Control of HIF-1{alpha} and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock.
Lung development requires coordinated signaling between airway and vascular growth, but the link between these processes remains unclear. Mammalian target of rapamycin complex-1 (mTORC1) can amplify hypoxia-inducible factor-1α (HIF-1α) vasculogenic activity through an NH(2)-terminal mTOR binding (TOS) motif. We hypothesized that this mechanism coordinates vasculogenesis with the fibroblast growth factor (FGF)-10/FGF-receptor2b/Spry2 regulator of airway branching. First, we tested if the HIF-1α TOS motif participated in epithelial-mesenchymal vascular signaling. mTORC1 activation by insulin significantly amplified HIF-1α activity at fetal Po(2) (23 mmHg) in human bronchial epithelium (16HBE14o-) and induced vascular traits (Flk1, sprouting) in cocultured human embryonic lung mesenchyme (HEL-12469). This enhanced activation of HIF-1α by mTORC1 was abolished on expression of a HIF-1α (F99A) TOS-mutant and also suppressed vascular differentiation of HEL-12469 cocultures. Next, we determined if vasculogenesis in fetal lung involved regulation of mTORC1 by the FGF-10/FGFR2b/Spry2 pathway. Fetal airway epithelium displayed distinct mTORC1 activity in situ, and its hyperactivation by TSC1(-/-) knockout induced widespread VEGF expression and disaggregation of Tie2-positive vascular bundles. FGF-10-coated beads grafted into fetal lung explants from Tie2-LacZ transgenic mice induced localized vascular differentiation in the peripheral mesenchyme. In rat fetal distal lung epithelial (FDLE) cells cultured at fetal Po(2), FGF-10 induced mTORC1 and amplified HIF-1α activity and VEGF secretion without induction of ERK1/2. This was accompanied by the formation of a complex between Spry2, the cCBL ubiquitin ligase, and the mTOR repressor, TSC2, which abolished GTPase activity directed against Rheb, the G protein inducer of mTORC1. Thus, mTORC1 links HIF-1α-driven vasculogenesis with the FGF-10/FGFR2b/Spry2 airway branching periodicity regulator.


[Attitudes of Medical Students Towards Alcohol-Related Disorders: Dependent on Intended Medical Specialization?]
The aim of this study was to identify subjective attitudes of medical students towards alcohol-related disorders (ARD) compared to other mental and somatic disorders. Medical students taking part in an online survey (n = 1875) rated ARD less severe compared to other disorders (p < 0.001), had a greater wish for social distance towards those affected (p < 0.001), held them more responsible (p < 0.001), and chose ARD more often as a disorder with a potential for financial savings in the health care system. Prospective psychiatrists selectively reported an increased desire for social distance and readiness for structural discrimination in terms of ARD but not for mental disorders per se. Since these attitudes might have unfavorable effects on the medical-patient relationship, it is of importance to address this issue already during medicine studies.


Transcriptional initiation is controlled by upstream GC-box interactions in a TATAA-less promoter.
Numerous genes contain TATAA-less promoters, and the control of transcriptional initiation in this important promoter class is not understood. We have determined that protein-DNA interactions at three of the four proximal GC box sequence elements in one such promoter, that of the hamster dihydrofolate reductase gene, control initiation and relative use of the major and minor start sites. Our results indicate that although the GC boxes are apparently equivalent with respect to factor binding, they are not equivalent with respect to function. At least two properly positioned GC boxes were required for initiation of transcription. Abolishment of DNA-protein interaction by site-specific mutation of the most proximal GC box (box I) resulted in a fivefold decrease in transcription from the major initiation site and a threefold increase in heterogeneous transcripts initiating from the vicinity of the minor start site in vitro and in vivo. Mutations that separately abolished interactions at GC boxes II and III while leaving GC box I intact affected the relative utilization of both the major and minor initiation sites as well as transcriptional efficiency of the promoter template in in vitro transcription and transient expression assays. Interaction at GC box IV when the three proximal boxes were in a wild-type configuration had no effect on transcription of the dihydrofolate reductase gene promoter. Thus, GC box interactions not only are required for efficient transcription but also regulate start site utilization in this TATAA-less promoter.


Methylenetetrahydrofolate reductase 677C-->T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial.
Low folate status and elevated plasma homocysteine are associated with increased risk of neural tube defects and cardiovascular disease. Homocysteine responses to folate may be influenced by genetic variants in folate metabolism. We determined the effect of folate-enhancing dietary interventions on plasma folate and plasma total homocysteine (tHcy) with respect to the methylenetetrahydrofolate reductase 677C-->T genotype. A total of 126 healthy subjects (42 TT, 42 CT, and 42 CC genotypes) completed 3 dietary interventions (4 mo each) in random order: 1) exclusion diet (avoidance of folic acid-fortified foods and ingestion of a placebo daily), 2) folate-rich diet (increased intake of fortified and naturally folate-rich foods to achieve 400 microg folate/d), and 3) supplement (exclusion diet plus a folate supplement of 400 microg/d). Plasma folate was higher (P < or = 0.001) and plasma tHcy lower (P < or = 0.001) after the folate-rich and supplement interventions than after the exclusion diet. Plasma folate was significantly greater after supplementation than after the folate-rich diet, but there was no significant difference in tHcy concentration (P = 0.72). TT homozygotes had higher plasma tHcy (14.5 compared with 8.9 micromol/L, P < or = 0.001) and lower plasma folate (14.8 compared with 19.0 nmol/L, P < or = 0.01) than did subjects with the CC genotype after the exclusion diet. CT heterozygotes had intermediate concentrations. The trend toward higher tHcy in TT homozygotes persisted throughout the study but was less marked with increasing folate intake (TT compared with CC after supplementation, P = 0.097). A folate-rich diet including folic acid-fortified foods or low-dose supplements effectively increases folate status. TT homozygotes require higher folate intakes than do individuals with the CT or CC genotype to achieve similar tHcy concentrations but are responsive to folate intervention.


Detection of cytomegalovirus by in situ hybridisation and immunohistochemistry using new monoclonal antibody CCH2: a comparison of methods.
In situ hybridisation, immunohistochemistry, and morphological analysis for the detection of cytomegalovirus (CMV) were compared in routinely processed tissue sections from a patient with acquired immune deficiency syndrome (AIDS) and widespread CMV infection. Both in situ hybridisation and immunohistochemistry with the monoclonal antibody CCH2 labelled all "owl's eye" cells intensely and, in addition, nuclei of some morphologically normal cells. Quantitative evaluation of the results showed that in situ hybridisation and immunohistochemistry with CCH2 were considerably more sensitive than purely morphological analysis, particularly in tissues with only a few cells infected by CMV. It is further shown that immunohistochemistry with CCH2 detected a higher figure of CMV infected cells than in situ hybridisation. In conclusion, both in situ hybridisation and immunohistochemistry are rapid, sensitive, and specific methods for CMV detection. For routine purposes, however, immunohistochemistry seems to be more suitable.


Predictors of Recurrence and Patterns of Initial Failure in Localized Ewing Sarcoma: A Contemporary 20-Year Experience.
The majority of patients with localized Ewing sarcoma will remain disease-free long term, but for those who suffer recurrence, successful treatment remains a challenge. Identification of clinicopathologic factors predictive of recurrence could suggest areas for treatment optimization. We sought to describe our experience regarding predictors of recurrence and patterns of first failure in patients receiving modern systemic therapy for nonmetastatic Ewing sarcoma. The medical records of pediatric and adult patients treated for localized Ewing sarcoma between 1999 and 2019 at Johns Hopkins Hospital were retrospectively analyzed. Local control was surgery, radiotherapy, or both. Recurrence-free survival (RFS) was calculated using the Kaplan-Meier method. Univariable and multivariable Cox proportional-hazards modeling was performed to obtain hazard ratios (HR) for recurrence. In 94 patients with initially localized disease, there were 21 recurrences: 4 local, 14 distant, and 3 combined. 5-year and 10-year RFS were 75.6% and 70.5%, respectively. On multivariable analysis including age at diagnosis and tumor size, <95% tumor necrosis following neoadjuvant chemotherapy (NAC; HR 14.3, p = 0.028) and radiological tumor size change during NAC (HR 1.04 per 1% decrease in size change, p = 0.032) were independent predictors of recurrence. Among patients experiencing distant recurrence, pulmonary metastases were present in 82% and were the only identifiable site of disease in 53%. Poor pathologic or radiologic response to NAC is predictive of recurrence in patients with localized Ewing sarcoma. Suboptimal tumor size reduction following chemotherapy provides a means to risk-stratify patients who do not undergo definitive resection. Isolated pulmonary recurrence was a common event.


Intraoperative Capsule Rupture, Postoperative Chemotherapy, and Survival of Women With Stage I Epithelial Ovarian Cancer.
To examine the incidence and prognostic effects of intraoperative capsule rupture and to assess the effectiveness of postoperative chemotherapy for intraoperative tumor rupture in apparent stage I epithelial ovarian cancer. This is a society-based retrospective observational study in Japan that examined 15,163 women with stage IA-IC1 epithelial ovarian cancer who underwent primary surgical treatment between 2002 and 2015. Associations between intraoperative capsule rupture and cause-specific survival, and between postoperative chemotherapy and cause-specific survival among intraoperatively ruptured cases were examined by histology type (clear cell n=6,107, endometrioid n=3,910, mucinous n=3,382, and serous n=1,764). Clear cell histology had the highest risk of intraoperative capsule rupture (57.3%), followed by endometrioid (48.8%), serous (41.8%), and mucinous (32.0%) histologies (P<.001). On multivariable analysis, clear cell type exhibited the largest effect of intraoperative capsule rupture on cause-specific survival (adjusted hazard ratio [HR] 1.99, 95% CI 1.45-2.75), followed by serous (adjusted HR, 1.61, 95% CI 0.84-3.11), mucinous (adjusted HR 1.28, 95% CI 0.79-2.09), and endometrioid (adjusted HR, 1.14, 95% CI 0.64-2.01) tumors. Postoperative chemotherapy for intraoperatively ruptured cases did not improve cause-specific survival in any histologic types in multivariable analysis: clear cell, adjusted HR 0.86, 95% CI 0.56-1.31; serous, adjusted HR 1.08, 95% CI 0.42-2.74; mucinous, adjusted HR 1.11, 95% CI 0.55-2.27; and endometrioid, adjusted HR 2.81, 95% CI 0.85-9.30 (all, P>.05). In the cohort-level analysis of ruptured cases (n=7,227), postoperative chemotherapy use has significantly decreased in mucinous (16.3% relative decrease), endometrioid (13.1% relative decrease), and clear cell (9.3% relative decrease) (all, P<.05); but, the cohort-level 5-year cause-specific survival rate did not change over time (all, P>.05). Among apparent stage I epithelial ovarian cancer, the clear cell type possesses a disproportionally high risk of capsule rupture during adnexectomy and is associated with the most adverse effect on survival. A decrease in the use of postoperative chemotherapy for intraoperatively ruptured cases in Japan is likely the result of increasing awareness of the absence of survival benefits.


NOTCH2 sensitizes the chondrocyte to the inflammatory response of tumor necrosis factor α.
Notch regulates the immune and inflammatory response and has been associated with the pathogenesis of osteoarthritis in humans and preclinical models of the disease. Notch2tm1.1Ecan mice harbor a NOTCH2 gain-of-function and are sensitized to osteoarthritis, but the mechanisms have not been explored. We examined the effects of tumor necrosis factor α (TNFα) in chondrocytes from Notch2tm1.1Ecan mice and found that NOTCH2 enhanced the effect of TNFα on Il6 and Il1b expression. Similar results were obtained in cells from a conditional model of NOTCH2 gain-of-function, Notch22.1Ecan mice, and following the expression of the NOTCH2 intracellular domain in vitro. Recombination signal-binding protein for immunoglobulin Kappa J region partners with the NOTCH2 intracellular domain to activate transcription; in the absence of Notch signaling it inhibits transcription, and Rbpj inactivation in chondrocytes resulted in Il6 induction. Although TNFα induced IL6 to a greater extent in the context of NOTCH2 activation, there was a concomitant inhibition of Notch target genes Hes1, Hey1, Hey2, and Heyl. Electrophoretic mobility shift assay demonstrated displacement of recombination signal-binding protein for immunoglobulin Kappa J region from DNA binding sites by TNFα explaining the increased Il6 expression and the concomitant decrease in Notch target genes. NOTCH2 enhanced the effect of TNFα on NF-κB signaling, and RNA-Seq revealed increased expression of pathways associated with inflammation and the phagosome in NOTCH2 overexpressing cells in the absence and presence of TNFα. Collectively, NOTCH2 has important interactions with TNFα resulting in the enhanced expression of Il6 and inflammatory pathways in chondrocytes.


Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism.
Malignant transformation is often accompanied by significant metabolic changes. To identify drivers underlying these changes, we calculated metabolic flux states for the NCI60 cell line collection and correlated the variance between metabolic states of these lines with their other properties. The analysis revealed a remarkably consistent structure underlying high flux metabolism. The three primary uptake pathways, glucose, glutamine and serine, are each characterized by three features: (1) metabolite uptake sufficient for the stoichiometric requirement to sustain observed growth, (2) overflow metabolism, which scales with excess nutrient uptake over the basal growth requirement, and (3) redox production, which also scales with nutrient uptake but greatly exceeds the requirement for growth. We discovered that resistance to chemotherapeutic drugs in these lines broadly correlates with the amount of glucose uptake. These results support an interpretation of the Warburg effect and glutamine addiction as features of a growth state that provides resistance to metabolic stress through excess redox and energy production. Furthermore, overflow metabolism observed may indicate that mitochondrial catabolic capacity is a key constraint setting an upper limit on the rate of cofactor production possible. These results provide a greater context within which the metabolic alterations in cancer can be understood.


Effect of 11β-HSD1 dehydrogenase activity on bone histomorphometry of glucocorticoid-induced osteoporotic male Sprague-Dawley rats.
Glucocorticoids cause osteoporosis by decreasing bone formation and increasing bone resorption activity. Glucocorticoid action in bones depends on the activity of 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, which plays an important role in regulating corticosteroids. 11β-HSD1 is expressed by human and rat osteoblasts. We aimed to investigate the relationship between 11β-HSD1 dehydrogenase activity and bone histomorphometric changes in glucocorticoid-induced osteoporotic bone in rats. A total of 30 male Sprague-Dawley rats (aged three months, weighing 200-250 g) were divided into three groups of ten each. Group 1 rats were the baseline control, which were sacrificed untreated at the beginning of the study. Group 2 rats underwent sham operation and were administered with vehicle olive oil intramuscularly at 0.05 ml/kg. Group 3 rats were adrenalectomised and administered with an intramuscular injection of dexamethasone 120 μg/kg body weight/day. The treatment was started two weeks after the operation, for a duration of two months. Plasma osteocalcin, plasma pyrodinoline, plasma corticosterone and 11β-HSD1 were measured, and bone histomorphometry analysis was performed. Dexamethasone treatment caused an increase in plasma corticosterone level, together with a significant reduction in 11β-HSD1 dehydrogenase activity of the bone, along with a higher plasma level of the bone resorption marker, pyridinoline. Dexamethasone treatment also caused a reduction in trabecular volume, number and thickness, and an increase in trabecular separation. Long-term glucocorticoid treatment reduces the 11β-HSD1 dehydrogenase activity in the bone, which can otherwise lead to bone loss due to the increased level of active glucocorticoids.


Rethinking cultural competence: insights from indigenous community treatment settings.
Multicultural professional psychologists routinely assert that psychotherapeutic interventions require culturally competent delivery for ethnoracial minority clients to protect the distinctive cultural orientations of these clients. Dominant disciplinary conceptualizations of cultural competence are "kind of person" models that emphasize specialized awareness, knowledge, and skills on the part of the practitioner. Even within psychology, this approach to cultural competence is controversial owing to professional misgivings concerning its culturally essentialist assumptions. Unfortunately, alternative "process-oriented" models of cultural competence emphasize such generic aspects of therapeutic interaction that they remain in danger of losing sight of culture altogether. Thus, for cultural competence to persist as a meaningful construct, an alternative approach that avoids both essentialism and generalism must be recovered. One means to capture this alternative is to shift focus away from culturally competent therapists toward culturally commensurate therapies. Indigenous communities in North America represent interesting sites for exploring this shift, owing to widespread political commitments to Aboriginal cultural reclamation in the context of postcoloniality. Two examples from indigenous communities illustrate a continuum of cultural commensurability that ranges from global psychotherapeutic approaches at one end to local healing traditions at the other. Location of culturally integrative efforts by indigenous communities along this continuum illustrates the possibility for local, agentic, and intentional deconstructions and reconstructions of mental health interventions in a culturally hybrid fashion.


Evaluating an Online Training Course to Develop and Sustain Cancer Navigation and Survivorship Programs.
To evaluate the impact of the Executive Training on Navigation and Survivorship (Executive Training) online training course, designed by the George Washington University Cancer Center, on nurses and other healthcare professionals. A volunteer sample of 499 healthcare professionals, including nurses and patient navigators, were recruited through multiple Internet-based channels. Participants completed questionnaires before and after each module and at the end of the training. Descriptive statistics were calculated, and paired t tests were used to assess pre- and post-test learning confidence gains for each module. Qualitative feedback from participants was also summarized. From pre- to post-test, each group demonstrated statistically significant improvements in confidence (p < 0.05) for all seven training modules. Confidence gains were statistically significant for 19 of 20 learning objectives (p < 0.05). Overall rating scores and qualitative feedback were positive. The Executive Training course prepares healthcare professionals from diverse backgrounds to establish navigation and survivorship programs. In addition, the training content addresses gaps in nursing education on planning and budgeting that can improve success.


Exposure to traffic emissions throughout life and risk of breast cancer: the Western New York Exposures and Breast Cancer (WEB) study.
We previously reported that total suspended particulates exposure (a measure of air pollution) at the time of birth was related to increased postmenopausal breast cancer risk. In this study, we examined breast cancer risk in relation to exposure to air pollution from traffic emissions throughout life. We conducted a case-control study of breast cancer. Participants were women, aged 35-79, residents of Erie and Niagara Counties. Cases had incident, primary, histologically confirmed breast cancer. Controls were randomly selected from the population, frequency-matched on age and race. Using lifetime residential histories, exposure to traffic emissions was modeled for each woman using her residence as a proxy. Estimates were calculated for residence at menarche, her first birth, and 20 and 10 years before interview. Unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Higher exposure to traffic emissions at the time of menarche was associated with increased risk of premenopausal breast cancer (OR 2.05, 95% CI 0.92-4.54, p for trend 0.03); and at the time of a woman's first birth for postmenopausal breast cancer (OR 2.57, 95% CI 1.16-5.69, p for trend 0.19). Statistically significant associations were limited to lifetime non-smokers; there was a significant interaction between exposure at time of menarche and smoking for premenopausal women. Our findings add to accumulating evidence that early life exposures impact breast cancer risk and provide indication of potential importance of traffic emissions in risk of breast cancer.


Vocal-tract resonances as indexical cues in rhesus monkeys.
Vocal-tract resonances (or formants) are acoustic signatures in the voice and are related to the shape and length of the vocal tract. Formants play an important role in human communication, helping us not only to distinguish several different speech sounds [1], but also to extract important information related to the physical characteristics of the speaker, so-called indexical cues. How did formants come to play such an important role in human vocal communication? One hypothesis suggests that the ancestral role of formant perception--a role that might be present in extant nonhuman primates--was to provide indexical cues [2-5]. Although formants are present in the acoustic structure of vowel-like calls of monkeys [3-8] and implicated in the discrimination of call types [8-10], it is not known whether they use this feature to extract indexical cues. Here, we investigate whether rhesus monkeys can use the formant structure in their "coo" calls to assess the age-related body size of conspecifics. Using a preferential-looking paradigm [11, 12] and synthetic coo calls in which formant structure simulated an adult/large- or juvenile/small-sounding individual, we demonstrate that untrained monkeys attend to formant cues and link large-sounding coos to large faces and small-sounding coos to small faces-in essence, they can, like humans [13], use formants as indicators of age-related body size.


Six cases of partial duplication-deficiency 21 syndrome: 21(dupq22delp23) due to maternal pericentric inversion: inv(21)(p12;q22). A family study.
Six probands, apparently not related, with a minimal phenotype of Down's syndrome were investigated between 1970 and 1984 in our laboratory. We found in all of them an identical chromosomal abnormality 46,XX or XY,-21,+ der21(dupq22delp23). The der 21 was due to aneusomie de recombinaison, each mother having an abnormal chromosome 21: inv(21)(p12;q22). The fathers' caryotypes were normal. All parents were young and healthy. Pedigrees were established in order to find a relationship between these families. Four of our probands could be related. Familial investigations are still in progress for the last two cases; the ancestors being born in the same small geographical area (within 50 km2) we think that we shall be able to establish a relationship with the others families.


Comparison of Emergent and Elective Surgeries of Endometriomas: Is Adnexal Torsion a Concern?
When a woman with an endometrioma presents with acute abdominal pain, it is unclear whether ovarian torsion should be suspected. To compare patient characteristics, imaging results, and surgical management of endometriomas in elective versus emergent surgeries. This retrospective cohort study included women treated at our institution during the period 1990-2015 who presented with histologically verified endometrioma and who underwent either planned surgery or emergent surgery due to suspected adnexal torsion. Of 225 surgeries performed, 174 were elective and 51 emergent. Patients in the emergent group were significantly younger (33.9 ± 11.1 vs. 39.01 ± 10.9 years, P = 0.004). Abdominal pain was the main complaint of all the emergent surgery patients and the leading complaint in 21% of the elective surgery patients (P < 0.001), with right-sided predominance in both groups. Sonographic parameters were similar in both groups. Bilateral ovarian cysts were noted in 11.7% and 11.0% of emergent and elective patients, respectively (P = 0.87). Laboratory evaluation was notable for a higher white blood cell count and CA125 levels among emergent patients. All patients in the emergent group and 93% of patients in the elective group were managed laparoscopically. No cases of torsion were noted. The rate of intra-pelvic adhesions was similar in both groups (56.8% vs. 66.6%, P = 0.19). Endometrioma may present with acute abdominal pain. However, adnexal torsion in these patients is rare. These cases can be managed using a minimally invasive approach, assuming an optimal surgical setting.


[HMG protein levels in cell nuclei with different proliferative and transcription activities].
It is shown that HMG1 and HMG2 proteins are present in the nuclei of the both actively proliferating and resting lymphocytes in the equally high amount. On the other hand, the same proteins are almost or even completely absent from the nuclei of all kinds of hepatocytes studied: nonproliferating hepatocytes from calf and rat liver and actively proliferating cells from rat regenerating liver and primary hepatoma. These results reveal a tissue specific distribution of HMG1 and HMG2 proteins and do not confirm the suggestions that HMG1 and HMG2 proteins are necessarily involved in chromatin replication or transcription. In contrast, HMG14 and HMG17 proteins have not shown the tissue specificity in our experiments. Besides, the content of these two proteins does not depend on the actual transcriptional activity of the tissues. These results confirm the suggestion that HMG14 and HMG17 proteins are present not only in the genes that are actually being transcribed, but in a broader set of genes.


[Bloodsucking midges from the nests of birds in the foothills of Western Sikhote-Alin].
The specific composition and number of midges in nest biotopes of birds of forest formations of Western Sikhote-Alin are given. 17 species of the genus Culicoides were found to attack 17 species of birds during the nesting period. The number of midges in nests depends both on the biotopical distribution of nests and mode of living of birds and on the total number of midges in nature. The most high percentage of females engorged with blood at nests was recorded in the obsoletus group, which is most abundant on man and at nests of birds of anthropogenic complex.


Fast impulsive noise removal.
A generic n-dimensional filter with the primary purpose of eliminating impulsive-like noise is presented. This recursive nonlinear filter is composed of two conditional rules, which are applied independently, in any order, one after the other. It identifies noisy items by inspection of their surrounding neighborhood, and afterwards it replaces their values with the most "conservative" ones out of their neighbors' values. In this way, no new values are introduced and the histogram distribution range is conserved. This n-dimensional filter can be decomposed recursively to a lower dimensional space, each time generating two sets of n(n-1)-dimensional filters. This study, which focuses on the case of two-dimensional signals (gray scale images), explores one possible implementation of this new filter and orients the evaluation of its performance toward the median filter, as this filter is the basis of many more sophisticated filters for impulsive noise reduction. Tests were carried out using both real and artificial images. We found this new filter to be much faster than the median filter while performing comparably in terms of both image information conservation and noise reduction, which suggests that it could replace the median filter for the preliminary processing included in state-of-the-art noise removal filters. This new filter should either eliminate or attenuate most noisy pixels in synthetic and natural images not excessively contaminated. It has a slight smoothing effect on nonnoisy image regions. In addition, it is scalable, easily implemented, and adaptable to specific applications.


Chronic obstructive pulmonary disease classification, phenotypes and risk assessment.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease. Various classification systems and phenotypes have been proposed. This review highlights the current classifications of COPD, describes the major phenotypes and provides a blue print for risk assessment of COPD. It is likely that more phenotypes and endotypes of COPD will be described paving the way to personalized medicine for patients with COPD.


Epidemiology of pervasive developmental disorders.
This article reviews the results of 43 studies published since 1966 that provided estimates for the prevalence of pervasive developmental disorders (PDDs), including autistic disorder, Asperger disorder, PDD not otherwise specified, and childhood disintegrative disorder. The prevalence of autistic disorder has increased in recent surveys and current estimates of prevalence are around 20/10,000, whereas the prevalence for PDD not otherwise specified is around 30/10,000 in recent surveys. Prevalence of Asperger disorder is much lower than that for autistic disorder and childhood disintegrative disorder is a very rare disorder with a prevalence of about 2/100,000. Combined all together, recent studies that have examined the whole spectrum of PDDs have consistently provided estimates in the 60-70/10,000 range, making PDD one of the most frequent childhood neurodevelopmental disorders. The meaning of the increase in prevalence in recent decades is reviewed. There is evidence that the broadening of the concept, the expansion of diagnostic criteria, the development of services, and improved awareness of the condition have played a major role in explaining this increase, although it cannot be ruled out that other factors might have also contributed to that trend.


Fluorescence in situ hybridization and optical mapping to correct scaffold arrangement in the tomato genome.
The order and orientation (arrangement) of all 91 sequenced scaffolds in the 12 pseudomolecules of the recently published tomato (Solanum lycopersicum, 2n = 2x = 24) genome sequence were positioned based on marker order in a high-density linkage map. Here, we report the arrangement of these scaffolds determined by two independent physical methods, bacterial artificial chromosome-fluorescence in situ hybridization (BAC-FISH) and optical mapping. By localizing BACs at the ends of scaffolds to spreads of tomato synaptonemal complexes (pachytene chromosomes), we showed that 45 scaffolds, representing one-third of the tomato genome, were arranged differently than predicted by the linkage map. These scaffolds occur mostly in pericentric heterochromatin where 77% of the tomato genome is located and where linkage mapping is less accurate due to reduced crossing over. Although useful for only part of the genome, optical mapping results were in complete agreement with scaffold arrangement by FISH but often disagreed with scaffold arrangement based on the linkage map. The scaffold arrangement based on FISH and optical mapping changes the positions of hundreds of markers in the linkage map, especially in heterochromatin. These results suggest that similar errors exist in pseudomolecules from other large genomes that have been assembled using only linkage maps to predict scaffold arrangement, and these errors can be corrected using FISH and/or optical mapping. Of note, BAC-FISH also permits estimates of the sizes of gaps between scaffolds, and unanchored BACs are often visualized by FISH in gaps between scaffolds and thus represent starting points for filling these gaps.


Persistent work-life conflict and health satisfaction - a representative longitudinal study in Switzerland.
The objectives of the present study were (1) to track work-life conflict in Switzerland during the years 2002 to 2008 and (2) to analyse the relationship between work-life conflict and health satisfaction, examining whether long-term work-life conflict leads to poor health satisfaction. The study is based on a representative longitudinal database (Swiss Household Panel), covering a six-year period containing seven waves of data collection. The sample includes 1261 persons, with 636 men and 625 women. Data was analysed by multi-level mixed models and analysis of variance with repeated measures. In the overall sample, there was no linear increase or decrease of work-life conflict detected, in either its time-based or strain-based form. People with higher education were more often found to have a strong work-life conflict (time- and strain-based), and more men demonstrated a strong time-based work-life conflict than women (12.2% vs. 5%). A negative relationship between work-life conflict and health satisfaction over time was found. People reporting strong work-life conflict at every wave reported lower health satisfaction than people with consistently weak work-life conflict. However, the health satisfaction of those with a continuously strong work-life conflict did not decrease during the study period. Both time-based and strain-based work-life conflict are strongly correlated to health satisfaction. However, no evidence was found for a persistent work-life conflict leading to poor health satisfaction.


[MMP-3 as a Biomarker of Disease Activity of Rheumatoid Arthritis].
The aim of this study was to confirm the clinical significance of serum MMP-3 measurement in the evalua- tion of disease activity and effectiveness of treatment in patients with rheumatoid arthritis (RA). MMP-3 was measured for 206 outpatients with RA during a period of 4 months, and also serially measured for RA patients treated with methotrexate(MTX) alone or together with infliximab (IFX). Serum MMP-3 was significantly correlated with CRP, SAA, and ESR. Significant correlation of serum MMP-3 was found not only with DAS28 (CRP) in female and male patients (p <0.0001 and p < 0.0051, respectively) but also with the EULAR classification criteria for the disease activity of RA. Among the items of DAS28(CRP), the strongest association of MMP-3 was found with swollen joint counts. Furthermore, MMP-3 levels increased with advances in Stage and Class of RA. MMP-3 levels gradually decreased 12 and 24 weeks after successful treatment with MTX (p=0.0188 and p=0.0179, respectively). Extent of the decrease was more prominent in patients with better response to MTX than in those with poor response. MMP-3 levels significantly decreased 6 weeks after IFX treatment and continued to decrease until 48 weeks. Significant decrease of MMP-3 level from before treatment was shown only in the good response group to IFX after 48 weeks of treatment. MMP-3 level was shown to be useful as a disease activity marker in RA patients. In addition, serial measurement of MMP-3 maybe helpful to evaluate the effect of treatments with MTX and IFX.


Anti-inflammatory effects exerted by Killox®, an innovative formulation of food supplement with curcumin, in urology.
In this Open Controlled Trial we administered an innovative formulation of food supplement with curcumin (Killox®) to test its efficacy, safety and compatibility with other drugs, in the therapy of post-surgery complications of transurethral resection of prostate (TURP) and transurethral resection of bladder (TURB), and in the prevention of late complications. Furthermore, Killox® effects were verified in subjects with benign prostatic hyperplasia (BPH). Killox® was administered to 40 TURP patients for 20 days, to 10 TURB patients for 10 days and to 30 BPH patients for 60 days. The study was an open controlled trial, approved by the internal Review Board, with a completely independent set of retrospective observations. In the subjects who underwent surgery the treatment warded off postoperative and late complications, whereas among controls, without anti-inflammatory therapy after surgery until one week later, 21 (52.5%) out of 40 TURP subjects and 4 (40%) out of 10 TURB subjects were still found with symptoms of inflammation and urinary burning, and they had to be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) for seven days. Moreover among controls 2 in TURP group presented an urethral stricture, and no one in TURB group. Killox® patients did not report any adverse effect and the therapy was well tolerated, instead among 21 control subjects, who were treated with NSAIDs, 7 reported nausea and epigastric pain. Also in BPH patients the product was effective in a satisfying manner, shortening the duration of irritation symptoms. Noteworthy, Killox® administration did not modify the efficacy of the other treatments. The effect of Killox® was found statistically significant vs controls. The therapeutic activity and safety of Killox® in urology allow physicians to administer a new efficient product in substitution of NSAIDs.


Optimized depth of field methodology using annular liquid crystal modulator assisted by image processing.
An optical-digital tunable depth of field (DOF) methodology is presented. The suggested methodology forms a fused image based on the sharpest similar depth regions from a set of source images taken with different phase masks. Each phase mask contains a different degree of DOF extension and is implemented by using an annular liquid crystal spatial light modulator, which consists of 16-ring electrodes positioned in the pupil plane. A detailed description of the optical setup and characterization of selected pupil phase masks as well as optimization of the binary phase mask for maximal DOF extension is presented. Experimental results are investigated both qualitatively and quantitatively. In addition, the algorithm's results are compared with those of some well-known fusion algorithms and proved its supremacy.


PLASMOLYSIS IN BACILLUS MEGATERIUM.
Weibull, Claes (Central Bacteriological Laboratory of Stockholm City, Stockholm, Sweden). Plasmolysis in Bacillus megaterium. J. Bacteriol. 89:1151-1154. 1965.-Sucrose solutions stronger than 1 m caused plasmolysis in Bacillus megaterium strain M, whereas concentrated NaCl and KNO(3) solutions were ineffective. In plasmolyzed cells, mesosome bodies were found in pockets between the cytoplasmic membrane and the cell wall. After plasmolysis, the cytoplasmic membrane appeared as a triple-layered structure, a "unit membrane." Plasmolysis did not markedly influence the viability of the cells.


Measuring future time perspective across adulthood: development and evaluation of a brief multidimensional questionnaire.
Despite calls for the consideration of future time perspective (FTP) as a multidimensional construct, mostly unidimensional measurement instruments have been used. This study had two objectives: (a) to develop a brief multidimensional questionnaire for assessing FTP in adulthood and evaluate its psychometric properties; and (b) to examine age associations and age-group differences of the dimensions of FTP. Data were collected from 625 community-residing adults between the ages of 18 and 93, representing young, middle-aged, and older adults. The psychometric evaluation involved exploratory factor analyses (EFA) and confirmatory FA (CFA), reliability and validity analyses, and measurement invariance testing. Zero-order and partial correlations were used to examine the association of the dimensions of FTP with age, and multivariate analysis of variance was used to examine age-group differences. EFA and CFA supported a three-factor solution: Future as Open, Future as Limited, and Future as Ambiguous. Metric measurement invariance for this factor structure was confirmed across the three age groups. Reliability and validity analyses provided evidence of sound psychometric properties of the brief questionnaire. Age was negatively associated with Future as Open and positively associated with Future as Limited. Young adults exhibited significantly greater ambiguity toward the future than middle-aged or older adults. This study provides evidence in support of the psychometric properties of a new brief multidimensional FTP scale. It also provides evidence for a pattern of age associations and age-group differences consistent with life-span developmental theory.


An evaluation of tobacco treatment specialist counseling performance using standardized patient interviews.
In the United States, tobacco treatment specialists are professionals from a variety of backgrounds trained to deliver moderate to intensive evidence-based tobacco treatment in a variety of settings across the country. This paper reports the results of a study that examined the extent to which specialists participating in a larger study adhered to clinical practice guidelines for tobacco dependence using standardized patient assessments. A total of 64 tobacco treatment specialists completed a survey and two audiotaped standardized patient interviews. Overall, 41% and 31% of tobacco treatment specialists demonstrated 80% or more of session content and interviewing skills assessed, respectively, when required to demonstrate the skill in both standardized patient interactions. These rates increased to 85% and 56%, respectively, when using the less stringent criteria of demonstrating the skill in at least one of the two standardized patient interactions. Tobacco treatment specialists who had attended a greater number of types of tobacco treatment training exhibited both greater coverage of session content (p<.06) and greater interviewing skills (p<.02). Those who had achieved certification as a tobacco treatment specialist exhibited greater coverage of session content (p<.02), and those perceiving more positive support from their agency for their services exhibited greater interviewing skills (p=.02). Although the tobacco treatment specialists evaluated appear to have the necessary skills to deliver guideline-based intervention, they demonstrated only moderate adherence to the guidelines when expected to do so consistently across multiple assessments. Findings suggest specific components of tobacco treatment and interviewing skills that would benefit from strengthening through training and support.


When does memory monitoring succeed versus fail? Comparing item-specific and relational encoding in the DRM paradigm.
We compared the effects of item-specific versus relational encoding on recognition memory in the Deese-Roediger-McDermott paradigm. In Experiment 1, we directly compared item-specific and relational encoding instructions, whereas in Experiments 2 and 3 we biased pleasantness and generation tasks, respectively, toward one or the other type of processing. A read condition was tested in each experiment for comparison purposes. Across experiments, item-specific and relational encoding both boosted correct recognition relative to reading, but only item-specific encoding typically reduced false recognition. Signal-detection measures revealed that less information was encoded about critical items after item-specific than after relational encoding. In contrast, item-specific and relational encoding led to equivalent increases in strategic monitoring at test (e.g., use of a distinctiveness heuristic). Thus, monitoring at test was less successful after relational than item-specific encoding because more information had been encoded about critical lures.


Assessing patient satisfaction with medication related services in hospital settings: a cross-sectional questionnaire survey in China.
There are few prior studies on patient satisfaction with medication related services and the potential value of measurements of patient satisfaction to the development of pharmaceutical care service (PCS) strategies in China. The objectives of the current study were to assess patient satisfaction with medication-related services in Chinese tertiary hospitals, examine the possible impact of PCS on patient satisfaction, and form a development strategy to establish PCS strategy prioritization. Self administered questionnaires were distributed to 540 patients before discharge from units in 18 tertiary general hospitals in six cities. The participants assessed their satisfaction with the hospital's medication-related services based on a 7-point Likert-type scale. A comparative analysis between PCS and non-PCS pilot hospitals was conducted to evaluate the impact of PCS on patient satisfaction. 501 valid questionnaires were collected: 247 samples from PCS pilot hospitals (PCS group) and 254 from non-PCS pilot hospitals (non-PCS group). Factor analysis resulted in three factors (dimensions): "consideration and explanation", "discharge instruction", and "efficacy and finance". The "efficacy and finance" scores indicated relative satisfaction with this dimension (mean = 5.63 ± 1.36). However, the items "medication costs" and "other medical costs" were the lowest scored attributes (means = 4.98 ± 1.62 and 4.95 ± 1.63), indicating that most of the participants were dissatisfied with these financial attributes. The median score in the "consideration and explanation" dimension in the PCS group was 6.27, in comparison with 5.81 in the non-PCS group. This statistically significant difference (p < 0.01) demonstrates that the major impact of PCS on patient satisfaction is observed in the "consideration and explanation" dimension. This study revealed low patient satisfaction with the financial aspects of medication-related services, which must be improved to provide better inpatient hospital service. The clinical effectiveness of medication therapy at these 18 tertiary hospitals could meet patients' expectations, but PCS did not increase the level of patient satisfaction in the "efficacy and finance" dimension. Future PCS strategy in China should focus on improving the clinical and economic outcomes of medication-related services.


Science-based health innovation in Uganda: creative strategies for applying research to development.
Uganda has a long history of health research, but still faces critical health problems. It has made a number of recent moves towards building science and technology capacity which could have an impact on local health, if innovation can be fostered and harnessed. Qualitative case study research methodology was used. Data were collected through reviews of academic literature and policy documents and through open-ended, face-to-face interviews with 30 people from across the science-based health innovation system, including government officials, researchers in research institutes and universities, entrepreneurs, international donors, and non-governmental organization representatives. Uganda has a range of institutions influencing science-based health innovation, with varying degrees of success. However, the country still lacks a coherent mechanism for effectively coordinating STI policy among all the stakeholders. Classified as a least developed country, Uganda has opted for exemptions from the TRIPS intellectual property protection regime that include permitting parallel importation and providing for compulsory licenses for pharmaceuticals. Uganda is unique in Africa in taking part in the Millennium Science Initiative (MSI), an ambitious though early-stage $30m project, funded jointly by the World Bank and Government of Uganda, to build science capacity and encourage entrepreneurship through funding industry-research collaboration. Two universities - Makerere and Mbarara - stand out in terms of health research, though as yet technology development and commercialization is weak. Uganda has several incubators which are producing low-tech products, and is beginning to move into higher-tech ones like diagnostics. Its pharmaceutical industry has started to create partnerships which encourage innovation. Science-based health product innovation is in its early stages in Uganda, as are policies for guiding its development. Nevertheless, there is political will for the development of STI in Uganda, demonstrated through personal initiatives of the President and the government's willingness to invest heavily for the long term in support of STI through the Millennium Science Initiative. Activities to support technology transfer and private-public collaboration have been put in motion; these need to be monitored, coordinated, and learned from. In the private sector, there are examples of incremental innovation to address neglected diseases driven by entrepreneurial individuals and South-South collaboration. Lessons can be learned from their experience that will help support Ugandan health innovation.


Cognitions and depressive symptoms among ethnic minority adolescents.
Cognitive models have guided effective intervention strategies in the treatment of depression. However, little is known about the cognitive model's relevance in different cultural ethnic groups in the United States. This study examines the cross-sectional and longitudinal associations among cognitive variables and depressive symptoms among African American, Caucasian, and Hispanic adolescents in the United States. Community adolescents (N = 450) ages 14-18 years (African American n = 79; Caucasian n = 273; Hispanic n = 98) provided information regarding their depressive symptoms and cognitions at two surveys, 6 months apart. Self-efficacy, cognitive errors, and hopelessness were associated with concurrent depressive symptoms at baseline. In addition, cognitive errors at baseline, controlling for baseline depressive symptoms and the occurrence of stressful events, predicted depressive symptoms at follow-up. Ethnic differences disappeared when parent education level was controlled. Our findings demonstrate support for the cognitive model of depression across ethnic groups. The importance of controlling for social class when examining ethnic differences in psychological variables is highlighted by our findings.


Challenges in multiple sclerosis diagnosis: Misunderstanding and misapplication of the McDonald criteria.
To assess comprehension and application of the McDonald criteria. Studies suggest that knowledge gaps for specific core elements of the McDonald criteria may contribute to multiple sclerosis (MS) misdiagnosis. Neurology residents (NR) and multiple sclerosis specialists (MSS) in North America completed a web-based survey. A total of 160 participants were included: 72 NR and 88 MSS. Syndromes incorrectly identified as typical of MS included: complete transverse myelopathy (35% NR and 15% MSS), intractable vomiting/nausea/hiccoughs (20% NR and 5% MSS), and bilateral optic neuritis/unilateral optic neuritis with poor visual recovery (17% NR and 10% MSS). Periventricular magnetic resonance imaging (MRI) lesions were correctly identified by 39% NR and 52% MSS, and juxtacortical lesions were correctly identified by 28% NR and 53% MSS. The correct definition of "periventricular" was chosen by 38% NR and 61% MSS, and that of "juxtacortical" was chosen by 19% NR and 54% MSS. Regions incorrectly identified for MRI dissemination in space fulfillment included the optic nerve (31% NR and 26% MSS) and the subcortical white matter (11% NR and 18% MSS). The majority of participants assessed previous non-specific neurological symptoms without objective evidence of a central nervous system (CNS) lesion as sufficient for clinical dissemination in time. The McDonald criteria are often misunderstood and misapplied. Concerted educational efforts may prevent MS misdiagnosis.


Incidence and predictors of bleeding in ACS patients treated with PCI and prasugrel or ticagrelor: An analysis from the RENAMI registry.
To evaluate "real life" incidence and independent predictors of major bleeding defined in ACS patients treated with PCI and current standard antithrombotic therapy with prasugrel or ticagrelor. The RENAMI project is a multicenter retrospective observational registry enrolling 4424 patients with ACS treated with PCI and prasugrel or ticagrelor plus aspirin. Primary endpoint was MACE (major adverse cardiovascular events). Secondary endpoints included each component of MACE, cardiovascular death (CV death), recurrence of ACS (reACS) and stroke. Eighty three (1.8%) patients developed out of hospital major bleedings after 14.1 ± 6.2 months. These patients had higher rates of MACE (14.5% vs 4.4%; p = 0.001) and of all-cause death (11% vs 2.1%; p < 0.001). Independent predictors of major bleeding were age >75 years (OR 2.00; 95% CI 1.18-3.41; p = 0.010) and female sex (OR 1.66; 95% CI 1.02-2.70; p = 0.041). BARC 3-5 bleeding was independently associated with all-cause mortality (OR 3.46; 95% CI 1.64-7.31; p 0.001). In ACS patients treated with PCI and ticagrelor or prasugrel, BARC 3-5 bleedings despite being uncommon negatively impacted on prognosis. Old and female patients are at increased risk, offering clinical indications for tailoring dual antiplatelet therapy.


The PCH family protein, Cdc15p, recruits two F-actin nucleation pathways to coordinate cytokinetic actin ring formation in Schizosaccharomyces pombe.
Cytokinetic actin ring (CAR) formation in Schizosaccharomyces pombe requires two independent actin nucleation pathways, one dependent on the Arp2/3 complex and another involving the formin Cdc12p. Here we investigate the role of the S. pombe Cdc15 homology family protein, Cdc15p, in CAR assembly and find that it interacts with proteins from both of these nucleation pathways. Cdc15p binds directly to the Arp2/3 complex activator Myo1p, which likely explains why actin patches and the Arp2/3 complex fail to be medially recruited during mitosis in cdc15 mutants. Cdc15p also binds directly to Cdc12p. Cdc15p and Cdc12p not only display mutual dependence for CAR localization, but also exist together in a ring-nucleating structure before CAR formation. The disruption of these interactions in cdc15 null cells is likely to be the reason for their complete lack of CARs. We propose a model in which Cdc15p plays a critical role in recruiting and coordinating the pathways essential for the assembly of medially located F-actin filaments and construction of the CAR.


Validating blood tests as a possible routine diagnostic assay of Alzheimer's disease.
In recent years exciting developments in disease modifying treatments for Alzheimer's disease (AD) have made accurate and timely diagnosis of this disease a priority. Blood biomarkers (BBMs) for amyloid pathology using improved immunoassay and mass spectrometry techniques have been an area of intense research for the last 10 years and are coming to the fore, as a real prospect to be used in the clinical diagnostics of the disease. The following review will update and discuss blood biomarkers that will be most useful in diagnosing AD and the context necessary for their implementation. It is clear we now have BBMs, and technology to measure them, that are capable of detecting amyloid pathology in AD. The challenge is to validate them across platforms and populations to incorporate them into clinical practice. It is important that implementation comes with education, we need to give clinicians the tools for appropriate use and interpretation. It is feasible that BBMs will be used to screen populations, initially for clinical trial entry but also therapeutic intervention in the foreseeable future. We now need to focus BBM research on other pathologies to ensure we accelerate development of therapeutics for all neurodegenerative diseases.


Evaluation of double-disk potentiation and disk potentiation tests using dipicolinic acid for detection of metallo-β-lactamase-producing pseudomonas spp. and Acinetobacter spp.
Accurate detection of metallo-β-lactamase (MBL)-producing Pseudomonas spp. and Acinetobacter spp. became very important with the increasing prevalence of carbapenem-nonsusceptible clinical isolates. The performance of phenotypic MBL detection methods may depend on the types of MBL and the characteristics of the isolates. A high false-positive rate is a problem with EDTA-based MBL detection methods. We evaluated the performance of double-disk potentiation tests (DDPTs) and disk potentiation tests (DPTs) with dipicolinic acid (DPA) using 44 isolates of Pseudomonas spp. and Acinetobacter spp. producing IMP-1-like, VIM-2-like, and SIM-1 type MBLs. Also, we characterized P. aeruginosa isolates with positive imipenem (IPM)-DPA DDPT, but negative meropenem (MEM)-DPA DDPT, and determined possibility of improving a DDPT by using MacConkey agar. Among five different DDPT methods, the IPM-DPA 250-μg method showed the highest sensitivity (97.7%) and specificity (100%). Among four DPT tests, the highest sensitivity (100%) was shown by the IPM-EDTA 1,900-μg disk method, but the specificity was very low (11.4%). Five of six P. aeruginosa isolates with false-negative DDPTs with MEM-DPA 250-μg disks carried bla(IMP-6,) and the high level resistance to MEM (MIC ≥ 512 μg/ml) was reduced by the presence of phenylalanine arginine β-naphtylamide. Improvement of DDPTs was observed when MacConkey agar was used instead of Mueller-Hinton agar. In conclusion, DPA is a better MBL inhibitor than EDTA for detection of Pseudomonas spp. and Acinetobacter spp. with IMP-1-like, VIM-2-like, and SIM-1-type MBLs. In DPA DDPTs, IPM disks perform better than MEM disks when the isolates are highly resistant to MEM due to the overexpression of efflux pumps.


Platelet size in myocardial infarction.
The mean platelet volume and platelet count were measured serially in 100 patients soon after myocardial infarction and again at a follow up clinic about seven weeks later. The results were compared with those in age matched controls. The mean platelet volume after infarction (mean 9.07 fl (SE 0.08] was significantly greater than in the controls (8.32 fl (SE 0.07); p less than 0.001), and was still raised at the follow up clinic (8.69 fl (SE 0.10); p less than 0.01). The mean platelet count on admission (275 X 10(9)/1 (SE 7] was significantly lower than in the control group (295 X 10(9)/1 (SE 5); p less than 0.05) and fell significantly during admission, with a mean change of -36 X 10(9)/1 (95% confidence limits -26, -45; p less than 0.01). At the follow up clinic the platelet count had risen to a level not significantly different from the admission value. As larger platelets are haemostatically more active, the finding of an increased mean platelet volume after myocardial infarction provides further evidence that abnormal platelet behaviour may be implicated in the process of infarction.


[Palliative care of non-resectable stenosed esophageal and cardiac cancer. A retrospective study of 31 patients treated with endoscopic argon "beam" coagulation].
The aim of this study was to describe the argon beam coagulation technique in the palliative treatment of patients with non-resectable carcinoma of the cardia and oesophagus and its requirements, complications, and tolerance. 31 patients, referred for palliation by ABC in a central hospital over a period of nearly four years (1.1.1998-31.8.2001), were evaluated retrospectively. Twenty-two men and nine women, median age 72 years (range 49-91), underwent a total of 163 treatments and a median of five treatments per patient (range 1-18). Re-canalisation enabling passage of the scope was achieved in 89% of treatments, and most of the patients had dysphagia grade = 2. The median range between reinterventions was 25 days (range 1-175). Perforation was seen in three patients and in 1.8% of treatments procedure-related mortality was 1.2%. The median hospital stay for each treatment was two days (range 1-27) and the median impatient stay as proportion survival time was 8%. The median survival was 190 days (range 7-612) and the one-year survival 19%. ABC is a well tolerated, safe, and effective treatment in patients with non-resectable cancer of the oesophagus or cardia and offers and acceptable complication rate and number of reinterventions compared with laser and stent placement. The technique is easy and inexpensive and requires no further restrictions than conventional monopolar electrocoagulation does.


Regulators of cell division in plant tissues : XXVIII. Metabolites of zeatin in sweet-corn kernels: Purifications and identifications using high-performance liquid chromatography and chemical-ionization mass spectrometry.
The cytokinins in certain fractions prepared from extracts of immature sweet-corn (Zea mays L.) kernels using polystyrene ion-exchange resins have been further investigated. Cytokinins active in the radish cotyledon bioassay were purified from these fractions and identified as 9-β-D-glucopyranosylzeatin, 9-β-D-glucopyranosyldihydrozeatin, O-β-D-glucopyranosylzeatin. and O-β-D-glucopyranosyl-9-β-D-ribofuranosylzeatin. In addition, compounds which resemble zeatin and its glycosides in chromatographic behaviour and in ultraviolet absorption characteristics were purified from extracts of the same material by high-performance liquid chromatography. In addition to zeatin and zeatin riboside, the following compounds were identified unambiguously: O-β-D-glucopyranosyl-9-β-D-ribofuranosyldihydrozeatin, O-β-D-glucopyranosyldihydrozeatin, and hihydrozeatin riboside. A further compound was tentatively identified as O-β-D-glucopyranosylzeatin, and at least two unidentified compounds appeared to be new derivatives of zeatin. In identifying the above compounds, chemical-ionization mass spectrometry proved to be an invaluable complementary technique, yielding spectra showing intense protonated-molecular-ion peaks and also prominent structure-related fragmentation that was either not evident or very minor in the electron-impact spectra. An assessment of the relative importance of the various possible mechanisms for cytokinin modification and inactivation in mature sweet-corn kernels was made by supplying [(3)H]zeatin and [(3)H]zeatin riboside to such kernels after excision. The principal metabolites of zeatin were adenine nucleotides, adenosine and adenine, while little of the metabolite radioactivity was attributable to known O-glucosides. Adenine nucleotides and adenine were the principal metabolites of zeatin riboside, while lesser metabolites were identified as adenosine, dihydrozeatin, and the O-glucosides of dihydrozeatin and dihydrozeatin riboside. Side-chain cleavage, rather than side-chain modification, appears to be the dominant form of cytokinin metabolism in mature sweet-corn kernels.


BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer.
This study aimed to compare the effects of bone morphogenetic protein BMP2/7 heterodimer and BMP homodimers on bone regeneration in bone defects model. Identical peri-implant bone defects model were created using proper controls on the frontal skull in 18 minipigs. Collagen sponges with low-dose (30 ng/mL) BMP2/7 heterodimer, BMP2 or BMP7 homodimer were filled in the defects. New bone formation and the expression of type I collagen (Col1), alkaline phosphatase (ALP) and osteocalcin (OCN) were evaluated after 2, 3, and 6 weeks of implantation. BMP2/7 resulted in significantly higher new bone areas percentage in the defect region than BMP2 and BMP7 (p<0.05). Immunohistochemical staining of Col1, ALP and OCN was stronger in BMP2/7 group than BMP2, BMP7 and control group (p<0.05). These results demonstrate that BMP2/7 heterodimer is a stronger inducer of osteoblastogenesis and could be applied at low dose to reduce the cost and side effects of BMP homodimers.


Liver receptor homolog-1 is essential for pregnancy.
Successful pregnancy requires coordination of an array of signals and factors from multiple tissues. One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis. It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans. Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation. Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation. To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death. Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization. These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta. It therefore has multiple, indispensible roles in establishing and sustaining pregnancy.


Ru-catalyzed sequence for the synthesis of cyclic amido-ethers.
Efficient synthesis of versatile building blocks for enabling medicinal chemistry research has always challenged synthetic chemists to develop innovative methods. Of particular interest are the methods that are amenable to the synthesis of chemically distinct and diverse classes of pharmaceutically relevant motifs. Herein we report a general method for the one-pot synthesis of cyclic α-amido-ethers containing different amide functionalities including lactams, tetramic acids and amino acids. For the incorporation of the nucleotide bases, a chemo and regioselective palladium-catalyzed transformation has been developed, providing rapid access to nucleoside analogs.


The effect of inhibitors of DNA repair on the genetic instability of Streptomyces cattleya.
Various streptomycetes show well defined instabilities that do not appear to be attributable to plasmid loss. The unstable phenotype, in many cases, arises at frequencies too high to be explained by point mutations. The frequency of instability can be enhanced by UV irradiation. Two major repair systems have been found in Escherichia coli: the 'error-free' system which is inhibited by caffeine and the 'error-prone' system which is inhibited by arsenite. Using spores of Streptomyces cattleya NRRL 8057 and the virulent actinophage VC11 we have shown that a caffeine inhibitable, host mediated UV repair system is active in spores during early development. Some evidence was also found for the presence of an arsenite inhibitable UV repair system. The caffeine inhibitable UV repair system was found to be involved in the induction of genetic instability in S. cattleya. The arsenite system may be implicated in the repair of such events. Genetic instability was also induced by single strand breaks in DNA caused by 32P.


Accuracy and reliability of determining the isometric point of the knee for multiligament knee reconstruction.
To compare the accuracy and reliability of the anatomic and radiographic techniques for identifying the isometric point of the knee. Only four specimens were used; however, eight experienced multiligament knee injury surgeons were recruited to address this limitation. Surgeons estimated the isometric point (EIP) on the medial and lateral sides using an anatomic and radiographic method. The x and y coordinates of the EIP were compared to the true isometric point (TIP). T-tests and interclass correlation coefficients (ICC) were performed to determine the accuracy and reliability between the methods. There was no difference in placement of the EIP on the medial side of the knee in the anterior/posterior (x; p = n.s.) and superior/inferior direction (y; p = n.s). The EIP was anterior (p = 0.001) to the TIP with the radiographic method on the lateral side and approached significance (p = 0.05) in the superior/inferior direction. The ICC (95% CI) for identifying the EIP on the medial side in the anterior/posterior direction using the anatomic method was 0.64 (0.28-0.96) and 0.11 (-0.06 to 0.77) in the superior/inferior direction. Using the radiographic method, the ICC in the anterior/posterior and superior/inferior direction was 0.49 (0.14-0.94) and 0.15 (-0.47 to 0.81), respectively. On the lateral side, the ICC for the anatomic method was 0.84 (0.56-0.99) in the anterior/posterior direction and 0.36 (0.05-0.90) in the superior/inferior direction. Using the radiographic method, the ICC in the anterior/posterior and superior/inferior direction was 0.61 (0.26-0.96) and 0.89 (0.67-0.99), respectively. There was no difference in accuracy on the medial side of the knee. On the lateral side, the anatomic method was more accurate in the anterior/posterior direction. Reliability was greater in the anterior/posterior direction on both sides of the knee. Surgeons were most likely to place the isometric point anterior and superior to the TIP on both the medial and lateral sides of the knee with either method which has the potential to cause graft lengthening. This should be taken into consideration during reconstruction/repair of the MCL/PMC and LCL/PLC.


Decellularized Graft for Repairing Severe Peripheral Nerve Injuries in Sheep.
Peripheral nerve injuries resulting in a nerve defect require surgical repair. The gold standard of autograft (AG) has several limitations, and therefore, new alternatives must be developed. The main objective of this study was to assess nerve regeneration through a long gap nerve injury (50 mm) in the peroneal nerve of sheep with a decellularized nerve allograft (DCA). A 5-cm long nerve gap was made in the peroneal nerve of sheep and repaired using an AG or using a DCA. Functional tests were performed once a month and electrophysiology and echography evaluations at 6.5 and 9 months postsurgery. Nerve grafts were harvested at 9 months for immunohistochemical and morphological analyses. The decellularization protocol completely eliminated the cells while preserving the extracellular matrix of the nerve. No significant differences were observed in functional tests of locomotion and pain response. Reinnervation of the tibialis anterior muscles occurred in all animals, with some delay in the DCA group compared with the AG group. Histology showed a preserved fascicular structure in both AG and DCA; however, the number of axons distal to the nerve graft was higher in AG than in DCA. The decellularized graft assayed supported effective axonal regeneration when used to repair a 5-cm long gap in the sheep. As expected, a delay in functional recovery was observed compared with the AG because of the lack of Schwann cells.


Dually responsive multiblock copolymers via RAFT polymerization: Synthesis of temperature- and redox-responsive copolymers of PNIPAM and PDMAEMA.
We report synthesis of temperature- and redox-responsive multiblock copolymers by reversible addition-fragmentation chain transfer (RAFT) polymerization. Well-defined α,ω-bis(dithioester)-functionalized poly(N-isopropylacrylamide) (PNIPAM) and poly(2-(dimethylamino) ethyl methacrylate) (PDMAEMA) were prepared using 1,4-bis(thiobenzoylthiomethyl)benzene and 1,4-bis(2-(thiobenzoylthio)prop-2-yl)benzene as RAFT agents, respectively. Dually responsive multiblock copolymers were synthesized in a single aminolysis/oxidation step from the α,ω-bis(dithioester)-terminated PNIPAM and PDMAEMA. The copolymers and their stimulus-responsive behavior were characterized by size exclusion chromatography, NMR, light scattering and atomic force microscopy. Due to the presence of redox-sensitive disulfide bonds between the blocks, the copolymers were readily reduced to the starting polymer blocks. The presence of temperature-responsive PNIPAM blocks provided the copolymers with the ability to assemble into core-shell nanostructures with hydrophobic PNIPAM as a core and cationic PDMAEMA as stabilizing shell when above the phase transition temperatures of PNIPAM. The temperature-induced assembly of the copolymers also showed substantial pH sensitivity. The phase transition temperature increased with decreasing pH, while molecular weight of the assemblies decreased.


A multi-parameter response prediction model for rituximab in rheumatoid arthritis.
To validate the IFN response gene (IRG) set for the prediction of non-response to rituximab in rheumatoid arthritis (RA) and assess the predictive performance upon combination of this gene set with clinical parameters. In two independent cohorts of 93 (cohort I) and 133 (cohort II) rituximab-starting RA patients, baseline peripheral blood expression of eight IRGs was determined, and averaged into an IFN score. Predictive performance of IFN score and clinical parameters was assessed by logistic regression. A multivariate prediction model was developed using a forward stepwise selection procedure. Patients with a decrease in disease activity score (ΔDAS28)≥1.8 after 6 months of therapy were considered responders. The mean IFN score was higher in non-responders compared to responders in both cohorts, but this difference was most pronounced in patients who did not use prednisone, as described before. Univariate analysis in cohort I showed that baseline DAS28, IFN score, DMARD use and negativity for IgM-RF and/or ACPA were associated with rituximab non-response. The multivariate model consisted of DAS28, IFN score and DMARD use, which showed an area under the curve (AUC) of 0.82. In cohort II, this model revealed a comparable AUC in PREDN-negative patients (0.78), but AUC in PREDN-positive patients was significantly lower (0.63), which seemed due to effect modification of the IFN score by prednisone. Combination of predictive parameters provided a promising model for the prediction of non-response to rituximab, with possibilities for optimization via definition of the exact interfering effect of prednisone on IFN score. NCT01126541, registered 18 May 2010.


Comparative outcomes of catheter-directed thrombolysis versus AngioJet pharmacomechanical catheter-directed thrombolysis for treatment of acute iliofemoral deep vein thrombosis.
The objective of this study was to compare the outcomes of pharmacomechanical thrombolysis and thrombectomy (PCDT) plus catheter-directed thrombolysis (CDT) vs CDT alone for the treatment of acute iliofemoral deep vein thrombosis (DVT) and summarize the clinical experience, safety outcomes, and short- and long-term efficacy. We performed a 4-year retrospective, case-control study. A total of 95 consecutive patients with acute symptomatic iliofemoral deep vein thrombosis (DVT) with a symptom duration of ≤7 days involving the iliac and/or common femoral veins underwent endovascular interventions. The patients were divided into two groups according to their clinical indications: PCDT plus CDT vs CDT alone. Statistical analyses were used to compare the clinical characteristics and outcomes between the two groups. Additionally, the patients were followed up for 3 to 36 months after treatment, and the proportions of post-thrombotic syndrome (PTS) and moderate to severe PTS were analyzed using the Kaplan-Meier survival method. A total of 95 consecutive patients were analyzed in this retrospective study, of whom, 51 underwent CDT alone and 44 underwent PCDT plus CDT. Between the two groups, in terms of immediate-term efficacy and safety, significant differences were found in the catheter retention time (60.64 ± 12.04 hours vs 19.42 ± 4.04 hours; P < .001), dosages of urokinase required (5.82 ± 0.81 million units vs 1.80 ± 0.64 million units; P < .001), the detumescence rate at 24 hours postoperatively (48.46% ± 8.62% vs 76.79% ± 7.98%; P = .026), the descent velocity of D-dimer per day (2266.28 ± 1358.26 μg/L/D vs 3842.34 ± 2048.02 μg/L/D; P = .018), total hospitalization stay (6.2 ± 1.40 days vs 3.8 ± 0.70 days; P = .024), number of postoperative angiograms (2.4 ± 0.80 vs 1.2 ± 0.30; P = .042), and grade III venous patency (>95% lysis: 54.5% vs 68.6%; P = .047). Furthermore, during the follow-up period, significant differences were found in the incidence of PTS (Villalta scale ≥5 or a venous ulcer: 47.0% vs 27.7%; P = .037), and the incidence proportion of moderate to severe PTS at 12 months (15.7% vs 4.5%; P = .024) and 24 months (35.3% vs 11.4%; P = .016). Compared with CDT alone, in the iliofemoral DVT subgroup with a symptom duration of ≤7 days, PCDT plus CDT could significantly relieve early leg symptoms, shorten the hospitalization stay, reduce bleeding complications, promote long-term venous patency, and decrease the occurrence of PTS and the incidence proportion of moderate to severe PTS. Thus, the short- and long-term outcomes both support the superiority of PCDT plus CDT vs CDT in this subgroup.


Chemistry in low-mass protostellar and protoplanetary regions.
When interstellar clouds collapse to form new stars and planets, the surrounding gas and dust become part of the infalling envelopes and rotating disks, thus providing the basic material from which new solar systems are formed. Instrumentation to probe the chemistry in low-mass star-forming regions has only recently become available. The results of a systematic program to study the abundances in solar-mass protostellar and protoplanetary regions are presented. Surveys at submillimeter and infrared wavelengths reveal a rich chemistry, including simple and complex (organic) gases, ices, polycyclic aromatic hydrocarbons, and silicates. Each of these species traces different aspects of the physical and chemical state of the objects as they evolve from deeply embedded protostars to pre-main sequence stars with planet-forming disks. Quantitative information on temperatures, densities, and abundances is obtained through molecular excitation and radiative transfer models as well as from analysis of solid-state line profiles. The chemical characteristics are dominated by freeze-out in the coldest regions and ice evaporation in the warmer zones. In the surface layers of disks, UV radiation controls the chemistry. The importance of complementary laboratory experiments and calculations to obtain basic molecular data is emphasized.


Adenohypophyseal response to hypophysiotropic hormones in male obese Zucker rats.
Description of the recessive, homozygote obese Zucker rat (fafa) includes disorders of growth and reproduction. The aim of this study was to compare responsiveness of adenohypophyseal cells, obtained from male fafa rats and from their lean siblings, to growth hormone-releasing factor (GRF) and to luteinizing hormone-releasing hormone (LHRH). Pituitary cells were cultured for 4 days and were then challenged with either GRF-29 (the NH2-terminal 29 amino acid GRF peptide that expresses full biological activity of its parent 44 amino acid molecule) or [D-Trp6]LHRH (LHRH-A, an LHRH agonist). Medium was assayed for growth hormone (GH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by radioimmunoassay. Dose-response curves were compared using the computer program ALLFIT. The median effective GRF-29 concentration (EC50) computed for hypophyseal cells cultured from lean animals (0.30 +/- 0.01 fM; means +/- SE of 4 experiments) was less (P less than 0.01) than that calculated for cells obtained from fafa rats (15.8 +/- 6.7 fM). In contrast, cells derived from lean littermates required a larger (EC50) concentration of LHRH-A than did gonadotrophs cultured from obese rats [58.2 +/- 1.2 vs. 10.7 +/- 1.2 pM (P less than 0.01) and 59.4 +/- 10.4 vs. 15.7 +/- 7.6 pM (P less than 0.05)] to secrete LH and FSH, respectively. Our data describe an attenuated pituitary response to GRF-29 and an enhanced response to LHRH-A in the fafa.


A role for endorphins in the pathophysiology of spinal cord injury.
These studies have demonstrated that the opiate-antagonist naloxone improves blood pressure and functional neurologic recovery after spinal injury. From these findings we suggest that endorphins are released in response to spinal injury and contribute to the hypotension and to the ultimate neurologic deficit. Naloxone's ability to reverse the presumed endorphin-mediated hypotension in this model supports the hypothesis that its therapeutic effects may be secondary to its improvement of spinal cord blood flow, thereby reducing the ischemic damage caused by spinal cord trauma.


Ultrafast laser inscription in ZBLAN integrated optics chips for mid-IR beam combination in astronomical interferometry.
Astronomical interferometry is a unique technique that allows observation with angular resolutions on the milliarcsec scale by combining the light of several apertures hundreds of meters apart. The PIONIER and GRAVITY instruments at the Very Large Telescope Interferometer have demonstrated that silica-based integrated optics (IO) provide a small-scale and highly stable solution for the interferometric beam combination process. Yet, important science cases such as exoplanet hunting or the spectroscopic characterization of exoplanetary atmospheres are favorable for observation in the mid-IR, namely the atmospheric windows L and L' band (3-4 µm), a wavelength range that is not covered by conventional silica-based IO. Here, we propose laser-inscribed IO 2×2 couplers in ZBLAN and experimentally assess the critical properties of the component for broadband mid-IR interferometry. We measure the splitting ratio over the 2.5 to 5.0 µm range and find excellent broadband contrast over the L (3.1-3.6 µm) and L' (3.6 - 4.0 µm) bands. Furthermore, we quantify the dispersion properties of the coupler and find a phase variation as low as 0.02 rad across the L and L' band, respectively. By optimizing the NA of our injection beam, we measured a very high total throughput of 58% over the L band including Fresnel reflection and coupling losses. We also compare our findings to recent advances in mid-IR IO in GLS and discuss its advantages and disadvantages for the implementation in future mid-IR interferometers.


Formation of gas-phase peptide ions and their dissociation in MALDI: insights from kinetic and ion yield studies.
Insights on mechanisms for the generation of gas-phase peptide ions and their dissociation in matrix-assisted laser desorption ionization (MALDI) gained from the kinetic and ion yield studies are presented. Even though the time-resolved photodissociation technique was initially used to determine the dissociation kinetics of peptide ions and their effective temperature, it was replaced by a simpler method utilizing dissociation yields from in-source decay (ISD) and post-source decay (PSD). The ion yields for a matrix and a peptide were measured by repeatedly irradiating a region on a sample and collecting ion signals until the sample in the region was completely depleted. Matrix- and peptide-derived gas-phase cations were found to be generated by pre-formed ion emission or by ion-pair emission followed by anion loss, but not by laser-induced ionization. The total number of ions, that is, matrix plus peptide, was found to be equal to the number of ions emitted from a pure matrix. A matrix plume was found to cool as it expanded, from around 800-1,000 K to 400-500 K. Dissociation of peptide ions along b/y channels was found to occur statistically, that is, following RRKM behavior. Small critical energy (E0 = 0.6-0.7 eV) and highly negative critical entropy (ΔS(‡) = -30 to -25 eu) suggested that the transition structure was stabilized by multiple intramolecular interactions.


US and international health professions' requirements for continuing professional development.
There is not a comprehensive global analysis of continuing professional development (CPD) and continuing education (CE) in the major health professions in published literature. The aim of this article is to summarize findings from the US and international literature on CPD and CE practices in the health professions, comparing the different requirements and frameworks to see what similarities and challenges exist and what the future focus should be for the pharmacy profession. A literature review was conducted on CPD and CE in selected health professions, namely pharmacy, medicine, nursing, ophthalmology, dentistry, public health, and psychology. Over 300 papers from the health professions were retrieved and screened. Relevant articles based on the abstracts and introductions were summarized into tabular form by profession, minimum requirements for licensure, nature of credits, guidelines on how to record CE and CPD activities, and specific CE and CPD definitions. Wide variations exist among the health professions. Lessons learned from this information can be used to further clarify and define the role of CE and CPD and self-directed lifelong learning in pharmacy and the health professions.


Ultrasonography and radiography to identify early post traumatic myosistis ossificans in an 18-year-old male: a case report.
The purpose of this case report is to describe a patient with post traumatic myositis ossificans (PTMO) of the anterior thigh following blunt trauma and discuss the incidence, clinical presentation, management, and imaging findings. An 18-year-old male presented to a chiropractic clinic with a chief complaint of left knee pain and reduced range of motion after an impact injury to his left anterior thigh during hurdling 6 weeks earlier. Immediately after the injury, he presented to the emergency department where radiography of the left knee was negative and he was diagnosed with a muscle sprain. Follow-up radiography and ultrasonography of the left knee in a chiropractic radiology department revealed ossification consistent with PTMO within his vastus intermedius. The patient underwent a course of rehabilitation for 2 months including ice, class IV cold laser and vibration applied to his anterior thigh, and myofascial release of his quadriceps musculature with targeted and progressive rehabilitative exercises. His left knee pain resolved within 2 weeks of care. He resumed sports participation (American football) pain-free, while wearing protective padding over the affected thigh, 1 month after presentation, which was approximately 2 1/2 months following his injury. This case demonstrates that ultrasonography may have the capability to detect early phases of PTMO approximately 2 weeks prior to radiographic evidence and to monitor progression throughout its course.


Genetic epidemiology of intracerebral hemorrhage.
We have previously reported that family history of intracerebral hemorrhage (ICH) was associated with both lobar and nonlobar ICH. We sought to further examine this finding by analyzing differences by age and by apolipoprotein E (Apo E) genotype. All cases of hemorrhagic stroke in the greater Cincinnati area were identified through retrospective screening, and a subset was invited to undergo a direct interview and genetic testing. Interviewed subjects were matched to 2 controls by age, race, and sex. Conditional stepwise logistic regression modeling was used to determine whether having a first-degree relative with an ICH (FHICH) was an independent risk factor for ICH. Between May 1997 and December 2002, we recruited 333 cases of ICH. FHICH was found to be an independent risk factor for both lobar ICH (odds ratio [OR] = 3.9; P = .04) and nonlobar ICH (OR ratio = 5.4; P = .01) after controlling for the presence of numerous variables. Among nonlobar ICH cases, the risk appeared to be predominately in those age < 70 years. The presence of Apo E4 was associated with lobar ICH at age >/= 70 years but not at age < 70 years. Family history of ICH appears to be a significant risk factor for nonlobar ICH at age < 70 years. The presence of Apo E4 appears to be a risk factor for lobar ICH at age >/= 70 years but not at age < 70 years. Family history of ICH is a risk factor for lobar ICH after controlling for the presence of Apo E4.


Occurrence of Temporomandibular Disorders among patients undergoing treatment for Obstructive Sleep Apnoea Syndrome (OSAS) using Mandibular Advancement Device (MAD): A Systematic Review conducted according to PRISMA guidelines and the Cochrane handbook for systematic reviews of interventions.
Patients undergoing mandibular advancement device (MAD) therapy for obstructive sleep apnea (OSA) may experience changes in jaw position and altered occlusion. This could potentially contribute to the development or exacerbation of TMD symptoms. The literature on the long-term impact of MAD treated for OSA on TMD is scarce. Hence, this review was undertaken to ascertain the occurrence of TMD in MAD users. A comprehensive search protocol was implemented across several online databases using MeSH keywords and Boolean operators. A standardised data extraction form was developed specifically for this review. Two reviewers independently extracted the data. RoB-2 was used to evaluate the methodological quality of the included studies. A total of 13 clinical studies were selected for this review. Some studies reported a significant reduction in the severity and frequency of TMD symptoms following MAD treatment. However, other studies did not observe significant changes in TMD symptoms or TMJ-related parameters from baseline to follow-up intervals. Temporary increases in TMJ-related pain or symptoms at the beginning of the follow-up period, which later subsided, were reported in some studies. Overall, MAD was not discontinued in any OSA patient due to TMDs. The findings reveal that different outcomes associated with TMD are affected differently by MAD treatment for OSAS. According to a few studies, MAD therapy significantly reduced the severity and frequency of TMD symptoms. Other research, however, found no appreciable modifications in TMD symptoms or TMJ-related indicators. Although the overall results point to no significant effect of MAD treatment on TMD symptoms, the disparity in results between studies highlights the need for additional studies using standardised approaches.


An Sp1/Sp3 binding polymorphism confers methylation protection.
Hundreds of genes show aberrant DNA hypermethylation in cancer, yet little is known about the causes of this hypermethylation. We identified RIL as a frequent methylation target in cancer. In search for factors that influence RIL hypermethylation, we found a 12-bp polymorphic sequence around its transcription start site that creates a long allele. Pyrosequencing of homozygous tumors revealed a 2.1-fold higher methylation for the short alleles (P<0.001). Bisulfite sequencing of cancers heterozygous for RIL showed that the short alleles are 3.1-fold more methylated than the long (P<0.001). The comparison of expression levels between unmethylated long and short EBV-transformed cell lines showed no difference in expression in vivo. Electrophorectic mobility shift assay showed that the inserted region of the long allele binds Sp1 and Sp3 transcription factors, a binding that is absent in the short allele. Transient transfection of RIL allele-specific transgenes showed no effects of the additional Sp1 site on transcription early on. However, stable transfection of methylation-seeded constructs showed gradually decreasing transcription levels from the short allele with eventual spreading of de novo methylation. In contrast, the long allele showed stable levels of expression over time as measured by luciferase and approximately 2-3-fold lower levels of methylation by bisulfite sequencing (P<0.001), suggesting that the polymorphic Sp1 site protects against time-dependent silencing. Our finding demonstrates that, in some genes, hypermethylation in cancer is dictated by protein-DNA interactions at the promoters and provides a novel mechanism by which genetic polymorphisms can influence an epigenetic state.


Epidermal growth factor alters the bax:bcl-w ratio following massive small bowel resection.
Following massive small bowel resection (SBR), the expression of bax and bcl-w is associated with increased enterocyte apoptosis. Epidermal growth factor (EGF) has been shown to enhance enterocyte proliferation and retard apoptosis in the adapting bowel. This study examined the effect of EGF on the expression of these bcl-2 family members during adaptation. Mice (C57Bl/6; n = 38) underwent a 50% SBR or sham operation and then were randomized to receive twice-daily orogastric saline or EGF (50 microg/kg/day). After 3 days, the remnant ileum was removed, apoptotic index (No. apoptotic bodies/crypt) calculated, and expression of mRNA and protein for bax and bcl-w quantified. EGF prevented the expected increase in the apoptotic index after SBR and altered the ratio of bax to bcl-w in favor of cell survival. Following massive small bowel resection, EGF retards rates of enterocyte apoptosis and modifies the expression of bcl-2 family members. By decreasing bax and increasing bcl-w expression, the balance between pro- and anti-apoptotic genes is shifted in favor of cell survival. Alteration of bcl-2 family member expression may be an important mechanism by which EGF reduces the increased enterocyte apoptosis that occurs after massive small bowel resection.


Helicobacter pylori eradication in gastric diffuse large B cell lymphoma.
Diffuse large B cell lymphoma (DLBCL) of the stomach is a heterogenous disease. There are tumors without histological evidence of mucosa-associated lymphoid tissue (MALT) lymphoma, which are classified as pure or de novo DLBCL and those with evidence of MALT, which are classified as DLBCL (MALT). The association between Helicobacter pylori (H. pylori) and gastric MALT lymphoma and remission with H. pylori eradication was shown in the 1990s. In recent years, scientists from Taiwan and others have shown that high-grade gastric lymphomas may be dependent on H. pylori and eradication of this microorganism is effective in these cases. This entity is biologically distinct from H. pylori (-) cases and has a better clinical outcome. There are sufficient data about the complete remission in some of these cases with brief treatment with antibiotics. With this strategy, it is possible to save some of these cases from the harmful effects of standard chemotherapy. It is time to treat these cases with H. pylori eradication. However, strict histopathological follow-up is crucial and histopathological response must be evaluated according to the scoring system proposed by Groupe d'Etude des Lymphomes de l'Adulte. If there is no sufficient response, chemotherapy must be given immediately. These results suggest that H. pylori dependency and high-grade transformation in gastric MALT lymphomas are distinct events.


Homoleptic pnictogen-chalcogen coordination complexes.
The synthesis and structural characterization of dicationic selenium and tellurium analogues of the carbodiphosphorane and triphosphenium families of compounds are reported. These complexes, [Ch(dppe)][OTf](2) [Ch = Se, Te; dppe = 1,2-bis(diphenylphosphino)ethane; OTf = trifluoromethanesulfonate], are formed using [Ch](2+) reagents via a ligand-exchange protocol and represent extremely rare examples of homoleptic pnictogen → chalcogen coordination complexes. The corresponding arsenic compounds were also prepared, [Ch(dpAse)][OTf](2) [Ch = Se, Te; dpAse = 1,2-bis(diphenylarsino)ethane], exhibiting the first instance of an arsenic → chalcogen dative bond. The electronic structures of these unique compounds were determined and compared to previously reported chalcogen dications.


Plasma GH responses to human GHRH-antagonist in normal subjects.
The effect of GHRH-antagonist [(N-Ac-Tyr1, D-Arg2) GRF-(1-29)-NH2] on plasma GH morning and evening secretion was evaluated in 14 normal subjects (10 males, 4 females, aged 19-25 years). Plasma GH was determined using a high sensitivity IRMA kit (detection limit, 0.006 micrograms/l). After intravenous infusion of GHRH-antagonist (100 micrograms/100 ml saline over 75 min) in the morning, plasma GH remained constant during the 150 min post-infusion (N = 6). In contrast, when GHRH-antagonist was administered in the evening, plasma GH showed a clear and gradual decrease through the initial 90 min and returned to baseline levels at 150 min. Plasma GH values were also significantly lower from 75 min to 135 min when compared to physiological fluctuations in plasma GH (P < 0.05). Other anterior pituitary hormones remained unaffected by GHRH-antagonist. In conclusion, our data suggest that evening basal GH secretion, but not morning GH secretion, is maintained by endogenous GHRH.


Entry of CART into brain is rapid but not inhibited by excess CART or leptin.
Cocaine- and amphetamine-regulated transcript (CART) is a new anorectic peptide found in the brain and periphery. It is closely associated with leptin, an anorectic agent saturably transported across the blood-brain barrier (BBB). Using multiple time-regression analysis, we found that CART has a rapid rate of entry into brain from blood. However, there was no self-inhibition with CART, even when perfused in blood-free buffer or in fasted mice, showing a lack of saturation. HPLC showed that at least 58% of the injected CART reached brain tissue in intact form, and capillary depletion with and without washout showed that the CART was not bound to endothelial cells or adherent to vascular components. There was no evidence for an efflux system out of the brain for CART. Thus CART can cross the BBB from blood to brain, but its rapid rate of entry is not inhibited by excess CART or leptin.


[Standardization in health care].
An opinion on standardization in medicine is presented in the article. Alternative methods of control over the medical practice as well as they key reasons preconditioning the necessity of introducing the standards are shortly defined on the basis of an example of using the visualization services in neurological practice.