Cardiovascular magnetic resonance predicts all-cause mortality in pulmonary hypertension associated with heart failure with preserved ejection fraction.
This study aimed to determine the prognostic value of cardiovascular magnetic resonance (CMR) in patients with heart failure with preserved ejection fraction and associated pulmonary hypertension (pulmonary hypertension-HFpEF). Patients with pulmonary hypertension-HFpEF were recruited from the ASPIRE registry and underwent right heart catheterisation (RHC) and CMR. On RHC, the inclusion criteria was a mean pulmonary artery pressure (MPAP) ≥ 25 mmHg and pulmonary arterial wedge pressure > 15 mmHg and, on CMR, a left atrial volume > 41 ml/m2 with left ventricular ejection fraction > 50%. Cox regression was performed to evaluate CMR against all-cause mortality. In this study, 116 patients with pulmonary hypertension-HFpEF were identified. Over a mean follow-up period of 3 ± 2 years, 61 patients with pulmonary hypertension-HFpEF died (53%). In univariate regression, 11 variables demonstrated association to mortality: indexed right ventricular (RV) volumes and stroke volume, right ventricular ejection fraction (RVEF), indexed RV mass, septal angle, pulmonary artery systolic/diastolic area and its relative area change. In multivariate regression, only three variables were independently associated with mortality: RVEF (HR 0.64, P < 0.001), indexed RV mass (HR 1.46, P < 0.001) and IV septal angle (HR 1.48, P < 0.001). Our CMR model had 0.76 area under the curve (P < 0.001) to predict mortality. This study confirms that pulmonary hypertension in patients with HFpEF is associated with a poor prognosis and we observe that CMR can risk stratify these patients and predict all-cause mortality. When patients with HFpEF develop pulmonary hypertension, CMR measures that reflect right ventricular afterload and function predict all-cause mortality.


SIMMER employs similarity algorithms to accurately identify human gut microbiome species and enzymes capable of known chemical transformations.
Bacteria within the gut microbiota possess the ability to metabolize a wide array of human drugs, foods, and toxins, but the responsible enzymes for these chemical events remain largely uncharacterized due to the time-consuming nature of current experimental approaches. Attempts have been made in the past to computationally predict which bacterial species and enzymes are responsible for chemical transformations in the gut environment, but with low accuracy due to minimal chemical representation and sequence similarity search schemes. Here, we present an in silico approach that employs chemical and protein Similarity algorithms that Identify MicrobioMe Enzymatic Reactions (SIMMER). We show that SIMMER accurately predicts the responsible species and enzymes for a queried reaction, unlike previous methods. We demonstrate SIMMER use cases in the context of drug metabolism by predicting previously uncharacterized enzymes for 88 drug transformations known to occur in the human gut. We validate these predictions on external datasets and provide an in vitro validation of SIMMER's predictions for metabolism of methotrexate, an anti-arthritic drug. After demonstrating its utility and accuracy, we made SIMMER available as both a command-line and web tool, with flexible input and output options for determining chemical transformations within the human gut. We present SIMMER as a computational addition to the microbiome researcher's toolbox, enabling them to make informed hypotheses before embarking on the lengthy laboratory experiments required to characterize novel bacterial enzymes that can alter human ingested compounds.


Occupational exposure to trichloroethylene and cancer risk for workers at the Paducah Gaseous Diffusion Plant.
The Paducah Gaseous Diffusion Plant (PGDP) became operational in 1952; it is located in the western part of Kentucky. We conducted a mortality study for adverse health effects that workers may have suffered while working at the plant, including exposures to chemicals. We studied a cohort of 6820 workers at the PGDP for the period 1953 to 2003; there were a total of 1672 deaths to cohort members. Trichloroethylene (TCE) is a specific concern for this workforce; exposure to TCE occurred primarily in departments that clean the process equipment. The Life Table Analysis System (LTAS) program developed by NIOSH was used to calculate the standardized mortality ratios for the worker cohort and standardized rate ratio relative to exposure to TCE (the U.S. population is the referent for ageadjustment). LTAS calculated a significantly low overall SMR for these workers of 0.76 (95% CI: 0.72-0.79). A further review of three major cancers of interest to Kentucky produced significantly low SMR for trachea, bronchus, lung cancer (0.75, 95% CI: 0.72-0.79) and high SMR for Non-Hodgkin's lymphoma (NHL) (1.49, 95% CI: 1.02-2.10). No significant SMR was observed for leukemia and no significant SRRs were observed for any disease. Both the leukemia and lung cancer results were examined and determined to reflect regional mortality patterns. However, the Non-Hodgkin's Lymphoma finding suggests a curious amplification when living cases are included with the mortality experience. Further examination is recommended of this recurrent finding from all three U.S. Gaseous Diffusion plants.


VviUCC1 Nucleotide Diversity, Linkage Disequilibrium and Association with Rachis Architecture Traits in Grapevine.
Cluster compactness is a trait with high agronomic relevance, affecting crop yield and grape composition. Rachis architecture is a major component of cluster compactness determinism, and is a target trait toward the breeding of grapevine varieties less susceptible to pests and diseases. Although its genetic basis is scarcely understood, a preliminary result indicated a possible involvement of the VviUCC1 gene. The aim of this study was to characterize the VviUCC1 gene in grapevine and to test the association between the natural variation observed for a series of rachis architecture traits and the polymorphisms detected in the VviUCC1 sequence. This gene encodes an uclacyanin plant-specific cell-wall protein involved in fiber formation and/or lignification processes. A high nucleotide diversity in the VviUCC1 gene promoter and coding regions was observed, but no critical effects were predicted in the protein domains, indicating a high level of conservation of its function in the cultivated grapevine. After correcting statistical models for genetic stratification and linkage disequilibrium effects, marker-trait association results revealed a series of single nucleotide polymorphisms (SNPs) significantly associated with cluster compactness and rachis traits variation. Two of them (Y-984 and K-88) affected two common cis-transcriptional regulatory elements, suggesting an effect on phenotype via gene expression regulation. This work reinforces the interest of further studies aiming to reveal the functional effect of the detected VviUCC1 variants on grapevine rachis architecture.


Hormonal contraception and risk of cardiovascular disease. An international perspective.
The most frequent major adverse effect of hormonal contraception is an increased risk of cardiovascular disease. The effect on the risk of venous thromboembolism (VTE), ischemic and hemorrhagic stroke, and myocardial infarction (MI) differs and is strongly influenced by smoking and the presence of other cardiovascular risks factors, such as hypertension and diabetes mellitus. The incidence of each disease rises with age and there are differences in risk among hormonal contraceptive preparations. This article provides a framework within which to assess the balance of risks among types of hormonal contraceptives according to individual circumstances. Data on cardiovascular disease mortality rates in women of reproductive age in different countries of the world were compiled from nationally reported statistics and supplemented where possible with reported disease incidence rates. Risks associated with current use of hormonal contraception were compiled from the most recent publications on the cardiovascular effects of steroid hormone contraception. These were combined to estimate the total cardiovascular incidence and mortality according to baseline cardiovascular risk and individual characteristics. Mortality rates for cardiovascular diseases are very low in women of reproductive age. Myocardial infarction mortality rates rise from < 0.4 per 100,000 woman-years at age 15-24 years to the range 2 to 7 per 100,000 woman-years at age 35-44 years. Stroke mortality rates similarly rise steeply with age and are between 3 and 5 times higher than those for MI. VTE mortality rates rise less steeply with age and are approximately one-tenth the MI mortality rates at age 35-44 years. The adverse effect of oral contraceptives (OC) on the risk of VTE is the most important contributor to the total number of cardiovascular cases attributable to OC use. The increased risk of stroke and MI dominate the patterns of mortality in OC users and smokers. The additional risks attributable to smoking are greater than the additional risks attributable to OC use. The risk attributable to OC use in women < 35 years of age is small, even if they smoke, but there are substantially increased risks in older women who both smoke and use OC. The additional mortality attributable to OC use can be reduced by screening users, as this results in lower relative risks of ischemic stroke and MI. Differences between OC types in the relative risk of VTE contribute little to the total cardiovascular mortality associated with OC use, even though the total number of cardiovascular events is increased. A potential reduction in the risk of MI with desogestrel and gestodene compared with levonorgestrel-containing OC would have little difference on overall mortality rates in women in their 20s and 30s, but may result in a net reduction in OC-attributable mortality in women aged 40-44 years who smoke. An overall quantification of the risks for different types of oral contraceptive users is necessary for an informed choice of contraceptive method, and any assessment of the balance of cardiovascular risks is complex. The model provides a tool to assess, at the level of the individual, the risks associated with use of different OC according to personal circumstances. It is important to consider the user's age and smoking status when determining OC attributable risks.


Well-Differentiated Adenocarcinoma Spreading Widely in the Gastric Submucosa.
A 56-year-old woman was referred to our hospital due to dry mouth. Diagnostic upper gastrointestinal endoscopy showed slightly elevated lesions both on the anterior wall and lesser curvature in the upper part of the stomach. Biopsy-proven tuble-forming atypical cells in the two lesions led us to treat the presumed early gastric cancers with endoscopic submucosal dissection (ESD). Pathological examination of the ESD specimen showed well-differentiated malignant cells spreading widely in the submucosa with positive lateral and deep margins. On retrospective image re-evaluation after ESD, we noticed the correlation between the presumed early gastric cancers and the multiple submucosal cyst-like lesions in the gastric wall on computed tomography. Under the tentative diagnosis of gastric cancers originating not from orthotopic gastric mucosa but from submucosal ectopic gastric gland, the patient underwent laparoscopic total gastrectomy and regional lymph node dissection, revealing the tumor infiltration to the serosa and regional lymph node swelling. Postoperative pathological evaluation showed lymph node metastases, multiple submucosal cyst-like lesions lined with a single layer of presumably benign epithelium, papillary adenocarcinoma cells in the submucosa, and tubular adenocarcinoma cells both in the mucosal and subserosal regions. The patient was discharged on the postoperative 7th day without any events and completed adjuvant chemotherapy on an outpatient basis. General surgeons should note that cyst-like lesion(s) in the gastric wall might be a predictor of extensive submucosal cancer cell spreading even in a case of well-differentiated gastric adenocarcinoma.


Radio-frequency tissue ablation of the liver: in vivo and ex vivo experiments with four different systems.
The aim of this study was to test the efficacy of four different radio-frequency ablation (RFA) systems in normal hepatic parenchyma in large animals. The RFA was applied to pig livers in vivo and to calf livers ex vivo using the Radionics cluster needle, RITA starburst XL needle, Radiotherapeutics Le Veen 4.0 needle, and the Berchtold 14-G saline-perfused 15-mm active-tip needle based on constructor specifications. The volume of tissue coagulation from RF was calculated from measurements of the vertical diameter (Dv) and transverse diameter (Dt). Lesion shape was characterized using the ratio between Dt/Dv. Radiotherapeutics and RITA produced in vivo lesion volume of 42+/-10, 39+/-4 cm3 with a reproducible spherical shape (Dt/Dv of 1.01+/-0.16 and 0.97+/-0.1, respectively). Radionics produced in vivo RF lesions volume of 29+/-11 cm3) with an ovoid shape (Dt/Dv 0.88+/-0.09). The RF lesions with the Berchtold device could not be assessed in vivo as 5 of 8 animals died during treatment. Ex vivo RF lesions had similar volumes with each system; however, the Radiotherapeutics device produced more reproducible shaped lesions than the other systems. In our experimental study, we found no difference between expandable needle systems in vivo. Cooled needles produced slightly smaller and ovoid shape in vivo lesions.


Economic Consequences of Ill-Health in Rural Ethiopia.
We use three years of household panel data to analyze the effects of ill-health on household economic outcomes in rural Ethiopia. We examine the immediate effects of various ill-health measures on health expenditure and labor supply, the subsequent coping responses, and finally the effect on income and consumption. We find evidence of substantial economic risk in terms of increased health expenditure and reduced agricultural productivity. Households are able to smooth consumption by resorting to intra-household labor substitution, borrowing and depleting assets. However, maintaining current consumption through borrowing and depletion of assets is unlikely to be sustainable and displays the need for health financing reforms and safety nets that reduce the financial consequences of ill-health.


Activity measures in anorexia nervosa.
Twenty-four-hour measurements of wrist and ankle kinetic energy expenditures were obtained on 20 hospitalized female anorectics during the first two weeks of their hospitalization. Kinetic energy was examined against measures of weight, depression, and Minnesota Multiphasic Personality Inventory scores in a regression analysis. Effect of cyproheptadine hydrochloride, amitriptyline hydrochloride, and placebo on activity was assessed. The results supported previous studies showing a positive relationship between weight gain and motor activity and challenge the commonly held notion that activity decreases in anorectics as their clinical condition improves. Motor activity was initially significantly suppressed by cyproheptadine and subsequently increased.


Piper betel leaf: a reservoir of potential xenohormetic nutraceuticals with cancer-fighting properties.
Plants contain a much greater diversity of bioactive compounds than any man-made chemical library. Heart-shaped Piper betel leaves are magnificent reservoirs of phenolic compounds with antiproliferative, antimutagenic, antibacterial, and antioxidant properties. Widely consumed in South Asian countries, the glossy leaf contains a multitude of biophenolics such as hydroxychavicol, eugenol, chavibetol, and piperols. Convincing data underscore the remarkable chemotherapeutic and chemopreventive potential of betel leaves against a variety of cancer types. The leaf constituents modulate an extensive array of signaling molecules such as transcription factors as well as reactive oxygen species (ROS) to control multiple nodes of various cellular proliferation and death pathways. Herein, we provide an overall perspective on the cancer-fighting benefits of the phenolic phytochemicals in betel leaves and a comprehensive overview of the mechanisms responsive to dose-driven ROS-mediated signaling cascades conscripted by bioactive phenolics to confer chemotherapeutic and chemopreventive advantages. Intriguingly, these ROS-triggered responses are contextual and may either elicit a protective xenohormetic antioxidant response to premalignant cells to constitute a chemopreventive effect or generate a curative chemotherapeutic response by pro-oxidatively augmenting the constitutively elevated ROS levels in cancer cells to tip the balance in favor of selective apoptosis induction in cancer cells while sparing normal ones. In conclusion, this review provides an update on how distinct ROS levels exist in normal versus cancer cells and how these levels can be strategically modulated and exploited for therapeutic gains. We emphasize the yet untapped potential of the evergreen vine, betel leaf, for chemopreventive and chemotherapeutic management of cancer.


Deep in situ microscopy for real-time analysis of mammalian cell populations in bioreactors.
An in situ microscope based on pulsed transmitted light illumination via optical fiber was combined to artificial-intelligence to enable for the first time an online cell classification according to well-known cellular morphological features. A 848 192-image database generated during a lab-scale production process of antibodies was processed using a convolutional neural network approach chosen for its accurate real-time object detection capabilities. In order to induce different cell death routes, hybridomas were grown in normal or suboptimal conditions in a stirred tank reactor, in the presence of substrate limitation, medium addition, pH regulation problem or oxygen depletion. Using such an optical system made it possible to monitor real-time the evolution of different classes of animal cells, among which viable, necrotic and apoptotic cells. A class of viable cells displaying bulges in feast or famine conditions was also revealed. Considered as a breakthrough in the catalogue of process analytical tools, in situ microscopy powered by artificial-intelligence is also of great interest for research.


[Nasogastric tubes: a lot of bother].
The insertion of the nasogastric tube is one of the procedure that produces the most discomfort for the patients and practitioners. The AA, with the make use of their clinical experience and the data of the literature, report some personal reflections about the management of the nasogastric tube. The AA also analyse some variables (choice of the tube, approach to the patient, insertion of the tube, examination of the position, fixation and removal) that can influence on discomfort of the patient. The choice of the most right SNG is an important moment for the correct insertion; an effect we need to adjust the material and diameter of the tube to the prearranged use. The common practice demonstrates that the collaboration with the patient, obtained by "direct" and "indirect" strategies, gives more possibilities to immediately success of this procedure. The literature explains that it is possible to decrease the discomfort with topical anesthesia; still there are some points of view to clarify. From analyse of the different methods to check the position of SNG, the pH test of the aspirating fluid is the best solution. Once examination of right placement, we need to fix in different points (at least two). From personal experience the removal of SNG is better tolerate that the insertion because the patient is more conscious to be on the mend. The principal recommendation is to abstain from insertion of SNG if it is not closely necessary!


Individual-level predictors for HIV testing among antenatal attendees in Lusaka, Zambia.
Despite the availability of antiretroviral prophylaxis, roughly one-fifth of public-sector antenatal patients decline HIV testing in Lusaka, Zambia. We administered a survey to determine individual-level predictors of HIV testing. Of 1064 antenatal attendees approached after pretest counseling, 1060 (>99%) participated. Of these, 686 (65%) agreed to HIV testing. On bivariate analysis controlling for clinic of attendance, women younger than 20 years old (adjusted RR [ARR] = 1.14), unmarried (ARR = 1.14), pregnant for the first time (ARR = 1.14), with lower educational attainment (ARR = 1.15), and with lower income (ARR = 1.14) were all more likely to undergo testing. When HIV risk was considered, women with low self-perceived risk were most likely to undergo HIV testing. As risk perception increased, likelihood for testing decreased (P for trend < 0.001). Although not statistically predictive, we identified prevalent community beliefs that may act as barriers to testing. Because individual-level characteristics were only weakly predictive of HIV testing, future work should concentrate on community-level factors.


A retrospective comparison of cognitive performance in individuals with advanced Parkinson's Disease in Hong Kong and Canada.
A deeper understanding of the cross-cultural applicability of cognitive tests across countries and cultures is needed to better equip neuropsychologists for the assessment of patients from diverse backgrounds. Our study compared cognitive test scores in patients with advanced Parkinson's disease (PD) at the Prince of Wales Hospital (n = 63; Hong Kong) and the Foothills Medical Center (n = 20; Calgary, Canada). The groups did not differ in age or sex (p > .05), but Western patients had significantly more years of education (M = 14.2, SD = 2.7) than Asian patients (M = 10.33, SD = 4.4). Cognitive tests administered to both groups included: digit span, verbal fluency (animals), the Boston Naming Test, and verbal memory (California Verbal Learning Test or Chinese Auditory Verbal Learning Test). Testing was completed before and 12 months after deep brain stimulation surgery. Results showed cognitive performance was similar across time, but significant group differences were found on digit span forward (longer among patients from Hong Kong; F(1, 75) = 44.155, p < .001) and the Boston Naming Test (higher percent spontaneous correct among patients from Canada; F(1, 62) = 7.218, p = .009, η2 = 0.104), after controlling for age, sex, and years of education. In conclusion, our findings provide preliminary support for the similarity of Chinese versions of tests originally developed for Western populations. Also, we caution that some aspects of testing may be susceptible to cultural bias and therefore warrant attention in clinical practice and refinement in future test development for Asian patients.


Detection of Bone Marrow Edema Pattern With Dual-Energy Computed Tomography of the Pig Mandible Treated With Radiotherapy and Surgery Compared With Magnetic Resonance Imaging.
The aim of the study was to investigate the accuracy of dual-energy computed tomography (DECT) compared with magnetic resonance (MR) imaging for the detection of edema of the mandible. Fifteen adult Göttingen mini pigs received irradiation to the mandible with an equivalent dose of 0, 25, 50, or 70 Gy. Six months after irradiation, all animals underwent DECT and MR imaging of the mandible. Magnetic resonance short tau inversion recovery (STIR) was used for the grading of the bone marrow edema (0-3). Dual-energy CT (80 and 140 kVp) was performed, and virtual noncalcium (VNCa) images were calculated. Increased signal intensity at STIR was found in the higher radiation groups. An increase of signal intensity in MR imaging was accompanied by a significant increase in the Hounsfield unit value of the VNCa images of the bone marrow (STIR: 0, 1, 2, 3; mean Hounsfield unit: -103, -90, -76, -34, respectively; P < 0.05; R = 0.388). The VNCa images derived from DECT are able to demonstrate bone marrow edema in radiation-induced bone changes in the mandible.


Precise timing of abrupt increase in dust activity in the Middle East coincident with 4.2 ka social change.
The extent to which climate change causes significant societal disruption remains controversial. An important example is the decline of the Akkadian Empire in northern Mesopotamia ∼4.2 ka, for which the existence of a coincident climate event is still uncertain. Here we present an Iranian stalagmite record spanning 5.2 ka to 3.7 ka, dated with 25 U/Th ages that provide an average age uncertainty of 31 y (1σ). We find two periods of increased Mg/Ca, beginning abruptly at 4.51 and 4.26 ka, and lasting 110 and 290 y, respectively. Each of these periods coincides with slower vertical stalagmite growth and a gradual increase in stable oxygen isotope ratios. The periods of high Mg/Ca are explained by periods of increased dust flux sourced from the Mesopotamia region, and the abrupt onset of this dustiness indicates threshold behavior in response to aridity. This interpretation is consistent with existing marine and terrestrial records from the broad region, which also suggest that the later, longer event beginning at 4.26 ka is of greater regional extent and/or amplitude. The chronological precision and high resolution of our record indicates that there is no significant difference, at decadal level, between the start date of the second, larger dust event and the timing of North Mesopotamia settlement abandonment, and furthermore reveals striking similarity between the total duration of the second dust event and settlement abandonment. The Iranian record demonstrates this region's threshold behavior in dust production, and its ability to maintain this climate state for multiple centuries naturally.


[Characteristics of prostatic cancer undetected in the first assessment of a screening program. Quality control].
To study the results of the second round in the subjects with negative tests in the first round of a prostate cancer screening program and to analyze the characteristics of the tumors that were not detected in the first round. Of 5188 males evaluated in a prostate cancer screening program, 976 with negative tests in the first round (804 with PSA < or = 4 ng/ml; 172 with PSA > 4 ng/ml and a negative biopsy) accepted to undergo subsequent tests. During the second round, 163 biopsies were indicated. The biopsy results and the characteristics of the tumors detected were analyzed. The biopsy yield was higher (but not significantly) in the first round (80 cancers/481 biopsies; 16.6%) than in the second round (13 cancers/115 biopsies; 11.3%). Of the 163 biopsies indicated in the second round, 115 were performed and 13 cancers were detected (10 of these patients had a high PSA in the first round). The univariate analysis showed no differences for age, PSA, PSA density, prostate volume, transrectal US findings, or Gleason score in the cases diagnosed in the first round and those detected in the second round. However, there was a higher proportion of tumors with abnormal DRE in the cancers detected in the first round than in the second round, (31.3% vs 7.7%, respectively; p = 0.02). There was a higher proportion of tumors clinically detected in the second round than in the first round (100% vs 75%, respectively; p = 0.043). The multivariate analysis only showed differences for the DRE findings (p = 0.045). A significant number of tumors are undetected in prostate cancer screening programs. Although the biopsy yield may be slightly lower in subsequent rounds, there is a strong trend of detecting more localized tumors (and therefore potentially curable). We have found no correlation between a greater prostate volume and tumors that were undetected in the first round.


The mortality risk of elevated serum transferrin saturation and consumption of dietary iron.
Recent data shows an increased mortality risk associated with elevated transferrin saturation. Because ingestion of dietary iron may contribute to iron overload in persons with elevated transferrin saturation, we investigated the relationship between elevated transferrin saturation, ingestion of dietary iron and red meat, and mortality. This 12-year cohort study used data from the second National Health and Nutrition Examination Survey 1976-1980 (NHANES II) and the NHANES II Mortality Study 1992. Population estimates were based on 9,229 persons aged 35 to 70 years at baseline. A Cox proportional hazards analysis was performed based on levels of transferrin saturation, intake of dietary iron, and intake of red meat. The analysis was conducted while controlling for demographics, severity of illness, body mass index, and smoking status. Unadjusted analyses indicated that those who had a high transferrin saturation and reported high dietary iron or red meat consumption had an increased mortality risk. The adjusted survival analysis indicated that persons with elevated transferrin saturation who reported high dietary iron intake had a hazard ratio for death of 2.90 (95% confidence interval [CI], 1.39-6.04) compared with those with normal transferrin saturation levels and reported low dietary iron intake. Persons who had a high transferrin saturation and reported high red meat consumption also had an increased hazard ratio for death (2.26; 95% CI, 1.45-3.52) compared with those who had normal transferrin saturation and reported low red meat consumption. Ingestion of large quantities of dietary iron and red meat in persons with high transferrin saturation is associated with an increase in mortality. Simple dietary restrictions may reduce the mortality risk associated with high transferrin saturation.


Haemolytic activity of stonustoxin from stonefish (Synanceja horrida) venom: pore formation and the role of cationic amino acid residues.
Stonustoxin (SNTX) is a two-subunit protein toxin purified from the venom of the stonefish (Synanceja horrida), which induces potent haemolytic activity. We examined the pore-forming property of this non-enzymic protein by an osmotic protection assay. SNTX-induced haemolysis was completely prevented by osmotic protectants of adequate size [poly(ethylene) glycol 3000; molecular diameter approx. 3.2 nm]. Uncharged molecules of smaller size, such as raffinose and poly(ethylene) glycol 1000-2000, failed to protect against cell lysis. These findings indicate that SNTX induces the formation of hydrophilic pores in the cell membrane, which results in the lysis of erythrocytes. Since cationic residues contribute significantly to the cytolytic activity of several other pore-forming toxins, we examined the role of positively charged lysine and arginine residues in the haemolytic activity of SNTX. SNTX lost its haemolytic activity when the positively charged side chains of lysine residues were neutralized or converted into negatively charged side chains upon carbamylation or succinylation respectively. The haemolytic activity of SNTX was also inhibited by the modification of positively charged arginine residues using 2,3-butanedione. The loss of haemolysis showed strong correlation with the number of Lys or Arg residues modified. CD analyses, however, showed that the conformation of SNTX was not significantly affected by these chemical modifications. Further, the haemolytic activity of SNTX was competitively inhibited by various negatively charged lipids, such as phosphatidylserine, cardiolipin and monosialogangliosides. These results indicate that SNTX induces potent haemolytic activity through the formation of pores in the cell membrane, and that cationic residues play a crucial role in its cytolytic mechanism.


Cholera toxin stimulates adenosine 3',5'-monophosphate synthesis and epithelial wound closure in the rabbit cornea.
Rabbit corneas were treated in vitro and in vivo with cholera toxin (CTX), a specific and irreversible activator of adenylate cyclase. Tissue pieces incubated in vitro in the presence of 10 mug/ml CTX for 15 min continuously synthesized adenosine 3',5'-monophosphate (cyclic AMP) at an increased rate for 3 hr in the absence of CTX in the medium. Corneas exposed for 10 min to CTX topically in vivo and after various time intervals incubated in vitro had an increased ability to synthesize cyclic AMP for at least 30 hr after topical treatment. Epithelial wounds, 6 mm in diameter, were made by brief exposure of corneas in vivo to filter disks soaked in heptanol. Wounds in corneas pretreated with CTX closed at a faster rate and earlier than wounds in corneas pretreated with inactivated CTX. We postulate that cyclic AMP mediates the initial events governing the rate of closure of an epithelial defect.


A historical and evolutionary perspective on the biological significance of circulating DNA and extracellular vesicles.
The discovery of quantitative and qualitative differences of the circulating DNA (cirDNA) between healthy and diseased individuals inclined researchers to investigate these molecules as potential biomarkers for non-invasive diagnosis and prognosis of various pathologies. However, except for some prenatal tests, cirDNA analyses have not been readily translated to clinical practice due to a lack of knowledge regarding its composition, function, and biological and evolutionary origins. We believe that, to fully grasp the nature of cirDNA and the extracellular vesicles (EVs) and protein complexes with which it is associated, it is necessary to probe the early and badly neglected work that contributed to the discovery and development of these concepts. Accordingly, this review consists of a schematic summary of the major events that developed and integrated the concepts of heredity, genetic information, cirDNA, EVs, and protein complexes. CirDNA enters target cells and provokes a myriad of gene regulatory effects associated with the messaging functions of various natures, disease progression, somatic genome variation, and transgenerational inheritance. This challenges the traditional views on each of the former topics. All of these discoveries can be traced directly back to the iconic works of Darwin, Lamarck, and their followers. The history of cirDNA that has been revisited here is rich in information that should be considered in clinical practice, when designing new experiments, and should be very useful for generating an empirically up-to-date view of cirDNA and EVs. Furthermore, we hope that it will invite many flights of speculation and stimulate further inquiry into its biological and evolutionary origins.


The utility of submitting fibroepithelial polyps for histological examination.
The fibroepithelial polyp (FEP) is a common cutaneous lesion that is often removed for medical or cosmetic reasons. We examined the utility of submitting clinically diagnosed FEPs for routine microscopic examination. We reviewed 11500 consecutive cutaneous pathology reports. Materials submitted with the clinical diagnosis of FEP or a synonym were reviewed and the histopathologic slides were examined. A comparison group of specimens submitted with the clinical diagnosis of melanocytic nevus was reviewed. The biopsy reports were generated at a regional non-hospital-based dermatopathology laboratory providing service to physicians (dermatologists and nondermatologists) practicing ambulatory medicine predominantly within a 4-state region (Ind, Ky, Tenn, and WVa). Of 1335 clinical specimens submitted as FEPs, there were 5 malignant tumors. In the comparison group of 697 clinically diagnosed melanocytic nevi, there were 6 malignant tumors. In comparison with clinically diagnosed melanocytic nevi, the likelihood that a lesion clinically diagnosed as FEP would be a malignant tumor on histological examination is very low (relative risk, 0.4). None of the lesions clinically diagnosed as FEPs by dermatologists proved to be malignant. Our data suggest there is an extremely low prevalence of malignancy in lesions clinically diagnosed as FEPs. We conclude that cutaneous lesions diagnosed as typical FEPs by dermatologists need not be submitted for microscopic examination.


Identification of a protein that interacts with tubulin dimers and increases the catastrophe rate of microtubules.
Using a polymerization inhibition assay, we have purified a small, heat stable protein that physically interacts with tubulin dimers and increases the catastrophe rate of microtubules. Sequence analysis identified this protein as oncoprotein 18 (Op18)/stathmin, a conserved phosphoprotein that is highly expressed in leukemia cells. Immunodepletion experiments in Xenopus egg extracts showed that Op18/stathmin is involved in physiological regulation of mitotic microtubule dynamics. Op18/stathmin is a microtubule regulator that preferentially interacts with unpolymerized subunits. It is a candidate for increasing the microtubule catastrophe rate in mitosis and might also regulate microtubule dynamics in response to external signals.


Microheterogeneity of actin gels formed under controlled linear shear.
The diffusion coefficients and fluorescence polarization properties of actin subjected to a known shear have been determined both during and after polymerization, using a modification of a cone-plate Wells-Brookfield rheometer that allows monitoring of samples with an epifluorescence microscope. Fluorescence polarization and fluorescence photobleaching recovery experiments using rhodamine-labeled actin as a tracer showed that under conditions of low shear (shear rates of 0.05 s-1), a spatial heterogeneity of polymerized actin was observed with respect to fluorescence intensity and the diffusion coefficients with actin mobility becoming quite variable in different regions of the sample. In addition, complex changes in fluorescence polarization were noted after stopping the shear. Actin filaments of controlled length were obtained using plasma gelsolin (gelsolin/actin molar ratios of 1:50 to 1:300). At ratios of 1:50, neither spatial heterogeneity nor changes in polarization were observed on subjecting the polymerized actin to shear. At ratios of approximately 1:100, a decrease on the intensity of fluorescence polarization occurs on stopping the shear. Longer filaments exhibit spatial micro-heterogeneity and complex changes in fluorescence polarization. In addition, at ratios of 1:100 or 1:300, the diffusion coefficient decreases as the total applied shear increased. This behavior is interpreted as bundling of filaments aligned under shear. We also find that the F-actin translational diffusion coefficients decrease as the total applied shear increases (shear rates between 0.05 and 12.66 s-1), as expected for a cumulative process. When chicken gizzard filamin was added to gelsolin-actin filaments (at filamin/actin molar ratios of 1:300 to 1:10), a similar decrease in the diffusion coefficients was observed for unsheared samples. Spatial microheterogeneity might be related to the effects of the shear field in the alignment of filaments, and the balance between a three-dimensional network and a microheterogeneous system (containing bundles or anisotropic phases) appears related to both shear and the presence of actin-binding proteins.


Calcium affects insulin release and membrane potential in islet beta-cells.
Insulin release from perfused rat pancreas was compared with membrane potentials of single beta-cells from perifused mouse islets during glucose stimulation (11.1 mM) in the presence of varying Ca and Mg concentrations. Depolarization was associated with insulin release and hyperpolarization with its suppression, irrespective of Ca concentration. After sudden reduction of Ca and Mg (to 0.05 and 0.01 mM, respectively), glucose-stimulated insulin release was maintained while the cell membrane depolarized, leading to a reversed pattern of burst activity. Readdition of Ca and Mg caused suppression of insulin release that paralleled hyperpolarization of the cell membrane. This suppression was transient, lasting < 5 min, and was due mainly to readdition of Ca. Patterns of insulin release during reduction of Ca and Mg in the presence of valinomycin (1 microM), diphenylhydantoin (25 microgram/ml), and ethyleneglycol-bis(beta-aminoethylether)-N,N'-tetraacetic acid (0.037 and 1.0 mM) were also studied. In conclusion, the relative concentrations of Ca and Mg and the membrane potential per se are important in the release of insulin. Also, under certain experimental conditions, Ca can block glucose-stimulated insulin release, possibly by increasing K+ permeability.


What we know and what we do not know about factors associated with and interventions to promote antiretroviral adherence.
Antiretroviral therapy (ART) adherence remains critical for achieving successful outcomes. Factors affecting ART adherence can occur at the individual level or be related to the treatment regimen, daily schedule, and/or interpersonal relationships. While treatment-related barriers have diminished with recent simplified ART regimens, guidelines still recommend considering regimen simplicity. ART readiness should be assessed prior to starting ART, with follow-up adherence assessments once ART is initiated, and at all subsequent clinical visits. Adherence interventions work best when multifaceted, targeted for at-risk and nonadherent participants, and tailored to individuals' needs. Successful interventions have included education and counseling, provision of social support, directly observed therapy, and financial incentives. Pillboxes and two-way short-text messaging service (SMS) reminders have been shown to be effective and are widely recommended tools for promoting ART adherence. Further research is needed to determine the optimal combination of adherence interventions, as well as generalizability, implementation, and cost-effectiveness.


Fibrous mini-collagens in hydra nematocysts.
Nematocysts (cnidocysts) are exocytotic organelles found in all cnidarians. Here, atomic force microscopy and field emission scanning electron microscopy reveal the structure of the nematocyst capsule wall. The outer wall consists of globular proteins of unknown function. The inner wall consists of bundles of collagen-like fibrils having a spacing of 50 to 100 nanometers and cross-striations at intervals of 32 nanometers. The fibrils consist of polymers of "mini-collagens," which are abundant in the nematocysts of Hydra. The distinct pattern of mini-collagen fibers in the inner wall can provide the tensile strength necessary to withstand the high osmotic pressure (15 megapascals) in the capsules.


Global Open Health Data Cooperatives Cloud in an Era of COVID-19 and Planetary Health.
Big data in both the public domain and the health care industry are growing rapidly, for example, with broad availability of next-generation sequencing and large-scale phenomics datasets on patient-reported outcomes. In parallel, we are witnessing new research approaches that demand sharing of data for the benefit of planetary society. Health data cooperatives (HDCs) is one such approach, where health data are owned and governed collectively by citizens who take part in the HDCs. Data stored in HDCs should remain readily available for translation to public health practice but at the same time, governed in a critically informed manner to ensure data integrity, veracity, and privacy, to name a few pressing concerns. As a solution, we suggest that data generated from high-throughput omics research and phenomics can be stored in an open cloud platform so that researchers around the globe can share health data and work collaboratively. We describe here the Global Open Health Data Cooperatives Cloud (GOHDCC) as a proposed cloud platform-based model for the sharing of health data between different HDCCs around the globe. GOHDCC's main objective is to share health data on a global scale for robust and responsible global science, research, and development. GOHDCC is a citizen-oriented model cooperatively governed by citizens. The model essentially represents a global sharing platform that could benefit all stakeholders along the health care value chain.


Case-control study of suicide attempts in the elderly.
Prior studies have inadequately explored the relationship between late-life suicidal behavior and subclinical/clinical symptoms. This study aimed to assess the risk associated with subclinical symptoms, mild cognitive impairment and clinical factors among late-life suicide attempters. Forty-three elderly patients aged 60 years and older who sought emergency services in a university-affiliated general hospital for attempting suicide and 43 comparison subjects participated in this study between March 2005 and December 2006. The comparison group was recruited by advertising in the community around the hospital. DSM-IV based diagnostic interview and screening instruments including the GDS, MMSE, BSRS-5 and APGAR were applied. Adjusted odds ratios were measured in the final multiple logistic regression model. Suicide attempters were more likely to meet a diagnosis of depressive disorder, after adjustments for BSRS-5 score and drinking habit. The adjusted odds of suicide among people with a BSRS-5 score of more than 5 points was 17.8 times higher than those with the BSRS score less than or equal to 5 points. Our findings support the significant impact on late-life suicidal behavior from the assessment of subclinical symptoms, including anxiety, depression, hostility, sleep condition and interpersonal symptoms. The assessment of subclinical symptoms by the BSRS-5 may help in the future prevention of late-life suicidal behavior in primary care settings.


Venus: dead or alive?
In situ nightside electric field observations from the Pioneer Venus Orbiter have been interpreted as evidence of extensive lightning in the lower atmosphere of Venus. The scenario, including proposed evidence of clustering of lightning over surface highland regions, has encouraged the acceptance of currently active volcanic output as part of several investigations of the dynamics and chemistry of the atmosphere and the geology of the planet. However, the correlation between the 100-hertz electric field events attributed to lightning and nightside ionization troughs resulting from the interaction of the solar wind with the ionosphere indicates that the noise results from locally generated plasma instabilities and not from any behavior of the lower atmosphere. Furthermore, analysis of the spatial distribution of the noise shows that it is not clustered over highland topography, but rather occurs at random throughout the latitude and longitude regions sampled by the orbiter during the first 5 years of operation, from 1978 to 1984. Thus the electric field observations do not identify lightning and do not provide a basis for inferring the presence of currently active volcanic output. In the absence of known evidence to the contrary, it appears that Venus is no longer active.


Molecular tracing of sexual HIV Type 1 transmission in the southwest border of China.
Since the first outbreak of HIV-1 was reported in heroin users in China in 1989, HIV-1 has spread steadily among injection drug users, leading to an exponential growth of nationwide outbreaks from 1998 to 2004. However, the impact of sexual transmission on outbreaks of HIV in China's general population is still unclear. Through a governmental HIV/AIDS surveillance program, an HIV serological study was conducted in volunteers between 1996 and 2005 in Xishuangbanna Dai Autonomous Prefecture of Yunnan province. We performed the transmission reconstruction by molecular epidemiological tracing in a subset of the HIV-1-seropositive individuals diagnosed during this survey. Neighbor joining and maximum likelihood trees based on the HIV-1 pol and env genes were implemented to provide information on putative epidemiological links, which were then confirmed by contact tracing. Of 25,390 volunteers, 501 (2%) accumulated cases of HIV-1 infection (21.1% in needle-sharing drug users, 77.3% in heterosexual adults, 0.4% in homosexual adults, and 1.2% in children born from infected mothers) were diagnosed. Among 44 heterosexually infected and antiretroviral-naive local-traceable individuals (27 infected with HIV-1 subtype CRF01_AE, 15 with CRF08_BC, 1 with G, and 1 with a new B/C recombinant), 18 (40.9%) were coclustered into 8 transmission chains with an average size of 2.25 infections per chain. Phylogenetic and epidemiological linkages confirmed eight heterosexual transmission events. This is the first report providing molecular epidemiological evidence of heterosexual transmission of HIV-1 in China's general population. The reconstruction of transmission of current HIV-1 outbreaks by molecular epidemiological tracing is instrumental in identifying sources of the epidemic and in defining prevention strategies.


Primary giant cell malignant fibrous histiocytoma of the kidney with staghorn calculi.
Malignant fibrous histiocytomas (MFH) as primary renal tumours are rare, with less than 50 cases described in the literature. We report a case of primary renal MFH of giant cell type in a 56-year-old man, who presented with bilateral dull flank pain, intermittent gross haematuria and body weight loss (6 kg in 3 months). Intravenous urography, computerized tomography (CT) and magnetic resonance image (MRI) showed right ureteral stones with mild hydronephrosis, and a solid mass at the lower pole of the left kidney associated with staghorn calculi, as well as tumour thrombi in the left renal vein and inferior vena cava. Left radical nephrectomy and evacuation of tumour thrombi from the left renal vein and inferior vena cava were performed. Histopathologic examination revealed malignant fibrous histiocytoma (MFH) of giant cell type. To the best of our knowledge, this is the first report of primary renal MFH associated with staghorn calculi.


Do antihistamines and decongestants prevent otitis media?
Many health care providers and parents believe antihistamines and decongestants are important adjuncts to antibiotic therapy in preventing and treating otitis media with effusion. Research does not support this practice.


Fire regimes, forest change, and self-organization in an old-growth mixed-conifer forest, Yosemite National Park, USA.
Fire is recognized as a keystone process in dry mixed-conifer forests that have been altered by decades of fire suppression, Restoration of fire disturbance to these forests is a guiding principle of resource management in the U.S. National Park Service. Policy implementation is often hindered by a poor understanding of forest conditions before fire exclusion, the characteristics of forest changes since excluding fire, and the influence of topographic or self-organizing controls on forest structure. In this study the spatial and temporal characteristics of fire regimes and forest structure are reconstructed in a 2125-ha mixed-conifer forest. Forests were multi-aged, burned frequently at low severity and fire-return interval, and forest structure did not vary with slope aspect, elevation, or slope position. Fire exclusion has caused an increase in forest density and basal area and a compositional shift to shade-tolerant and fire-intolerant species. The median point fire-return interval and extent of a fire was 10 yr and 115 ha, respectively. The pre-Euro-American settlement fire rotation of 13 yr increased to 378 yr after 1905. The position of fire scars within tree rings indicates that 79% of fires burned in the midsummer to fall period. The spatial pattern of burns exhibited self-organizing behavior. Area burned was 10-fold greater when an area had not been burned by the previous fire. Fires were frequent and widespread, but patches of similar aged trees were < 0.2 ha, suggesting small fire-caused canopy openings. Managers need to apply multiple burns at short intervals for a sustained period to reduce surface fuels and create small canopy openings characteristic of the reference forest. By coupling explicit reference conditions with consideration of current conditions and projected climate change, management activities can balance restoration and risk management.


Effect of deception of distance on prolonged cycling performance.
This study examined the effect of deception of distance end-point on prolonged cycling performance. 21 subjects were randomly allocated to three groups (n = 7 per group). Each group completed three self-paced time-trials separated by one day. Subjects were told that each trial was a 30-km time-trial and were required to complete the distance in the fastest time possible. Following the initial trial of 30 km, one group completed Trial 2 with a longer distance (long distance group; 36 km), another group with a shorter distance (24 km; short distance group), and the third group as control (30 km; control). Each group then completed a third time-trial of 30 km. At no time was the deception of distance in Trial 2 disclosed to the subjects, and all sources of physiological and mechanical feedback were withheld during the trials. Data from Trials 1 and 3 were analysed by repeated-measures analysis of covariance. Time to complete Trial 1 was similar among groups (approximately 65 min.). Following the deception in Trial 2 the time to complete the 30 km in Trial 3 was increased for the short distance group, decreased for the long distance group, whilst the time for the control group remained unchanged. The times to complete the 30 km on Trials 1 and 3 were matched by changes in power output throughout the trials. It is concluded that subjects deceived of the actual distance completed will complete the subsequent performance trial based on perceived effort rather than on actual distance.


Pneumococcal surface adhesin A (PsaA): a review.
Pneumococcal surface adhesin A (PsaA) is a surface-exposed common 37-kilodalton multi-functional lipoprotein detected on all known serotypes of Streptococcus pneumoniae. This lipoprotein belongs to the ABC-type transport protein complex that transports Mn2+; it is also an adhesin that plays a major role in pneumococcal attachment to the host cell and virulence. PsaA is immunogenic and natural nasopharyngeal colonization of pneumococci elicits an increase in antibody towards PsaA. Hence, PsaA is being actively evaluated as a component of a vaccine in formulations composed of pneumococcal common proteins. PsaA has been expressed as an E. coli recombinant protein, purified, and evaluated in a phase one clinical trial. This article reviews PsaA, its structure and role in pneumococcal virulence, immunogenicity, and potential to reduce nasopharyngeal colonization (a major prerequisite for pneumococcal pathogenesis) as a component of a common pneumococcal protein vaccine.


Segmental dystonia induced by wearing glasses with a ribbon: an unusual case of a reverse sensory geste.
Craniocervical muscles are the most frequently involved in dystonia, which can be either focal of segmental. While often experiencing an increase in dystonia with voluntary motor activity, many patients report temporary relief with geste antagoniste. We describe a patient who presented a peculiar craniocervical segmental dystonia, triggered by putting on glasses with a ribbon.


Magnetic resonance imaging in Huntington disease.
Four patients with Huntington disease were imaged using CT and inversion-recovery magnetic resonance (MR) imaging. In all four patients the caudate nucleus and corpus striatum were well demonstrated and noted to be atrophic. MR is believed to be superior to CT for imaging morphologic changes of Huntington disease.


kDNA minicircles of the major sequence class of C. fasciculata contain a single region of bent helix widely separated from the two origins of replication.
The major sequence class of Crithidia fasciculata minicircles is shown to have a single region of bent helical DNA widely separated from the two replication origins located 180 degrees apart on the minicircle map. The position of the bend in the DNA has been mapped both by gel electrophoretic methods and by direct electron microscopic observation of the DNA. This sequence directed bending is apparently the result of homopolymeric dA X dT tracts 4-6 base pairs long repeated in phase with the helix screw. The region of the bend contains nineteen such homopolymeric tracts in a region of about 200 base pairs with sixteen of the tracts oriented in the same direction.


Cranberry extract inhibits low density lipoprotein oxidation.
Cranberry juice consumption is often used for the treatment of urinary tract infections, but the effect of cranberry juice on heart disease has not been investigated. We evaluated how a cranberry extract containing 1,548 mg gallic acid equivalents/liter (initial pH=2.50) affected low density lipoprotein (LDL) oxidation induced by 10 micromolar cupric sulfate. When LDL oxidation took place in the presence of diluted cranberry extracts, the formation of thiobarbituric acid reactive substances (TBARS) and LDL electrophoretic mobility were reduced. LDL electrophoretic migration was also reduced when the cranberry extract had a pH of 7.00 prior to dilution. This study suggests that cranberry extracts have the ability to inhibit the oxidative modification of LDL particles.


Polarization-independent and omnidirectional nearly perfect absorber with ultra-thin 2D subwavelength metal grating in the visible region.
A polarization-independent and omnidirectional nearly perfect absorber in the visible region has been proposed. The absorber is two-layer structure consisting of a subwavelength metal grating layer embedded in the high refractive index and lossless dielectric layer on the metal substrate. Extraordinary optical absorption with absorption peaks of over 99% can be achieved over the whole visible region for both TM and TE polarization. This absorption is attributed to cavity mode (CM) resonance caused by the coupled surface plasmon polaritons (SPP). Through adjusting the grating thickness, the absorption peak can be tuned linearly, which is highly advantageous to design various absorbers. Furthermore, the absorbance retains ultra-high over a wide angular range of incidence for both TM and TE polarization. This nearly perfect absorber offers great potential in the refractive index (RI) sensors, integrated photodetectors, solar cells and so on.


Turmeric (Curcuma longa)-induced reduction in urinary mutagens.
Rats were fed turmeric at various levels in the diet for up to 3 months and then exposed to benzo[a]pyrene (B[a]P) or 3-methylcholanthrene (3-MC) by ip injection. Urinary mutagens were detected using the Salmonella typhimurium assay. Turmeric fed at 0.5% and above inhibited B[a]P- and 3-MC-mediated mutagenicity. Turmeric did not adversely affect the food intake, or weight gain of the rats and no histological changes were detected. These findings are significant in view of the widespread exposure of humans to polycyclic aromatic hydrocarbons. The study has also revealed a useful in vivo model for testing the antimutagenicity.


ACK family tyrosine kinase activity is a component of Dcdc42 signaling during dorsal closure in Drosophila melanogaster.
We have characterized Drosophila melanogaster ACK (DACK), one of two members of the ACK family of nonreceptor tyrosine kinases in Drosophila. The ACKs are likely effectors for the small GTPase Cdc42, but signaling by these proteins remains poorly defined. ACK family tyrosine kinase activity functions downstream of Drosophila Cdc42 during dorsal closure of the embryo, as overexpression of DACK can rescue the dorsal closure defects caused by dominant-negative Dcdc42. Similar to known participants in dorsal closure, DACK is enriched in the leading edge cells of the advancing epidermis, but it does not signal through activation of the Jun amino-terminal kinase cascade operating in these cells. Transcription of DACK is responsive to changes in Dcdc42 signaling specifically at the leading edge and in the amnioserosa, two tissues involved in dorsal closure. Unlike other members of the ACK family, DACK does not contain a conserved Cdc42-binding motif, and transcriptional regulation may be one route by which Dcdc42 can affect DACK function. Expression of wild-type and kinase-dead DACK transgenes in embryos, and in the developing wing and eye, reveals that ACK family tyrosine kinase activity is involved in a range of developmental events similar to that of Dcdc42.


Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury.
Profibrotic cells that develop upon injury generate permanent scar tissue and impair organ recovery, though their origin and fate are unclear. Here we show that transient expression of ADAM12 (a disintegrin and metalloprotease 12) identifies a distinct proinflammatory subset of platelet-derived growth factor receptor-α-positive stromal cells that are activated upon acute injury in the muscle and dermis. By inducible genetic fate mapping, we demonstrate in vivo that injury-induced ADAM12(+) cells are specific progenitors of a major fraction of collagen-overproducing cells generated during scarring, which are progressively eliminated during healing. Genetic ablation of ADAM12(+) cells, or knockdown of ADAM12, is sufficient to limit generation of profibrotic cells and interstitial collagen accumulation. ADAM12(+) cells induced upon injury are developmentally distinct from muscle and skin lineage cells and are derived from fetal ADAM12(+) cells programmed during vascular wall development. Thus, our data identify injury-activated profibrotic progenitors residing in the perivascular space that can be targeted through ADAM12 to limit tissue scarring.


STEMI, Cardiogenic Shock, and Mortality in Patients Admitted for Acute Angiography: Associations and Predictions from Plasma Proteome Data.
Acute myocardial infarction (AMI) remains a major cause of mortality and morbidity, and cardiogenic shock (CS) a major cause of hospital mortality after AMI. Especially for ST elevation myocardial infarction (STEMI) patients, fast intervention is essential.Few proteins have proven clinically applicable for AMI. Most proposed biomarkers are based on a priori hypothesis-driven studies of single proteins, not enabling identification of novel candidates. For clinical use, the ability to predict AMI is important; however, studies of proteins in prediction models are surprisingly scarce.Consequently, we applied proteome data for identifying proteins associated with definitive STEMI, CS, and all-cause mortality after admission, and examined the ability of the proteins to predict these outcomes. Proteome-wide data of 497 patients with suspected STEMI were investigated; 381 patients were diagnosed with STEMI, 35 with CS, and 51 died during the first year. Data analysis was conducted by logistic and Cox regression modeling for association analysis, and by multivariable LASSO regression models for prediction modeling.Association studies identified 4 and 29 proteins associated with definitive STEMI or mortality, respectively. Prediction models for CS and mortality (holding two and five proteins, respectively) improved the prediction ability as compared with protein-free prediction models; AUC of 0.92 and 0.89, respectively. The association analyses propose individual proteins as putative protein biomarkers for definitive STEMI and survival after suspected STEMI, while the prediction models put forward sets of proteins with putative predicting ability of CS and survival. These proteins may be verified as biomarkers of potential clinical relevance.


A comparison of linear and nonlinear statistical techniques in performance attribution.
Performance attribution is usually conducted under the linear framework of multifactor models. Although commonly used by practitioners in finance, linear multifactor models are known to be less than satisfactory in many situations. After a brief survey of nonlinear methods, nonlinear statistical techniques are applied to performance attribution of a portfolio constructed from a fixed universe of stocks using factors derived from some commonly used cross sectional linear multifactor models. By rebalancing this portfolio monthly, the cumulative returns for procedures based on standard linear multifactor model and three nonlinear techniques-model selection, additive models, and neural networks-are calculated and compared. It is found that the first two nonlinear techniques, especially in combination, outperform the standard linear model. The results in the neural-network case are inconclusive because of the great variety of possible models. Although these methods are more complicated and may require some tuning, toolboxes are developed and suggestions on calibration are proposed. This paper demonstrates the usefulness of modern nonlinear statistical techniques in performance attribution.


Detection of methicillin-resistant Staphylococcus aureus (MRSA) from growth on mannitol salt oxacillin agar using PCR for nosocomial surveillance.
This study evaluated a polymerase chain reaction (PCR) method for detection of methicillin-resistant Staphylococcus aureus (MRSA) in specimens referred for nosocomial surveillance. PCR was used to detect the mecA and nuc gene targets using yellow growth on mannitol salt agar containing 6 mg/liter oxacillin (MSO-6) as a source of DNA (N = 645). The diagnostic values for PCR compared with culture methods were 97% specificity, 100% sensitivity, 96% positive predictive value, and 100% negative predictive value. Total cost for PCR per test is $3.62 compared to $4.77 for culture. However, the total cost per specimen is significantly lower due to only 20% of all surveillance specimens producing yellow colonies on MSO-6. The average turnaround time for the PCR method is 48 h compared with 82 h for culture. PCR amplification of mecA and nuc genes using yellow colonies on MSO-6 is a simple, fast, accurate and cost-effective method for routine use in clinical laboratories for detecting MRSA in surveillance specimens.


Society for Endocrinology Competency Framework for Adult Endocrine Nursing: 2nd edition.
This competency framework was developed by a working group of endocrine specialist nurses with the support of the Society for Endocrinology to enhance the clinical care that adults with an endocrine disorder receive. Nurses should be able to demonstrate that they are functioning at an optimal level in order for patients to receive appropriate care. By formulating a competency framework from which an adult endocrine nurse specialist can work, it is envisaged that their development as professional practitioners can be enhanced. This is the second edition of the Competency Framework for Adult Endocrine Nursing. It introduces four new competencies on benign adrenal tumours, hypo- and hyperparathyroidism, osteoporosis and polycystic ovary syndrome. The authors and the Society for Endocrinology welcome constructive feedback on the document, both nationally and internationally, in anticipation that further developments and ideas can be incorporated into future versions.


Acalculous cholecystitis in the neonate.
Pediatric acalculous cholecystitis is a well-described though uncommon affliction. However, during the neonatal period nonlithogenic biliary disease is extremely unusual and only isolated reports of this problem exist. Nine previously reported cases are reviewed, and an additional case of a 6-day-old female neonate with a right-upper-quadrant mass is presented in detail. Inflammatory gallbladder disease in the neonate is often associated with concurrent systemic illness. An abdominal mass is palpable in almost all cases. Diagnosis may be confirmed in these patients by radionuclide scanning and ultrasonography. The treatment is cholecystectomy.


Localization and role of NPC1L1 in cholesterol absorption in human intestine.
Recent studies have documented the presence of Niemann-Pick C1-Like 1 (NPC1L1) in the small intestine and its capacity to transport cholesterol in mice and rats. The current investigation was undertaken to explore the localization and function of NPC1L1 in human enterocytes. Cell fractionation experiments revealed an NPC1L1 association with apical membrane of the enterocyte in human jejunum. Signal was also detected in lysosomes, endosomes, and mitochondria. Confirmation of cellular NPC1L1 distribution was obtained by immunocytochemistry. Knockdown of NPC1L1 caused a decline in the ability of Caco-2 cells to capture micellar [(14)C]free cholesterol. Furthermore, this NPC1L1 suppression resulted in increased and decreased mRNA levels and activity of HMG-CoA reductase, the rate-limiting step in cholesterol synthesis, and of ACAT, the key enzyme in cholesterol esterification, respectively. An increase was also noted in the transcriptional factor sterol-regulatory element binding protein that modulates cholesterol homeostasis. Efforts were devoted to define the impact of NPC1L1 knockdown on other mediators of cholesterol uptake. RT-PCR evidence is presented to show the significant decrease in the levels of scavenger receptor class B type I (SR-BI) with no changes in ABCA1, ABCG5, and cluster determinant 36 in NPC1L1-deficient Caco-2 cells. Together, our data suggest that NPC1L1 contributes to intestinal cholesterol homeostasis and possibly cooperates with SR-BI to mediate cholesterol absorption in humans.


Antibodies to components of extractable nuclear antigen. Clinical characteristics of patients.
Forty-four patients with antibodies to ribonuclease-sensitive extractable nuclear antigen (ENA), ribonuclease-resistant ENA, or both, are described. Most patients with antiribonucleoprotein (anti-RNP) antibodies have overlapping features of systemic lupus erythematosus (SLE), progressive systemic sclerosis (PSS), and polymyositis, and have a low incidence of nephritis. Most patients with antibody solely to ribonuclease-insensitive ENA have SLE; these patients with SLE are typical of the general SLE population, except that they demonstrate an increased incidence of Raynaud phenomenon. Furthermore, it is shown that antibody to ENA may occur in other rheumatic and nonrheumatic diseases, and that not all patients who have a clinical overlap of SLE and PSS that is suggestive of mixed connective tissue disease have anti-RNP antibody.


OPRM1 receptor as new biomarker to help the prediction of post mastectomy pain and recurrence in breast cancer.
Breast cancer is the most common type of cancer among women worldwide. Short-term postsurgical recovery is complicated by many factors, including imbalanced inflammatory and immune response, acute pain associated with functional impairment, and chronic postmastectomy pain (CPMP), developed by about 25-60% of patients. Opioids, most common drugs used for treatment of cancer pain, are immunosuppressive, and therefore, they might directly and/or indirectly influence long-term cancer recurrence. Moreover, they also produce endocrinopathy, which consists primarily of hypothalamic-pituitary-gonadal axis or hypothalamic-pituitary-adrenal axis dysfunction. The interindividual variability in both CPMP and opioid response is believed to be largely underlined by genetic variability in the gene locus for μ-opioid receptor (OPRM1) that modulates opioid pharmacodynamics. For this reason, OPRM1 genotype may play a key role both in short-term postmastectomy outcome and in long-term follow-up, becoming a new biomarker for breast cancer recurrence in patients suffering from chronic postmastectomy pain managed by opioid therapy. Hence OPRM1 might be used in near future to customize the opioid therapy, avoiding not only opioid side effects but also the disease progression. In this review we evaluate the literature state of the art on this topic and possible steps towards obtaining the safest individualized postmastectomy analgesic therapy. Therefore, a personalized pain treatment strategy might be useful to both manage pain and control cancer disease progression.


Theme: neurology--optic nerve sheath diameter measurement as a risk marker for significant intracranial hypertension.
Raised intracranial pressure (ICP) is a frequent condition in many medical and surgical situations and is often difficult to detect. Noninvasive estimates of raised ICP are of interest to allow rapid detection of significant intracranial hypertension. In the anterior part of the optic nerve, the sheath is distensible and can inflate in the case of raised pressure in the cerebrospinal fluid. Measurement of optic nerve sheath diameter using ocular sonography or MRI has been shown to correctly estimate the risk of raised ICP in various settings, including traumatic brain injury. Ocular sonography is simple, rapid, noninvasive and can be performed at the patient's bedside, but it requires training and experience. The cut-off value for ICP greater than 20 mmHg is 5.8 mm, with a 90% probability of correct diagnosis. When raised ICP is suspected, but invasive ICP monitoring cannot be used or is not clearly recommended, this estimation of the risk of raised ICP may be of great clinical value, aiding in the detection of patients at risk of raised ICP.


How to plan and manage an individual participant data meta-analysis. An illustrative toolkit.
Individual participant data meta-analyses (IPD-MAs) have several benefits over standard aggregate data meta-analyses, including the consideration of additional participants, follow-up time, and the joint consideration of study- and participant-level heterogeneity for improved diagnostic and prognostic model development and evaluation. However, IPD-MAs are resource-intensive and require careful budgeting of time from data contributing groups, a dedicated management team, diversity of expertise, clearly documented data sharing and authorship agreements, and consistent and clear communication. We present a toolkit to facilitate the implementation and management of IPD-MAs, from study recruitment to retrospective harmonization. The toolkit was developed and refined over our work on multiple multinational IPD-MA projects over the last 13 years. The toolkit's budget and email templates, agreements, project management spreadsheets, and standard operating procedures are meant to facilitate routine IPD-MA tasks to expedite implementing and managing future IPD-MA projects.


Probing the functional role of Ca2+ in the oxygen-evolving complex of photosystem II by metal ion inhibition.
Photosynthetic oxygen evolution in photosystem II (PSII) takes place in the oxygen-evolving complex (OEC) that is comprised of a tetranuclear manganese cluster (Mn4), a redox-active tyrosine residue (YZ), and Ca2+ and Cl- cofactors. The OEC is successively oxidized by the absorption of 4 quanta of light that results in the oxidation of water and the release of O2. Ca2+ is an essential cofactor in the water-oxidation reaction, as its depletion causes the loss of the oxygen-evolution activity in PSII. In recent X-ray crystal structures, Ca2+ has been revealed to be associated with the Mn4 cluster of PSII. Although several mechanisms have been proposed for the water-oxidation reaction of PSII, the role of Ca2+ in oxygen evolution remains unclear. In this study, we probe the role of Ca2+ in oxygen evolution by monitoring the S1 to S2 state transition in PSII membranes and PSII core complexes upon inhibition of oxygen evolution by Dy3+, Cu2+, and Cd2+ ions. By using a cation-exchange procedure in which Ca2+ is not removed prior to addition of the studied cations, we achieve a high degree of reversible inhibition of PSII membranes and PSII core complexes by Dy3+, Cu2+, and Cd2+ ions. EPR spectroscopy is used to quantitate the number of bound Dy3+ and Cu2+ ions per PSII center and to determine the proximity of Dy3+ to other paramagnetic centers in PSII. We observe, for the first time, the S2 state multiline electron paramagnetic resonance (EPR) signal in Dy3+- and Cd2+-inhibited PSII and conclude that the Ca2+ cofactor is not specifically required for the S1 to S2 state transition of PSII. This observation provides direct support for the proposal that Ca2+ plays a structural role in the early S-state transitions, which can be fulfilled by other cations of similar ionic radius, and that the functional role of Ca2+ to activate water in the O-O bond-forming reaction that occurs in the final step of the S state cycle can only be fulfilled by Ca2+ and Sr2+, which have similar Lewis acidities.


A Framework for Sensorimotor Cross-Perception and Cross-Behavior Knowledge Transfer for Object Categorization.
From an early age, humans learn to develop an intuition for the physical nature of the objects around them by using exploratory behaviors. Such exploration provides observations of how objects feel, sound, look, and move as a result of actions applied on them. Previous works in robotics have shown that robots can also use such behaviors (e.g., lifting, pressing, shaking) to infer object properties that camera input alone cannot detect. Such learned representations are specific to each individual robot and cannot currently be transferred directly to another robot with different sensors and actions. Moreover, sensor failure can cause a robot to lose a specific sensory modality which may prevent it from using perceptual models that require it as input. To address these limitations, we propose a framework for knowledge transfer across behaviors and sensory modalities such that: (1) knowledge can be transferred from one or more robots to another, and, (2) knowledge can be transferred from one or more sensory modalities to another. We propose two different models for transfer based on variational auto-encoders and encoder-decoder networks. The main hypothesis behind our approach is that if two or more robots share multi-sensory object observations of a shared set of objects, then those observations can be used to establish mappings between multiple features spaces, each corresponding to a combination of an exploratory behavior and a sensory modality. We evaluate our approach on a category recognition task using a dataset in which a robot used 9 behaviors, coupled with 4 sensory modalities, performed multiple times on 100 objects. The results indicate that sensorimotor knowledge about objects can be transferred both across behaviors and across sensory modalities, such that a new robot (or the same robot, but with a different set of sensors) can bootstrap its category recognition models without having to exhaustively explore the full set of objects.


Instrument for measuring the misalignments of ocular surfaces.
A compact and robust instrument for measuring the alignment of ocular surfaces has been designed and used in living eyes. It is based on recording Purkinje images (reflections of light at the ocular surfaces) at nine different angular fixations. A complete analysis on the causes of misalignments of Purkinje images and its relations with those physical variables to be measured (global eye tilt, lens decentration and lens tilt) is presented. A research prototype based on these ideas was built and tested in normal and pseudophakic eyes (after cataract surgery). The new analysis techniques, together with the semicircular extended source and multiple fixation tests that we used, are significant improvements towards a robust approach to measuring the misalignments of the ocular surfaces in vivo. This instrument will be of use in both basic studies of the eye's optics and clinical ophthalmology.


Anatomic (positional) variation of maxillary wisdom teeth with special regard to the maxillary sinus.
The removal of wisdom teeth is one of the most common interventions in oral surgery. In order to avoid complications, a profound knowledge of the anatomy of teeth and adjacent tissues is crucial. In the case of maxillary wisdom teeth, their relationship to the maxillary sinus, to the pterygoid fossa, to the maxillary tuber and the adjacent venous plexus is particularly important. Three-dimensional (3D) imaging, for example by means of cone beam computed tomography (CBCT), is increasingly utilized in practice. However, the necessity of CBCT imaging is still a matter of intensive debate. The aim of this study was to describe the anatomic (positional) variation of maxillary wisdom teeth and, based on these findings, to elucidate the additional benefit of such imaging. A retrospective case study was performed using patients examined by means of CBCT imaging in the Department of Dento-Maxillofacial Radiology during the period from 2008 to 2013. Primary study variables comprised the spatial relationship of the teeth to the maxillary sinus, the degree of retention and root development, the covering of the root with bone and mucosa, the root configuration, and the developmental stage of the tooth. In addition, the association of the inclination of teeth in the transversal and sagittal plane with the above variables was evaluated. Descriptive statistical parameters were calculated for all results of the examination. In total, CBCT recordings of 713 maxillary wisdom teeth from 430 patients were evaluated. Their mean age was 29.8 years, and the proportion of male patients slightly prevailed (54.4%). Most teeth exhibited fully developed roots (64.1%). Overall 22.9% of third molars were impacted, 32.3% were retained, and 6.5% were erupting. In more than a third of the patients, wisdom teeth were in occlusion. The inclination of the third molars both in the transversal and sagittal plane was significantly associated with the distance of the root from the maxillary sinus as well as with the bony covering of the root. Owing to the possibility of evaluating preoperatively the relationship of a wisdom tooth to the maxillary sinus and to other anatomic structures, we recommend the use of CBCT, whenever conventional radiography fails to provide adequate information about the critical anatomic circumstances of maxillary third molars. However, CBCT should, at least nowadays, not be utilized as the standard radiographic examination.


Range extension of the optical delay line in white light interferometry.
We propose an effective and promising method to extend the continuous range of the optical delay line in white light interferometry. The method adopts the combination of switchable fixed delays and a continuous-scanning stage laid in one arm of the interferometer. Moreover, a fiber ring constructed by a fiber coupler is employed in the other arm to achieve self-calibration and improve the delay precision, voiding the use of a specialized measurement instrument. The range-extension method maintains the original performances of the stage just through the process of orderly copying and jointing. The setup with 16 parallel fixed delay paths is experimentally demonstrated. The insertion loss of the optical delay line will not increase as the range extension and keeps an average of 1.45 dB with a fluctuation of ±0.15 dB(3σ) over a delay range of 37.2 m without a blind zone. In addition, the delay precision as a function of the port number of the optical switch does not deteriorate and remains at a level of 10.21 μm with a standard deviation of 0.08 μm. The loss and delay precision features enable the proposed structure to be extended without limitation, which is particularly significant for practical applications.


PAWS1 controls Wnt signalling through association with casein kinase 1α.
The BMP and Wnt signalling pathways determine axis specification during embryonic development. Our previous work has shown that PAWS1 (also known as FAM83G) interacts with SMAD1 and modulates BMP signalling. Here, surprisingly, we show that overexpression of PAWS1 in Xenopus embryos activates Wnt signalling and causes complete axis duplication. Consistent with these observations in Xenopus, Wnt signalling is diminished in U2OS osteosarcoma cells lacking PAWS1, while BMP signalling is unaffected. We show that PAWS1 interacts and co-localises with the α isoform of casein kinase 1 (CK1), and that PAWS1 mutations incapable of binding CK1 fail both to activate Wnt signalling and to elicit axis duplication in Xenopus embryos.


[A comparative study of the hemolytic activity of triterpene polyols of the dammarane series].
We studied membranotropic effect of dammarane-type triterpenes (isolated from birch leaves) with a variable side chain structure, as well as the number and configuration of OH groups as a function of temperature and pH. Polyols with an acyclic side chain and four OH groups proved to have a higher hemolytic activity as compared to polyols with three or five hydroxyl groups. The triterpenes, with tetrahydrofurane cycle as the side chain, exert a hemolytic effect at a more acidic pH (5.0) and higher temperature (45 degrees C), as compared to the polyols with acyclic side chain. Irrespective of the side chain structure, the compounds with a 24(S) configuration lysed the erythrocytes at lower rate, as compared to the compounds with a 24(R) configuration.


Optimal Design of a Compliant Constant-Force Mechanism to Deliver a Nearly Constant Output Force Over a Range of Input Displacements.
This study presents an optimal design procedure, including topology and geometry optimization methods to design a compliant constant-force mechanism, which can generate a nearly constant output force over a range of input displacements. The proposed constant-force mechanism is a passive force regulation device that can be used in various applications such as precision manipulation and overload protection. The numerical optimization problem is treated as an error minimization problem between output and objective forces. Both material and geometric nonlinearities are considered in topology and geometry optimization steps. Although the element stiffness for void and gray elements after topology optimization are quite small comparing with solid elements, their existence also contributes to the output force characteristic of the synthesized mechanisms. As these low-stiffness elements are not easy to manufacture in physical prototype, a helical compression spring is introduced in the topology optimized constant-force mechanism to account for the effect of low-stiffness elements, and an additional geometry optimization step is utilized to identify the spring constant as well as to fine-tune the geometric parameters. The optimized constant-force mechanism is prototyped by three-dimensional printing using flexible thermoplastic elastomer. The experimental results show that the proposed design can generate a nearly constant output force in the input displacement range of 3-6 mm. The developed constant-force mechanism is installed on an electric gripper drive mounted on a robot arm for robotic picking and placing application. Test results show the constant-force gripper can be used in handling of size-varied fragile objects.


Benign cystic teratoma of the ovary: a 6-year review.
Benign cystic teratoma of the ovary was diagnosed histologically in 118 patients over 6 years at the Sir Mortimer B. Davis-Jewish General Hospital in Montreal. The charts were reviewed with respect to population distribution, symptomatology, diagnostic procedures and treatment. Of the 118 patients, 85.6% were younger than 40 years. Only 3.4% had documented recurrence and 6.8% were pregnant. Roentgenograms of the pelvis revealed calcification in 64.1% of cases. Ultrasonography of the pelvis failed to make the diagnosis in 19.4%. The majority of patients had a Pfannenstiel incision (78.8%) and underwent oophorectomy (55.3%). In half the patients the contralateral ovary was only palpated.


Ultrastructural features of minute chromosomes in a methotrexate-resistant mouse 3T3 cell line.
The Miller spreading procedure was applied to mouse metaphase spreads of methotrexate-resistant 3T3 cells that contain large numbers of minute chromosomes and dihydrofolate reductase genes. There is substantial variation in both size and numbers of minutes in individual cells, the smallest of which (estimated as 5 X 10(3) kilobase pairs) would be undetected by standard light microscopic analyses. Minute chromosomes are composed of nucleosomal chromatin, which is organized into typical higher order fibers that are folded to form rosette-like structures characteristic of normal chromosome organization. There is no evidence that the DNA in minutes is linear. Minutes exist singly and in pairs, and members of a pair are connected by higher order chromatin fibers, suggesting that they are topologically interlocked. They are often closely apposed to chromosomal telomeres or arms, a configuration that may be involved in their distribution at mitosis. In addition to typical minutes, which do not possess kinetochores, a small marker chromosome possessing all of the features of a centromere region is present in parental and resistant cells. An unusual feature of this cell line is the retention of resistance, minute chromosomes, and amplified dihydrofolate reductase genes; most methotrexate-resistant mouse cell lines with minute chromosomes lose these properties when grown in the absence of methotrexate.


[Verrucous carcinoma of the penis: report of 2 cases].
To report two cases of verrucous carcinoma of the penis, a rare tumor with a characteristic course and specific treatment that accounts for approximately 1% of tumors in the male. Two patients, aged 86 and 51 years, with verrucous carcinoma of the penis are described. Treatment was by partial penectomy and resection of the glans penis, respectively. The anatomopathological characteristics and prognostic aspects are reviewed. Verrucous carcinoma of the penis usually presents as an exophytic lesion in the glans penis or prepuce and should be distinguished from epidermoid carcinoma which carries a worse prognosis and requires a different therapeutic approach. The differential diagnosis is based on the biopsy findings. Verrucous carcinoma of the penis carries a good prognosis and can be managed by conservative surgery (partial penectomy).


Serum uric acid does not predict incident metabolic syndrome in a population with high prevalence of obesity.
To evaluate whether uric acid (UA) predicts 4-yr incidence of metabolic syndrome (MetS) in non-diabetic participants of the Strong Heart Study (SHS) cohort. In this population-based prospective study we analyzed 1499 American Indians (890 women), without diabetes or MetS, controlled during the 4th SHS exam and re-examined 4 years later during the 5th SHS exam. Participants were divided into sex-specific tertiles of UA and the first two tertiles (group N) were compared with the third tertile (group H). Body mass index (BMI = 28.3 ± 7 vs. 31.1 ± 7 kg/m(2)), fat-free mass (FFM = 52.0 ± 14 vs. 54.9 ± 11 kg), waist-to-hip ratio, HOMA-IR (3.66 vs. 4.26), BP and indices of inflammation were significantly higher in group H than in group N (all p < 0.001). Incident MetS at the time of the 5th exam was more frequent in group H than group N (35 vs. 28%, OR 1.44 (95% CI = 1.10-1.91; p < 0.01). This association was still significant (OR = 1.13, p = 0.04) independently of family relatedness, sex, history of hypertension, HOMA-IR, central adiposity and renal function, but disappeared when fat-free mass was included in the model. In the SHS, UA levels are associated to parameters of insulin resistance and to indices of inflammation. UA levels, however, do not predict incident MetS independently of the initial obesity-related increased FFM.


Risk factor profile for atherosclerosis among young adults in Israel--results of a large-scale survey from the young adult periodic examinations in Israel (YAPEIS) database.
Assessing the prevalence of relevant risk factors among young adults is a critical step in the process of preventing atherosclerotic cardiovascular diseases (ASCVD) later in life. The Israel Defense Force Periodic Health Examination Center performs a routine check-up for subjects aged 25-45 years. Medical history, physical examination notes, laboratory results and ECG tracings are recorded, computerized and processed to form the Young Adults Periodic Examinations in Israel (YAPEIS) database. Data representing 31,640 subjects (27,769 males and 3871 females) examined between the years 1991-1999 were analyzed. The prevalence of documented risk factors for ASCVD were evaluated. The results of all parameters were graded categorically as low, moderate or high and the Framingham risk score was calculated. Fifty-one percent of the study participants were found to be overweight (body mass index > or = 25 kg/m2), 8.5% had high systolic blood pressure and 14.6% had high diastolic blood pressure. The prevalence of hypercholesterolemia and hyperglycemia was found to be 44.7 and 9.7%, respectively. Thirty-two percent of the subjects smoked cigarettes, and 76.7% reported not performing any routine physical activity. Furthermore, 31.8% had a Framingham score indicating a greater than 5% risk for developing a coronary event within the next 10 years. As expected, the prevalence of these risk factors increased with age and were found to be less frequent among females. Thus we conclude that many young Israeli adults hold significant risk factors for future ASCVD. Many of these risk factors are modifiable, and risk behavior is often amenable to alteration. Awareness to the high prevalence of risk factors among young adults should spark vigorous health-promotion programs as well as screening, education, and interventional measures aimed at altering the expected outcome of future ASCVD.


Common infections in older adults.
Infectious diseases account for one third of all deaths in people 65 years and older. Early detection is more difficult in the elderly because the typical signs and symptoms, such as fever and leukocytosis, are frequently absent. A change in mental status or decline in function may be the only presenting problem in an older patient with an infection. An estimated 90 percent of deaths resulting from pneumonia occur in people 65 years and older. Mortality resulting from influenza also occurs primarily in the elderly. Urinary tract infections are the most common cause of bacteremia in older adults. Asymptomatic bacteriuria occurs frequently in the elderly; however, antibiotic treatment does not appear to be efficacious. The recent rise of antibiotic-resistant bacteria (e.g., methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus) is a particular problem in the elderly because they are exposed to infections at higher rates in hospital and institutional settings. Treatment of colonization and active infection is problematic; strict adherence to hygiene practices is necessary to prevent the spread of resistant organisms.


Osteoinductive agents. Basic science and clinical applications.
Demineralized bone matrix (DBM) is well characterized as an osteoinductive agent. This article reviews the historical perspectives and current body of knowledge on the mechanisms of induced osteogenesis and the factors contained within DBM, which can induce bone formation. The use of DBM and osteoinductive agents to treat bone defects and nonunions in both animal models and human conditions in orthopedic and reconstructive surgery are discussed.


Bioabsorbable implants for subtalar arthroereisis in pediatric flatfoot.
Flatfoot is a common condition in growing-age patients. Despite its common presentation, nowadays surgical indications and treatments are still debated. Arthroereisis is a widely used technique, and several implants designs have been proposed over time. Despite the good results shown in the literature, the main drawback of these techniques has always been the need for a second surgery for implant removal. Bioabsorbable devices have been introduced to overcome this necessity.Correct approach to the patient, indications and contraindications and available studies on bioabsorbable implants for subtalar arthroereisis in pediatric flatfoot were analyzed in this narrative review. Even if only a few studies have been published in the literature, bioabsorbable implants showed good clinical results comparable to non-absorbable implants and with a rare necessity for implant removal or revision. When correct indications and proper surgical technique are followed, arthroereisis with bioabsorbable implants appears to be an effective solution for the treatment of pediatric flexible flatfoot.


Use of a novel histone deacetylase inhibitor to induce apoptosis in cell lines of acute lymphoblastic leukemia.
Chromatin structure and thereby transcription is controlled by the level of acetylation of histones, which is determined by the balance between histone acetyl transferase (HAT) activity and histone deacetylase (HDAC) activity. HDAC inhibitors are a class of compounds able to regulate gene expression by modulating chromatin structure. There are two major classes of HDAC inhibitors: the hydroxamic acid derivatives such as trichostatin A (TSA) or SAHA, and the butyrates such as phenyl-butyrate. HDAC inhibitors interfere with differentiation, proliferation and apoptosis in tumor cells. Here, we investigated the activity of a new hydroxamic acid derivative, LAQ824, on lymphoblastic cells. Four different pre-B lymphoblastic cell lines: Sup-B15 and TMD-5, both t(9;22) positive, SEM, t(4;11) positive, and NALM-6 cells were exposed to the hydroxamic acid derivatives, LAQ824 and TSA. Histone hyperacetylation, apoptosis, cell cycle and related pathways were assessed by flow cytometry and Western blotting. LAQ824 significantly inhibited the proliferation of leukemic lymphoblastic cell lines. The effect of LAQ824 was due to increased apoptosis accompanied by activation of caspase-3 and caspase-9, cleavage of poly(ADP-ribose)-polymerase (PARP) as well as by down-regulation of Bcl-2 and disruption of the mitochondrial membrane potential. Surprisingly, LAQ824-induced apoptosis was at least partially independent of caspase activation as indicated by the fact that LAQ824-induced apoptosis was inhibited only partially in both t(9;22) positive Sup-B15 and TMD-5 cells, whereas no inhibition was observed in t(4;11) positive SEM cells upon exposure to the polycaspase inhibitor zVAD-fmk. Our study establishes that LAQ824 is a promising agent for the therapy of acute lymphoblastic leukemia.