher sympathetic tone, cardiac hypertrophy, and reduced ejection fraction compared with the untrained WKY group. In addition, reduced coronary bed reactivity due to increased flow, and less ventricular contractile response to dobutamine and salbutamol administration were observed. The trained SHR group showed fewer differences in echocardiographic parameters as the untrained SHR group. However, the trained SHR group showed a reduction in the cardiac sympathetic influence, greater coronary bed reactivity, and increased left intraventricular pressure. In conclusion, aerobic physical training seems to reduce cardiac sympathetic influence and increase contractile strength in SHR rats, besides the minimal effects on cardiac morphology. This reduction suggests intrinsic cardiac adaptations resulting in beneficial adjustments of coronary bed reactivity associated with greater left ventricular contraction.


Investigation of volatiles evolution during the alcoholic fermentation of grape must using free and immobilized cells with the help of solid phase microextraction (SPME) headspace sampling.
A biocatalyst was prepared by immobilization of Saccharomyces cerevisiae strain AXAZ-1 on delignified cellulosic material (DCM). Repeated batch fermentations were conducted using these biocatalysts and free cells, separately, at temperatures of 20, 15, and 10 degrees C. Solid phase microextraction (SPME) was used in monitoring the formation of volatile alcohols, acetate esters, and ethyl esters of fatty acids. The kinetics of volatile production were similar for free and immobilized cells. In all cases immobilized cells showed a better rate of volatile production, which was directly connected to sugar consumption. The main difference observed was in propanol production, which increased with temperature decrease for the immobilized cells, whereas it remained constant for the free ones. In the case of immobilized cells significant amounts of esters were also produced. It is well-known that esters contribute to the fruity aroma of wine. It was also established that SPME is a very sensitive, accurate, and reliable technique and can be used without any reservation in the characterization of volatile constituents of wine.


Fast recovery, high sensitivity NMR probe and preamplifier for low frequencies.
The design of a probe-preamplifier combination which reduces the NMR receiver recovery time following a pulse by a factor of at least twenty at 5 MHz is described. The preamplifier, which has a noise figure of 1.3 dB, employs negative feedback to damp the probe coil (a typical effective Q is 7), but maintains the signal-to-noise ratio that one would expect from an undamped coil. In addition, the use of a short phase-inverted pulse following the main transmitter pulse serves to reduce drastically the ring-down of the probe for those high voltages where the preamplifier is inoperative. Optimum utilization of transmitter power in achieving fast pulse rise times is also discussed, as well as elimination of ''phase-glitch'' by proper tuning and the use of a broadband transmitter.


Viagra releases the brakes on melanoma growth.
Use of the phosphodiesterase 5 (PDE5) blocker sildenafil (Viagra) has been linked to an increased risk of melanoma. In a recent study we discovered a growth-promoting cGMP pathway in melanoma cells. cGMP degradation via PDE5 acts as a brake on this pathway. Inhibition of PDE5 releases this brake, providing a mechanism for the promelanoma effects of sildenafil.


The role of midwifery associations in the professional development of midwifery.
Midwifery associations have an important role in several subjects such as professionalisation, developing neonatal health, reducing maternal-fetal mortality, planning labor, professional recognition, planning legislative regulations, developing the profession, and offering quality birth services. The purpose of this study is to explain the contributions of well-known midwifery associations in the world, and in particular in Turkey, to the professional development of midwifery, as well as similarities of midwifery associations in Turkey with other associations, including the position of Turkey in associationalism. The associations have enabled the profession of midwifery to progress, gain autonomy, be legally protected and become more professional. In order for the associations in Turkey to operate effectively, it is recommended that their membership is increased so as to represent more midwives and thus gain more political power and to advance evidence-based applications in midwifery care.


Multiresidue analysis of 59 nonallowed substances and other contaminants in cosmetics.
A method was developed for the determination of 59 glucocorticoids, sex hormones, nonsteroidal anti-inflammatory drugs, antibiotics, and other contaminants in cosmetics simultaneously by ultra high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Acetonitrile was used to extract the sample, and the mixed sorbents were dispersed for purification. With the optimal conditions, the optimized pretreatment processes led to no significant interference on analysis from an extremely complicated sample matrix, and the linear ranges of 59 analytes were 0-480.0 μg/kg with the correlation coefficients above 0.99 and the limits of quantification (S/N≥10) were 5-40 μg/kg. Statistical evaluation revealed that the average recoveries were in the range of 61.2-131.2%, and relative standard deviations were in the range of 2.0-22.8%, meanwhile the interday precision ranged from 3.8 to 21.8%. This method is simple, fast, and credible, and it can be applied to simultaneous screening and determination of various classes of substances under investigations illegally presented in cosmetic products, covering a wide diversity of polarities, and pKa values.


Association between secondhand smoke exposure and blood lead and cadmium concentration in community dwelling women: the fifth Korea National Health and Nutrition Examination Survey (2010-2012).
To assess the association between secondhand smoke exposure and blood lead and cadmium concentration in women in South Korea. Population-based cross-sectional study. South Korea (Korea National Health and Nutrition Examination Survey V). 1490 non-smoking women who took part in the fifth Korea National Health and Nutrition Examination Survey (2010-2012), in which blood levels of lead and cadmium were measured. The primary outcome was blood levels of lead and cadmium in accordance with the duration of secondhand smoke exposure. The adjusted mean level of blood cadmium in women who were never exposed to secondhand smoke was 1.21 (0.02) µg/L. Among women who were exposed less than 1 h/day, the mean cadmium level was 1.13 (0.03) µg/L, and for those exposed for more than 1 h, the mean level was 1.46 (0.06) µg/L. In particular, there was a significant association between duration of secondhand smoke exposure at the workplace and blood cadmium concentration. The adjusted mean level of blood cadmium concentration in the never exposed women's group was less than that in the 1 h and more exposed group, and the 1 h and more at workplace exposed group: 1.20, 1.24 and 1.50 µg/L, respectively. We could not find any association between lead concentration in the blood and secondhand smoke exposure status. This study showed that exposure to secondhand smoke and blood cadmium levels are associated. Especially, there was a significant association at the workplace. Therefore, social and political efforts for reducing the exposure to secondhand smoke at the workplace are needed in order to promote a healthier working environment for women.


Attempts to switch the writing hand: relationships to age and side of hand preference.
The recent suggestion that left-handedness is a mortality risk factor has prompted extensive media attention and has renewed research interest in generational differences in hand preference incidence and training. It is argued that differential generational training effects (the modification hypothesis), rather than decreased survival fitness (the elimination hypothesis), account for the lower numbers of individuals classified as left-handers in contemporary samples over the age of 60 years. A total of 633 individuals (aged 13-83 years) were queried about attempts to switch hand preference. Forty-one (6.5%) described efforts to shift preference in the rightward direction; of these, 21 (3.3%) reported attempted rightward writing hand shifts. The percentage of older adult left-handers, who reported right shifts in writing, was greater than the percentage of younger left-handers who described such attempts. Comparisons between the group reporting right shifts and those reporting no shift experiences suggested that the age-related decrease in leftward preference was specific to a decrease in the incidence of left-hand writing among older adults.


Heart rate variability and ventricular arrhythmia in clinically stable patients with hypertrophic cardiomyopathy.
To investigate whether autonomic nervous dysfunction exists and to determine the relationship between autonomic nervous activity and ventricular arrhythmias in clinically stable patients with hypertrophic cardiomyopathy (HCM), we studied heart rate variability (HRV) in 21 patients with HCM and 10 age-matched healthy control subjects. Patients were divided into 2 groups: HCM I (14 patients without nonsustained ventricular tachycardia, defined as 3 or more consecutive ventricular premature beats) and HCM II (7 patients with nonsustained ventricular tachycardia). HRV was measured on 24-h ECG monitorings using both nonspectral and spectral methods (fast Fourier transform, FFT). We assessed autonomic nervous activity based on high-frequency (HF; 0.15-0.40 Hz, an index of parasympathetic nervous activity) and the low- to high-frequency power ratio (L/H ratio; an index of sympathetic nervous activity) during daytime and night-time separately. There were no significant differences in any index of HRV between the HCM I and control groups. HF in the HCM II group was significantly lower than that of both the HCM I and control groups during the day and at night, whereas the L/H ratio at night-time was significantly higher in the HCM II group than in the HCM I and control groups. These data demonstrate that, in clinically stable HCM patients without nonsustained ventricular tachycardia, autonomic nervous activity was not different to that of healthy control subjects, whereas in HCM patients with nonsustained ventricular tachycardia, parasympathetic nervous activity was reduced throughout the 24-h period, and sympathetic nervous activity at night was increased compared with healthy control subjects. Thus, HCM patients with nonsustained ventricular tachycardia have to be treated even if they do not exhibit significant clinical manifestation.


Human parathyroid hormone (PTH)-related protein and human PTH: comparative biological activities on human bone cells and bone resorption.
Human PTH-related protein (hPTHrP) has been characterized as a product of tumor cells with sequence homology to the biologically active amino-terminal portion of human PTH (hPTH). We measured the relative activities of synthetic amino-terminal sequences of hPTH-(1-34) and hPTHrP-(1-34) to stimulate production of cAMP in intact human SaOS-2 osteosarcoma cells. Both peptides enhanced cAMP production at concentrations of 2.5-7.5 X 10(-10) M, had parallel dose-response curves, and were of essentially equal potency. Preincubation of SaOS-2 cells with hPTH-(1-34) or hPTHrP-(1-34) for 1 or 4 h induced homologous desensitization to a second challenge with the same peptide as well as heterologous desensitization to the other PTH peptide, but had little or no effect on the action of vasoactive intestinal peptide; the magnitudes of homologous and heterologous desensitization induced by the same doses of hPTHrP-(1-34) or hPTH-(1-34) were similar. Bone resorption-stimulating activity was measured using 40Ca2+ release from neonatal mouse calvariae in organ culture after 72 h of incubation. hPTHrP-(1-34) gave a dose-response between 0.2 and 5 ng/ml (5 X 10(-11) and 1.2 X 10(-9) M), was about 3 times more potent than Lilly bovine PTH standard (assuming a SA of 3000 U/mg; 100 U/ml), gave the same maximum response as hPTH-(1-34), and was 20-30% as potent as hPTH-(1-34). Neither hPTH-(1-34) nor hPTHrP-(1-34) enhanced prostaglandin production in mouse calvariae, and indomethacin did not inhibit the bone resorption-stimulating activities of either peptide. We conclude that hPTHrP-(1-34) and hPTH-(1-34) have similar high specific biological activities to stimulate production of cAMP in human osteoblast-like cells, but that hPTHrP-(1-34) is modestly less potent than hPTH-(1-34) to stimulate bone resorption in mouse calvariae.


Co-overexpression of Met and hepatocyte growth factor promotes systemic metastasis in NCI-H460 non-small cell lung carcinoma cells.
Complete resection of early-stage non-small cell lung cancer (NSCLC) is potentially curative, yet approximately 50% of patients are at risk for developing metastatic recurrence. Met, the receptor for hepatocyte growth factor (HGF) is a receptor tyrosine kinase with demonstrated roles in regulating cellular proliferation, motility, morphogenesis, and apoptosis. Met receptor and its ligand, HGF, are commonly overexpressed in NSCLC, and their overexpression has been associated with poor prognosis, which could potentially involve a paracrine and/or autocrine activation loop. However, there is as yet no direct evidence that HGF-Met signaling directly promotes metastasis in NSCLC cells. Using retroviral transduction, we overexpressed the human c-met and hgf complementary DNA, alone or in combination in the NCI-H460 human large cell carcinoma cell line. The HGF/Met co-overexpressing (H460-HGF/Met) cells demonstrated enhanced tumorigenicity in xenograft SCID mice. When these cells are implanted orthotopically into the lungs of nude rats, only the H460-HGF/Met cells showed higher spontaneous metastases to distant organs including bone, brain, and kidney. These results provide evidence that autocrine overactivation of the Met- HGF loop enhances systemic metastases in NSCLC. Targeted interference of this loop may potentially be an effective adjuvant therapy to improve survival of early-stage NSCLC patients.


A fluorescent reporter reveals on/off regulation of the Shigella type III secretion apparatus during entry and cell-to-cell spread.
Numerous pathogenic Gram-negative bacteria use a type three secretion apparatus (T3SA) to translocate effector proteins into host cells. Detecting and monitoring the T3SA of intracellular bacteria within intact host cells has been challenging. Taking advantage of the tight coupling between T3S effector-gene transcription and T3SA activity in Shigella flexneri, together with a fast-maturing green fluorescent protein, we developed reporters to monitor T3SA activity in real time. These reporters reveal a dynamic temporal regulation of the T3SA during the course of infection. T3SA is activated initially during bacterial entry and downregulated subsequently when bacteria gain access to the host cell cytoplasm, allowing replenishment of the bacterial stores of T3S substrates necessary for invading neighboring cells. Reactivation of the T3SA was strictly dependent on actin-based motility and formation of plasma membrane protrusions during cell-to-cell spread. Thus, the T3SA is subject to a tight on/off regulation within the bacterial intracellular niche.


Combined magnetic resonance imaging and spectroscopic imaging approach to molecular imaging of prostate cancer.
Magnetic resonance spectroscopic imaging (MRSI) provides a noninvasive method of detecting small molecular markers (historically the metabolites choline and citrate) within the cytosol and extracellular spaces of the prostate, and is performed in conjunction with high-resolution anatomic imaging. Recent studies in pre-prostatectomy patients have indicated that the metabolic information provided by MRSI combined with the anatomical information provided by MRI can significantly improve the assessment of cancer location and extent within the prostate, extracapsular spread, and cancer aggressiveness. Additionally, pre- and post-therapy studies have demonstrated the potential of MRI/MRSI to provide a direct measure of the presence and spatial extent of prostate cancer after therapy, a measure of the time course of response, and information concerning the mechanism of therapeutic response. In addition to detecting metabolic biomarkers of disease behavior and therapeutic response, MRI/MRSI guidance can improve tissue selection for ex vivo analysis. High-resolution magic angle spinning ((1)H HR-MAS) spectroscopy provides a full chemical analysis of MRI/MRSI-targeted tissues prior to pathologic and immunohistochemical analyses of the same tissue. Preliminary (1)H HR-MAS spectroscopy studies have already identified unique spectral patterns for healthy glandular and stromal tissues and prostate cancer, determined the composition of the composite in vivo choline peak, and identified the polyamine spermine as a new metabolic marker of prostate cancer. The addition of imaging sequences that provide other functional information within the same exam (dynamic contrast uptake imaging and diffusion-weighted imaging) have also demonstrated the potential to further increase the accuracy of prostate cancer detection and characterization.