Effect of prenatal programming and postnatal rearing on glomerular filtration rate in adult rats.
The present study examined whether a prenatal low-protein diet programs a decrease in glomerular filtration rate (GFR) and an increase in systolic blood pressure (BP). In addition, we examined whether altering the postnatal nutritional environment of nursing neonatal rats affected GFR and BP when rats were studied as adults. Pregnant rats were fed a normal (20%) protein diet or a low-protein diet (6%) during the last half of pregnancy until birth, when rats were fed a 20% protein diet. Mature adult rats from the prenatal low-protein group had systolic hypertension and a GFR of 0.38 ± 0.03 versus 0.57 ± 0.05 ml·min(-1)·100 g body wt(-1) in the 20% group (P < 0.01). In cross-fostering experiments, mothers continued on the same prenatal diet until weaning. Prenatal 6% protein rats cross-fostered to a 20% mother on day 1 of life had a GFR of 0.53 ± 0.05 ml·min(-1)·100 g body wt(-1), which was not different than the 20% group cross-fostered to a different 20% mother (0.45 ± 0.04 ml·min(-1)·100 g body wt(-1)). BP in the 6% to 20% group was comparable with the 20% to 20% group. Offspring of rats fed either 20% or 6% protein diets during pregnancy and cross-fostered to a 6% mother had elevated BP but a comparable GFR normalized to body weight as the 20% to 20% control group. Thus, a prenatal low-protein diet causes hypertension and a reduction in GFR in mature adult offspring, which can be modified by postnatal rearing.


A sensitive serum-free colorimetric assay for the detection of cytotoxic effects of pesticides.
A new method of cell quantification in the Hybritest bioassay is described. This test is based on culturing the hybridoma cell line 1E6 in the serum-free medium RPMI-SR3 and determination of cytotoxicity by growth inhibition. By employing a tetrazolium salt (MTT), the cell number were quantified colorimetrically using an ELISA reader. This assay carried out in microtiter plates saved time, labour and expenses. It was demonstrated that the sensitivity of 1E6 to pesticide toxicity (glyphosate and cypermethrine) was considerably higher in serum-free medium than in serum-containing medium. Furthermore, it is suggested that this assay may represent an alternative to the use of living animals in toxicological experiments.


Considerations for Drug Development in Myelodysplastic Syndromes.
Myelodysplastic syndromes (MDS) have historically been challenging diseases for drug development due to their biology, preclinical modeling, and the affected patient population. In April 2022, the FDA convened a panel of regulators and academic experts in MDS to discuss approaches to improve MDS drug development. The panel reviewed challenges in MDS clinical trial design and endpoints and outlined considerations for future trial design in MDS to facilitate drug development to meaningfully meet patient needs. Challenges for defining clinical benefit in patients with MDS include cumbersome response criteria, standardized transfusion thresholds, and application and validation of patient reported outcome instruments. Clinical trials should reflect the biology of disease evolution, the advanced age of patients with MDS, and how patients are treated in real-world settings to maximize the likelihood of identifying active drugs. In patients with lower-risk disease, response criteria for anemic patients should be based on baseline transfusion dependency, improvement in symptoms, and quality of life. For higher-risk patients with MDS, trials should include guidance to prevent dose reductions or delays that could limit efficacy, specify minimal durations of treatment (in the absence of toxicity or progression), and have endpoints focused on overall survival and durable responses. MDS trials should be designed from the outset to allow the practicable application of new therapies in this high-needs population, with drugs that can be administered and tolerated in community settings, and with endpoints that meaningfully improve patients' lives over existing therapies.


Bacterial mechanosensitive channels--MscS: evolution's solution to creating sensitivity in function.
The discovery of mechanosensing channels has changed our understanding of bacterial physiology. The mechanosensitive channel of small conductance (MscS) is perhaps the most intensively studied of these channels. MscS has at least two states: closed, which does not allow solutes to exit the cytoplasm, and open, which allows rapid efflux of solvent and solutes. The ability to appropriately open or close the channel (gating) is critical to bacterial survival. We briefly review the science that led to the isolation and identification of MscS. We concentrate on the structure-function relationship of the channel, in particular the structural and biochemical approaches to understanding channel gating. We highlight the troubling discrepancies between the various models developed to understand MscS gating.


A comparison of diet quality and cardiovascular and inflammatory responses between aerobically trained male adults following either a long-term vegan or omnivorous dietary pattern.
Vegan dietary patterns are increasingly being adopted by endurance athletes, yet research examining the influence of this dietary pattern on exercise-related physiology is limited. This pilot study, therefore, aimed to explore nutrient status, diet quality and cardiovascular and inflammatory responses in aerobically trained adult males following vegan and omnivorous dietary patterns during aerobic exercise. An incremental ramp running test was used to assess peak oxygen consumption (VO2peak ) in males aged 18-55 years, engaging in >4 h training/week. Exercise testing was performed during walking and steady-state running conditions (60% and 90% of VO2peak ). Participants were grouped by dietary pattern type and were equivalent for age, training volume and VO2peak . When compared to the omnivorous group (n = 8, age 35.6 years, VO2peak 55.7 mL/kg/min), the vegan group (n = 12, age 33.4 years, VO2peak 56.4 m/kg/min) consumed more energy from carbohydrates (p = 0.007), and less energy from protein (p = 0.001) while exhibiting a higher overall diet quality score (p = 0.008). No differences in inflammatory biomarkers were observed before or after running. Total red blood cell count, haemoglobin and haematocrit levels were lower in the vegan dietary group. In summary, aerobically trained males, following a long-term vegan diet, can tolerate a short bout of running broadly comparatively to their omnivore counterparts. More arduous endurance exercise conditions should be explored to further uncover potential outcomes of consuming a vegan dietary pattern and exercise-related physiology.


Impact of lifestyle habits on the prevalence of the metabolic syndrome among Greek adults from the ATTICA study.
Individuals with the metabolic syndrome (MS) are at high risk for coronary heart disease and may benefit from aggressive lifestyle modification. In this study, we evaluated the effect of leisure time physical activity (PA) and the Mediterranean diet (MD) on the prevalence of the MS. The ATTICA study is a health and nutritional survey. On the basis of a multistage, random sampling, 1128 men and 1154 women (>18 years old) without any evidence of cardiovascular disease or diabetes mellitus were enrolled from the greater Athens area during 2001 to 2002. The MS was defined according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria. PA was determined from a detailed questionnaire and graded according to the kcal/min expanded. MD was assessed through a validated nutrient questionnaire. The overall prevalence of the MS was 453 of 2282 subjects (19.8%). Of these subjects, 284 (25.2%) were men and 169 (14.6%) were women (P <.001). The prevalence of the MS increased accordingly to age (P for trend <.001). With multiple logistic regression analysis, the odds ratio of having the MS when the participant consumed the MD was 0.81 (95% CI, 0.68-0.976), and when even a little to moderate PA (<7 kcal/min)was reported, the odds ratio was 0.75 (95% CI, 0.65-0.86). The higher levels of inflammation and coagulation markers among participants with MS did not explain much of the aforementioned effect of lifestyle modification. MS is common in Greece and is becoming even more common in the middle-aged population. The suggested therapeutic lifestyle approach may contribute to the reduction of the prevalence of the MS, beyond the levels of several lipid, inflammation, and coagulation markers.


3D printing materials and their use in medical education: a review of current technology and trends for the future.
3D printing is a new technology in constant evolution. It has rapidly expanded and is now being used in health education. Patient-specific models with anatomical fidelity created from imaging dataset have the potential to significantly improve the knowledge and skills of a new generation of surgeons. This review outlines five technical steps required to complete a printed model: They include (1) selecting the anatomical area of interest, (2) the creation of the 3D geometry, (3) the optimisation of the file for the printing and the appropriate selection of (4) the 3D printer and (5) materials. All of these steps require time, expertise and money. A thorough understanding of educational needs is therefore essential in order to optimise educational value. At present, most of the available printing materials are rigid and therefore not optimum for flexibility and elasticity unlike biological tissue. We believe that the manipuation and tuning of material properties through the creation of composites and/or blending materials will eventually allow for the creation of patient-specific models which have both anatomical and tissue fidelity.


Primary angiitis of the central nervous system.
Primary angiitis of the central nervous system (PACNS) is a rare form of vasculitis of unknown cause. The mean age of onset is 50 years, and men are affected twice as often as women. Headache and encephalopathy are the most frequent initial symptoms. Stroke or focal symptoms develop in less than 20% of patients at the onset of disease and are uncommon in the absence of headache or encephalopathy. Symptoms or signs of vasculitis outside of the central nervous system are rare; serologic markers of inflammation are typically normal. Magnetic resonance imaging of the brain is abnormal in more than 90% of patients, but the pattern of abnormal findings is not specific. Cerebrospinal fluid analysis is also usually abnormal because of modest, nonspecific elevations in total protein level or white blood cell count. Angiography has a low sensitivity and low specificity. Most patients suspected of having PACNS have another disease. The diagnosis of PACNS is established by brain biopsy. The differential diagnosis of PACNS is broad and includes reversal cerebral vasoconstriction. In contrast to patients with PACNS, patients with reversal cerebral vasoconstriction are more often young women who experience a thunderclap headache and have a normal cerebrospinal fluid analysis. Patients with biopsy-proven PACNS are treated with cyclophosphamide and prednisone.


Taste responsiveness and diet preference in autoimmune MRL mice.
One of the most profound behavioural deficits in lupus-prone MRL-lpr mice is blunted responsiveness to sweet solutions. Given the systemic nature of autoimmune/inflammatory disease, it was not clear whether impaired taste sensitivity or motivated response to palatable food underlie this deficit. The present study compares response rates of MRL-lpr mice (which develop disease early), congenic MRL +/+ mice (which develop disease later in life) and non-autoimmune Swiss Webster (SW) mice to different tastes and diets. Healthy SW mice showed the highest responsiveness to palatable stimulation throughout the study. Conversely, the preference for palatable solutions progressively declined in MRL-lpr mice as the disease developed. No differences between the two MRL substrains were seen in responsiveness to quinine or saline, suggesting that blunted responsiveness to palatable solutions cannot be accounted for by reduced taste sensory function (hypogeusia). In addition, changes in response rates to palatable solutions were associated with systemic upregulation of pro-inflammatory cytokines. With a new cohort of mice fed on carbohydrate-rich and fat-rich diets, we also examined whether reduced sucrose intake in MRL-lpr mice can be accounted for by a reduced craving for carbohydrates. Contrary to this expectation, diseased MRL-lpr mice preferred carbohydrate-rich food while consuming a food mass comparable to controls. These results further support the hypothesis that the onset of lupus-like disease alters motivated behaviour, independent of changes in neurologic function and food metabolism.


Biocompatibility and Cytotoxic Evaluation of New Sorbent Cartridges for Blood Hemoperfusion.
The use of adsorption cartridges for hemoperfusion (HP) is rapidly evolving. For these devices, the potential induced cytotoxicity is an important issue. The aim of this study was to investigate potential in vitro cytotoxic effects of different sorbent cartridges, HA130, HA230, HA330, HA380 (Jafron, China), on U937 monocytes. Monocytes were exposed to the sorbent material in static and dynamic manners. In static test, cell medium samples were collected after 24 h of incubation in the cartridges. In dynamic test, HP modality has been carried out and samples at 30, 60, 90, and 120 min were collected. Compared to control samples, there was no evidence of increased necrosis or apoptosis in monocytes exposed to the cartridges both in the static and dynamic tests. Our in vitro testing suggests that HA cartridges carry an optimal level of biocompatibility and their use in HP is not associated with adverse reactions or signs of cytotoxicity.


The effect of deoxycholic acid on calcium ions in the cytoplasm of gastric mucosal cells in rabbits.
Lack of decrease in the level of calcium ions in the cytoplasm after incubation of cell suspension with deoxycholic acid (DC) may be an early sign of cellular damage. The purpose of the study was to find out whether an increase in free calcium level in the cytoplasm preceded other signs of damage and whether calcium channel blockade may inhibit calcium increase in the cytoplasm. The cell suspension from the gastric mucosa in rabbits was incubated with DC in various concentrations. The calcium level was measured by means of spectrofluorimetry after prior incubation with FURA 2/AM. The viability of cells was determined by measuring oxygen consumption and using trypan blue test. Deoxycholic acid in the concentration of 0.2 mM produced an increase in [Ca2+]i from 177 +/- 5 to 285 +/- 24 nM. Incubation of the cell suspension with 0,5 mM DC also produced an abrupt increase in [Ca2+]i from 177 +/- 5 nM to 639 +/- 49 nM. In addition, the studies showed that 0,2 mM DC despite increasing free calcium level in the cytoplasm did not reduce the cell viability. It was revealed on the basis of oxygen consumption and trypan blue test. The studies showed that an increased intracellular [Ca2+]i may be a very early sign of their damage.


[Gastric polyps: prognosis and treatment].
49 patients, previously treated for epithelial gastric polyps by resection or excision, were re-examined up to 22 years later. Except for those who had died of other diseases, in five histologically confirmed and in one a probable (radiologically) gastric carcinoma had been found. Three cases of gastric carcinoma without symptoms were discovered in the course of endoscopic follow-up examination. Two of these patients underwent radical operation (early carcinoma), while the third one proved to be inoperable. It is concluded that gastric polyps must be removed endoscopically or operatively and examined histologically: simple observation must be rejected. If the polyp is hyperplastic, local removal is sufficient. If there is a pure adenoma, two-third resection is essential. This is also true of hyperplasiogenic polyps if they are present in large numbers, while polypectomy is sufficient if solitary. Polyposis usually requires subtotal or total resection. Each patient with such polyps is exposed to a higher risk of gastric carcinoma. For this reason annual endoscopic control is necessary even if there are no symptoms.


Studies on the inhibitory effect of isavuconazole on flumatinib metabolism in vitro and in vivo.
As the validated agent for the treatment of chronic myelogenous leukemia (CML), flumatinib is a novel oral tyrosine kinase inhibitor (TKI) with higher potency and selectivity for BCR-ABL1 kinase compared to imatinib. Many patients experience aspergillosis infection and they may start using isavuconazole, which is an inhibitor of CYP3A4. However, there is no study on their interaction in vitro and in vivo. In the present study, the concentrations of flumatinib and its major metabolite M1 were rapidly determined using an stable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The half-maximal inhibitory concentration (IC50) was 6.66 μM in human liver microsomes (HLM), while 0.62 μM in rat liver microsomes (RLM) and 2.90 μM in recombinant human CYP3A4 (rCYP3A4). Furthermore, the mechanisms of inhibition of flumatinib in human liver microsomes, rat liver microsomes and rCYP3A4 by isavuconazole were mixed. Moreover, ketoconazole, posaconazole, and isavuconazole showed more potent inhibitory effects than itraconazole, fluconazole, and voriconazole on HLM-mediated flumatinib metabolism. In pharmacokinetic experiments of rats, it was observed that isavuconazole could greatly change the pharmacokinetic parameters of flumatinib, including AUC(0-t), AUC(0-∞), Cmax and CLz/F, but had no effect on the metabolism of M1. According to the results of in vitro and in vivo studies, the metabolism of flumatinib was inhibited by isavuconazole, suggesting that isavuconazole may raise the plasma concentration of flumatinib. Thus, it is important to take special care of the interactions between flumatinib and isavuconazole in clinical applications.


Assessment of Altered Cholesterol Homeostasis by Xenobiotics Using Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry.
Cholesterol and cholesterol-derived oxysterols are critical for embryonic development, synapse formation and function, and myelination, among other biological functions. Indeed, alterations in levels of cholesterol, sterol precursors, and oxysterols result in a variety of developmental disorders, emphasizing the importance of cholesterol homeostasis. The ability of xenobiotics to reproduce similar phenotypes by altering cholesterol homeostasis has increasingly become of interest. Therefore, the ability to quantitatively assess alterations in cholesterol homeostasis resulting from exposure to xenobiotics is of value. This unit describes methods for the quantitative assessment of altered post-squalene cholesterol biosynthesis and subsequent oxysterol formation in various sample types using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Understanding alterations in cholesterol homeostasis resulting from xenobiotic exposure can provide key insight into the toxicant's mechanism of action and resulting phenotype. © 2018 by John Wiley & Sons, Inc.


Clinical characteristics and 3-month outcomes in cancer patients with incidental versus clinically suspected and confirmed pulmonary embolism.
Current guidelines suggest treating cancer patients with incidental pulmonary embolism (PE) similarly to those with clinically suspected and confirmed PE. However, the natural history of these presentations has not been thoroughly compared. We used the data from the RIETE (Registro Informatizado de Enfermedad TromboEmbólica) registry to compare the 3-month outcomes in patients with active cancer and incidental PE versus those with clinically suspected and confirmed PE. The primary outcome was 90-day all-cause mortality. Secondary outcomes were PE-related mortality, symptomatic PE recurrences and major bleeding. From July 2012 to January 2019, 946 cancer patients with incidental asymptomatic PE and 2274 with clinically suspected and confirmed PE were enrolled. Most patients (95% versus 90%) received low-molecular-weight heparin therapy. During the first 90 days, 598 patients died, including 42 from PE. Patients with incidental PE had a lower all-cause mortality rate than those with suspected and confirmed PE (11% versus 22%; OR 0.43, 95% CI 0.34-0.54). Results were consistent for PE-related mortality (0.3% versus 1.7%; OR 0.18, 95% CI 0.06-0.59). Multivariable analysis confirmed that patients with incidental PE were at lower risk of death (adjusted OR 0.43, 95% CI 0.34-0.56). Overall, 29 (0.9%) patients developed symptomatic PE recurrences, and 122 (3.8%) had major bleeding. There were no significant differences in PE recurrences (OR 0.62, 95% CI 0.25-1.54) or major bleeding (OR 0.78, 95% CI 0.51-1.18). Cancer patients with incidental PE had a lower mortality rate than those with clinically suspected and confirmed PE. Further studies are required to validate these findings, and to explore optimal management strategies in these patients.


A Longitudinal Study of Stress During Pregnancy, Children's Sleep and Polygenic Risk for Poor Sleep in the General Pediatric Population.
Early life stress is robustly associated with poor sleep across life. Preliminary studies suggest that these associations may begin already in utero. Here, we study the longitudinal associations of prenatal psychosocial stress with sleep across childhood, and assess whether prenatal stress interacts with genetic liability for poor sleep.The study is embedded in the Generation R population-based birth cohort. Caregivers reported on prenatal psychosocial stress (life events, contextual, parental or interpersonal stressors) and on children's sleep at ages 2 months, 1.5, 2, 3 and 6 years. The study sample consisted of 4,930 children; polygenic risk scores for sleep traits were available in 2,063.Prenatal stress was consistently associated with more sleep problems across assessments. Effect sizes ranged from small (B = 0.21, 95%CI: 0.14;0.27) at 2 months to medium (B = 0.45, 95%CI: 0.38;0.53) at 2 years. Prenatal stress was moreover associated with shorter sleep duration at 2 months (Bhrs = -0.22, 95%CI: -0.32;-0.12) and at 2 years (Bhrs = -0.04, 95%CI -0.07; -0.001), but not at 3 years (Bhrs = 0.02, 95%CI: -0.02;0.06). Prenatal negative life events interacted with polygenic risk for insomnia to exacerbate sleep problems at 6 years (Binteraction = 0.07, 95%CI: 0.02;0.13).Psychosocial stress during pregnancy has negative associations with children's sleep that persist across childhood, and are exacerbated by genetic liability for insomnia. Associations with sleep duration were more pronounced in infancy and seem to attenuate with age. These findings highlight the role of the prenatal environment for developing sleep regulation, and could inform early intervention programs targeting sleep in children from high-risk pregnancies.


Variationally localized search direction method for constrained optimization of non-orthogonal, localized orbitals in electronic structure calculations.
A new method for the constrained optimization of non-orthogonal, spatially localized orbitals using direct energy minimization techniques, in the context of electronic structure calculations, is presented. The variationally localized search direction (VLSD) method, as it was named, ensures that strict localization constraints are imposed upon the search direction vectors exactly, analytically and in a fully variational fashion. In contrast, the truncated search direction (TSD) method, of standard use in many electronic structure approaches with localization constraints, relies on the approximation that the truncated search direction vectors of the unconstrained problem resemble the exact search direction vectors of the constrained problem. With the TSD method, in order to maintain the localization constraints, a part of the pre-calculated information that is stored in the search direction vectors has to be deleted via an ad hoc, non-variational truncation step. The results on an extensive set of test molecules show that, in general, calculations with the VLSD method require less iterations to converge than with the TSD method for any size of the localization region. It was found that in calculations on certain systems where the TSD method is forced to delete a very large amount of information, the VLSD method is capable of achieving convergence in up to three times less iterations. Validation tests show that structural and electronic properties calculated with either method are accurate and in agreement with other electronic structure approaches.


Informed consent for extended-wear patients.
Because of the risk of complication posed by extended-wear lenses, contact lens practitioners must comply with the requirements of informed consent, which obligate the optometrist to communicate these risks to patients. Documentation of informed consent can be obtained by using printed agreements that describe the risks of wear, instructions for lens care, wearing schedules, and required follow-up evaluations. In determining wearing schedules for patients, optometrists should not recommend more than 7 days (ie, 6 nights) of continuous wear without demonstrable benefit to the patient, and informed consent requirements should be complied with and adequate documentation retained whenever extended periods of wear are contemplated. For wearers of disposable lenses, informed consent is necessary because practitioners are not able to inspect lenses prior to wear. Patients must be advised to remove lenses if pain, redness, reduced acuity, discharge, or photophobia result and to return for examination when these symptoms occur. Documentation of this warning and of other aspects of disposable lens wear may be provided by a printed agreement.


Management of children with pancreatic head mass.
The management of children with a mass in the head of the pancreas is not well defined. The medical records of 3 children with obstructive jaundice because of a mass in the head of the pancreas over a 4-year period were reviewed retrospectively. Abdominal ultrasonography and computed tomography showed intrahepatic and extrahepatic ductal dilatation and a pancreatic mass. Intraoperative frozen section revealed no evidence of malignancy. These patients were separately managed by pylorus-preserving pancreaticoduodenectomy, cholecystectomy and Roux-en-Y choledochojejunostomy, common duct exploration, and T-tube drainage. The final pathology of the pancreatic head mass in all cases demonstrated chronic pancreatitis. Follow-up at an average of 7 months postoperatively showed no recurrence of obstructive jaundice. Unlike adults with a mass in the head of the pancreas, it is recommended that children with similar presentation should undergo biopsy and biliary diversion rather than resection as the primary therapy. Adults presenting with similar radiologic and clinical features would be treated by a pancreaticoduodenectomy in the absence of histologic evidence of malignancy. This series would suggest histologic conformation should be obtained before radical surgery in children.


[The dynamics of the concentration of atrial natriuretic factor depending on changes in the arterial pressure level in patients with arterial hypertension].
The purpose of the study was to explore the dynamics of the concentration of atrial natriuretic hormone (ANH) in response to changes in arterial pressure including those induced by hypertonic crisis, 7-day hypotensive monotherapy with the drugs having different action mode, and the acute test with the basic hypotensive drugs. 75 patients suffering from arterial hypertension were entered into the study. Measurements of the concentration of ANH in blood plasma were performed by radioimmunoassay with the aid of the kits manufactured by the Amersham Company (Great Britain). The activity of renin and aldosterone was determined by radioimmunoassay according to the standard technique. A strong positive correlation was revealed between the concentration of ANH and the level of both systolic and diastolic AP. A significant rise of the concentration of ANH elicited by hypertonic crisis reflects the growth of the tension of the depressor mechanisms by which AP is regulated. The lack of significant changes in the level of ANH during the acute pharmacological tests and effective continuous treatment with the hypotensive drugs attests to the existence of the complex mechanisms that regulate ANH secretion, determined not only by the level of AP.


Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs.
The capacity of platelets to generate thromboxane A2, reflected by measurement of serum thromboxane B2 (TxB2), greatly exceeds the systemic production of thromboxane in vivo. Thus, it is possible that substantial but incomplete inhibition of thromboxane formation ex vivo would still allow marked augmentation of thromboxane production in vivo. To address this hypothesis, we administered aspirin 120 mg, a selective inhibitor of thromboxane synthase (TxSl), 3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid (UK-38, 485) 200 mg, and a combination of both drugs to 12 healthy volunteers and measured the effects on serum TxB2 and urinary 2,3-dinor-thromboxane B2 (Tx-M), an index of endogenous thromboxane biosynthesis. Although serum TxB2 was maximally inhibited by 94 +/- 1% after aspirin and 96 +/- 2% after the TxSl, maximal depression of Tx-M was only 28 +/- 8% and 37 +/- 9%, respectively. Combination of aspirin with the TxSl resulted in a small but significant increase in inhibition of thromboxane generation ex vivo (98 +/- 1% v 94 +/- 1%; P less than 0.05), but a disproportionately greater fall in thromboxane synthesis in vivo (58 +/- 7%; P less than 0.01). Consistent with further inhibition of platelet thromboxane synthesis, addition of the TxSl abolished the transient decline in prostacyclin formation after aspirin alone. Administration of a lower dose of aspirin (20 mg) to 6 healthy subjects caused a small reduction in Tx-M (12 +/- 4%; P less than 0.05) and inhibited serum TxB2 by 48 +/- 2%. The relationship between inhibition of platelet capacity to form thromboxane ex vivo (serum TxB2) and synthesis in vivo (Tx-M) departed markedly from the line of identity. When total blockade of the capacity of platelets to generate thromboxane is approached, minor decrements in capacity result in a disproportionate depression of actual thromboxane biosynthesis. These results imply that pharmacologic inhibition of serum TxB2 must be virtually complete before thromboxane-dependent platelet activation is influenced in vivo.


The critical role of hydroxyl groups in water vapor sensing of graphene oxide.
Excellent adsorption of water vapor on the surface of graphene oxide (GO), which contains several inherited functional groups, leads to the development of improved humidity monitoring systems that can urgently meet the high industrial demand. In this study, we fabricated a GO-based humidity sensor and investigated the influence of hydroxyl group concentration on its performance. The sensor exhibited excellent humidity sensing performance in terms of sensitivity (sensor response ∼40 for 90% RH), selectivity, stability (both long-term and short-term) and reaction time (τ res = 8.5 s and τ rec = 13 s). Additionally, this sensor does not require external power consumption for heating; thus, the aforementioned performance (recorded at room temperature) with an applied voltage of 0.1 V can significantly reduce the power/energy consumption to about ∼1.314 × 10-4 kW h per year. In the future, this type of sensor can be integrated into smart humidity monitoring systems to not only monitor but also control the humidity levels on a specific application area. Based on complementary characterization techniques, such as XRD, AFM, Raman and electrical measurement, here, we propose a physical-chemical sensing model to elucidate the aforementioned sensor characteristics.


Current status of mammalian target of rapamycin inhibitors in lung cancer.
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a critical role in the control of cell growth and proliferation. The mTOR integrates mitogenic signals and intracellular nutrient levels to activate eukaryotic initiation factor 4E-binding protein-1 and the 40S ribosomal protein S6 kinase, which controls protein translation and cell cycle progression. Abnormal activation of signaling pathways proximal and distal to mTOR appears to occur frequently in human cancer, making mTOR an attractive target for anticancer drug development. Inhibitors of mTOR, including the naturally occurring inhibitor rapamycin as well as newer agents against this target, are currently in clinical development for cancer treatment. In preclinical studies, these agents have shown significant effects against a variety of preclinical models of cancer. In early clinical studies, mTOR inhibitors have been well tolerated, resulted in plasma levels able to inhibit mTOR in normal and tumor tissues of patients treated with the drug, and resulted in antitumor responses in patients with different tumor types including lung cancer. These agents are now in late phases of clinical development. As with other targeted agents, the key issues in the future will be to elucidate the molecular factors predicting a favorable response to the drugs as well as the rational integration with other targeted agents with activity in lung cancer, such as inhibitors of the epidermal growth factor receptor tyrosine kinase.


Effect of 17beta-estradiol or alendronate on the bone densitometry, bone histomorphometry and bone metabolism of ovariectomized rats.
The objective of the present study was to evaluate the effect of 17beta-estradiol or alendronate in preventing bone loss in 3-month-old ovariectomized Wistar rats. One group underwent sham ovariectomy (control, N = 10), and the remaining three underwent double ovariectomy. One ovariectomized group did not receive any treatment (OVX, N = 12). A second received subcutaneous 17beta-estradiol at a dose of 30 microg/kg for 6 weeks (OVX-E, N = 11) and a third, subcutaneous alendronate at a dose of 0.1 mg/kg for 6 weeks (OVX-A, N = 8). Histomorphometry, densitometry, osteocalcin and deoxypyridinoline measurements were applied to all groups. After 6 weeks there was a significant decrease in bone mineral density (BMD) at the trabecular site (distal femur) in OVX rats. Both alendronate and 17beta-estradiol increased the BMD of ovariectomized rats, with the BMD of the OVX-A group being higher than that of the OVX-E group. Histomorphometry of the distal femur showed a decrease in trabecular volume in the untreated group (OVX), and an increase in the two treated groups, principally in the alendronate group. In OVX-A there was a greater increase in trabecular number. An increase in trabecular thickness, however, was seen only in the OVX-E group. There was also a decrease in bone turnover in both OVX-E and OVX-A. The osteocalcin and deoxypyridinoline levels were decreased in both treated groups, mainly in OVX-A. Although both drugs were effective in inhibiting bone loss, alendronate proved to be more effective than estradiol at the doses used in increasing bone mass.


Voluntary testing for human immunodeficiency virus (HIV) in a prison population with a high prevalence of HIV.
This study evaluated voluntary testing for human immunodeficiency virus (HIV) in a prison population with a high HIV seroprevalence. Data on demographic variables and participation in voluntary testing were linked to a blinded HIV serosurvey of consecutive Maryland prison entrants (April-July 1991). Among 2,842 entrants, HIV seroprevalence was 8.5% (men, 7.9%; women, 15.3%). Voluntary testing was accepted by 47% of the entrants, and it identified 34% of the HIV-seropositive inmates detected by serosurvey. Refusers of testing were more likely to test HIV-seropositive than were accepters (adjusted odds ratio (OR) = 1.84, 95% confidence interval (CI) 1.58-2.16). Refusers and accepters of testing had similar risk factors for HIV infection, chiefly current syphilis infection (adjusted OR = 5.96, 95% CI 3.15-10.27) and prior injected drug use (adjusted OR = 4.26, 95% CI 3.15-5.76). Among 100 entrants asked why they refused testing, primary reasons given included low risk of HIV, fear of testing HIV-seropositive, and lack of interest. Voluntary testing appears only moderately successful in identifying HIV-seropositive inmates in a high-seroprevalence prison population. However, the alternative, mandatory HIV testing of prisoners, can be construed as discriminatory and unethical when similar screening is not imposed on the population at large. Data presented here suggest strategies to improve acceptance of voluntary testing, especially by high risk inmates.


Serotonin toxicity of serotonergic psychedelics.
In recent years, psychedelic substances with serotonergic mechanisms have accumulated substantial evidence that they may provide therapeutic benefits for people suffering with psychiatric symptoms. Psychiatric disorders targeted by these psychedelic-assisted therapies are managed with serotonergic drugs like selective serotonin reuptake inhibitors (SSRIs) as the current standard of care, so it is important to evaluate the potential risks of drug-drug interactions and serotonin toxicity (ST) between these agents. A critical evaluation of the scientific literature is necessary to delineate the risks of ST when combining psychedelics with available serotonergic pharmacotherapy options. This review article describes signs and symptoms of ST, characterizes mechanisms of ST risk, summarizes what is known about serotonergic psychedelic drug interactions, and outlines potential management strategies. True ST typically occurs with a serotonergic drug overdose or in combinations in which a drug that can increase intrasynaptic serotonin is combined with a monoamine oxidase inhibitor (MAOI). Serotonergic psychotropics that do not contain MAOIs are low risk in combination with psychedelics that also do not contain MAOIs. Signs and symptoms warranting immediate medical attention include myoclonus, extreme and fluctuating vital signs, agitation or comatose mental state, muscle rigidity, pronounced hyperthermia (fever), and/or seizure activity. Serotonin-related adverse reactions exist along a spectrum with serotonin syndrome being the most severe manifestations of ST. Due to varying serotonergic mechanisms of psychedelics and psychotropics, with varying propensities to increase intrasynaptic serotonin, some combinations may present a significant risk for serotonin toxicity (ST) while others are likely benign.


Theory-and evidence-based development and process evaluation of the Move More for Life program: a tailored-print intervention designed to promote physical activity among post-treatment breast cancer survivors.
Several physical activity interventions have been effective in improving the health outcomes of breast cancer survivors. However, few interventions have provided detailed descriptions regarding how such interventions work. To develop evidence-based practice in this field, detailed descriptions of intervention development and delivery is needed. This paper aims to (1) describe the theory-and evidence-based development of the Move More for Life program, a physical activity program for breast cancer survivors; and (2) serve as an exemplar for theory-based applied research. The program-planning model outlined by Kreuter and colleagues was used to develop the computer-tailored intervention. The tailoring guide developed by Kreuter and colleagues served as a useful program planning tool in terms of integrating theory and evidence-based best practice into intervention strategies. Overall, participants rated the intervention positively, with the majority reporting that the tailored materials caught their attention, were personally relevant to them, and were useful for helping them to change their behaviour. However, there was considerable room for improvement. The Move More for Life program is an example of a theory-based, low-cost and potentially sustainable strategy to physical activity promotion and may stand as an exemplar for Social Cognitive Theory-based applied research. By providing a detailed description of the development of the Move More for Life program, a critical evaluation of the working mechanisms of the intervention is possible, and will guide researchers in the replication or adaption and re-application of the specified techniques. This has potential implications for researchers examining physical activity promotion among cancer survivors and for researchers exploring distance-based physical activity promotion techniques among other populations. Australian New Zealand Clinical Trials Registry (ANZCTR) identifier: ACTRN12611001061921.


Tumor-targeted delivery of IL-2 by NKG2D leads to accumulation of antigen-specific CD8+ T cells in the tumor loci and enhanced anti-tumor effects.
Interleukin-2 (IL-2) has been shown to promote tumor-specific T-cell proliferation and differentiation but systemic administration of IL-2 results in significant toxicity. Therefore, a strategy that can specifically deliver IL-2 to the tumor location may alleviate concerns of toxicity. Because NKG2D ligands have been shown to be highly expressed in many cancer cells but not in healthy cells, we reason that a chimeric protein consisting of NKG2D linked to IL-2 will lead to the specific targeting of IL-2 to the tumor location. Therefore, we created chimeric proteins consisting of NKG2D linked to Gaussia luciferase (GLuc; a marker protein) or IL-2 to form NKG2D-Fc-GLuc and NKG2D-Fc-IL2, respectively. We demonstrated that NKG2D linked to GLuc was able to deliver GLuc to the tumor location in vivo. Furthermore, we showed that TC-1 tumor-bearing mice intramuscularly injected with DNA encoding NKG2D-Fc-IL2, followed by electroporation, exhibited an increased number of luciferase-expressing E7-specific CD8+ T cells at the tumor location. More importantly, treatment with the DNA construct encoding NKG2D-Fc-IL2 significantly enhanced the therapeutic anti-tumor effects generated by intradermal vaccination with therapeutic HPV DNA in tumor-bearing mice. Therefore, by linking NKG2D to IL2, we are able to specifically deliver IL-2 to the tumor location, enhancing antigen-specific T-cell immune response and controlling tumor growth. Our approach represents a platform technology to specifically deliver proteins of interest to tumor loci.


Clinical and therapeutic impact of 18F-FDG PET/CT whole-body acquisition including lower limbs in patients with malignant melanoma.
To assess the added benefit of scanning lower limbs in addition to the usual whole-body positron emission tomography/computed tomography (PET/CT) scan in patients with no known or suspected primary or metastatic melanoma involving the lower limbs. This is a retrospective study of 122 consecutive patients [174 2-[¹⁸F]-fluoro-2-deoxy-D-glucose (FDG) PET/CT] who underwent FDG PET/CT for staging of melanoma at different time points in the course of the disease from October 2005 to February 2009 at the Brest University Hospital. Reports of whole-body PET/CT scans including lower limbs were reviewed. PET/CT abnormalities on the lower extremities were tabulated by location and correlated with pathology, other imaging studies and at least a 6-month clinical follow-up. The usefulness of lower limbs acquisition in clinical management was evaluated according to imagery findings. Among the 174 consecutive PET/CT scans performed in 122 patients, 33 scans in 28 patients highlighted abnormal FDG uptakes considered as equivocal or suggestive of malignancy in the lower limbs. In 28 cases, uptakes were located at once in the lower limbs and in the rest of the body (lung, liver, mediastinal and sub-diaphragmatic lymph nodes, adrenal glands, bone) corresponding to disseminated disease. In five cases, PET/CT uptakes were located only in lower limbs; each pathological uptake corresponded to benign lesions. Lower limbs findings never impacted clinical and therapeutic decision. Lower limbs additional PET/CT acquisition seems to offer poor additional benefit with none unexpected lesion detected and routine skull base to upper thigh images might be sufficient for this subset of patients.


Apolipoprotein E, CI and B gene polymorphisms in a sample of patients with coronary heart disease in the Kuwaiti population.
The objective of this study was to investigate the possible association of clinical variables and apolipoprotein (APOE, APOCI and APOB) polymorphisms with the development of myocardial infraction (MI) and coronary heart disease (CHD) in Kuwaitis. APOE, APOCI and APOB genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism in 143 Kuwaiti CHD patients with (n = 88) and without (n = 55) MI and in 122 controls matched for gender and age. Statistical and genetic analyses of the genotype, allele and haplotype frequencies, as well as regression analyses of genetic and clinical variables were done. There was a statistically significant association between CHD and medical history of diabetes mellitus (p < 0.001), hypertension (p < 0.01), high cholesterol (p < 0.05) and family history of CHD (p < 0.001). A highly significant association (p < 0.001) was found, with an adjusted odds ratio of 9.32, for family history and the development of MI. No significant differences were found for allele or genotype frequencies between CHD patients and controls. The strong effect of family history suggests a major genetic component for the development of CHD in Kuwaitis, but this association does not appear to be related to the APO genes studied here. The results in this study encourages future research into these and other polymorphisms and their potential association with MI and CHD in the Kuwaiti population.


Characterization and cloning of enterotoxin genes of Salmonella typhimurium.
Five of fifty five strains of Salmonella typhimurium of human origin was hybridized with both the LT-A and LT-B gene of Escherichia coli. The remarkably erythromatous and indurated response on rabbit skin and significant elongation of Chinese Hamster Ovary (CHO) cells indicated the production of enterotoxin of these isolates. The Salmonella enterotoxin is heat-labile and is not a secretory product. The LT gene of E. coli was used to analyze the chromosome and plasmid DNA from Salmonella typhimurium strains for toxin gene sequences. Southern blot analysis demonstrated that the toxin gene was located on the plasmid but not on the chromosome. Restriction enzymes BamHI, EcoRI, HindIII and PstI were used to analyze the DNA isolated from salmonella strains Nos.22, 52, 55 and 59. Three DNA fragments with size of 5.2 Kb of strain 22, 5.0 Kb of strain 52 and 8.6 Kb of strain 59 were identified as containing the enterotoxin gene. Plasmid pUC19 was used as the vector to clone these DNA fragments in E. coli. The rabbit skin permeability test indicated that Salmonella enterotoxin could be synthesized at readily detectable levels in these transformed E. coli.


The evolution of diastolic dysfunction in the hypertensive disease.
To investigate the effects of cardiac remodelling on left ventricular (LV) diastolic function, as evaluated by tissue Doppler and blood-pool indices, with respect to loading as expressed by wall stress. Cardiac remodelling is the major pathophysiological result of increased blood pressure and manifests as changes in the size, shape, and function of the heart. We evaluated 90 hypertensive patients and 30 healthy volunteers. The hypertensive patients were divided into three groups: (i) HTN-N: normal remodelling (n= 30), (ii) HTN-CR: concentric remodelling (n= 30), and (iii) HTN-CH: concentric hypertrophy (n= 30). Mitral annular early diastolic (Ea) velocities were recorded. Filling pressures (E/Ea), relative wall thickness, LV mass index, DT, isovolumic relaxation time (IVRT), E/A ratio, and longitudinal wall stress (LWS) were also measured. Diastolic dysfunction (DD) was diagnosed based on published criteria. Progressive and increased incidence of DD with advancement of LV remodelling and an increase in LV mass was noted. Wall stress-loading was higher in the HTN-N group and lower in the HTN-CR and HTN-CH groups, despite the more deteriorated diastolic function in the latter groups. DD appeared early, even in the HTN-N group, which had a 36.6% incidence of DD compared to a 13% age-related incidence in the control group (P < 0.05). When the control group was used to define the reference values for septal Ea with the cut-off set as 2SD below the mean, the HTN-N, HTN-CR, and HTN-CH groups had abnormal diastolic function at 16.6, 26.6, and 56.6% incidence rates, respectively. Septal (Ea) was correlated with LVMI (r= -0.55), RWT (r= -0.56), Age (r= -0.52), BMI (r= -0.31), SBP (r= -0.54), PP (r= -0.55), and MAP (r= -0.39), all at P < 0.05. The correlations of blood-pool indices (DT, IVRT, and E/A) with the above parameters were less than that of tissue Doppler imaging (Septal and mean Ea). In a multivariate model, LVMI (beta= -0.25), SBP (beta = -0.26), and age (beta= -0.24) R(2)= 0.49 were found to be independent predictors of DD. DD appears early in hypertensive disease, before the onset of abnormal remodelling or LV hypertrophy. With progression of the remodelling process and the advance of LVH, diastolic function progressively deteriorates. Tissue Doppler indices are better correlated with clinical and echocardiographic parameters of LV remodelling compared to blood-pool indices.


Mycobacterium doricum sp. nov.
A novel mycobacterial species is described in this study. The strain was isolated from the cerebrospinal fluid of a severely immunocompromised AIDS patient. It was scotochromogenic and slow-growing. Characteristic features for its differentiation from other mycobacteria are its lipid pattern and the unique gene sequences within the hypervariable regions of the 16S rDNA. The strain shows susceptibility to current antimycobacterial drugs. The pathogenicity of the novel mycobacterium and its clinical significance are not certain, as the neurological symptoms of the patient could also be due to concomitant infection with Cryptococcus neoformans. The name Mycobacterium doricum sp. nov. is proposed for the novel mycobacterium; the type strain is strain FI-13295T (= DSM 44339T = CIP 106867T).


Exploring multimodal semantic control impairments in semantic aphasia: evidence from naturalistic object use.
Semantic processing can break down in qualitatively distinct ways in different neuropsychological populations. Previous studies have shown that patients with multimodal semantic impairments following stroke - referred to as semantic aphasia (SA) - show deficits on a range of conceptual tasks due to a failure of semantic control processes in the context of prefrontal and/or temporoparietal infarction. Although a deficit of semantic control would be expected to impair performance in all modalities in parallel, most previous research in this patient group has focussed primarily on tasks employing words. This study explored the consequences of deregulated semantic cognition for an indisputably non-verbal task-naturalistic object use. Patients with SA performed more poorly than control participants on a range of everyday tasks assessed by the Naturalistic Action Test (NAT, Schwartz, M. F., Buxbaum, L. J., Ferraro, M., Veramonti, T., & Segal, M. (2002). Naturalistic action test. Thames Valley Test Company). Moreover, their scores on this assessment correlated with those obtained on language-based semantic tasks, suggesting that a common deficit could underlie the impairment in both modalities. As previously observed in the verbal domain, performance on the NAT was poorer when control processes were taxed by dual-task situations and the inclusion of semantically related distracting objects. A number of characteristics of the patients' action sequences were specifically indicative of deregulated semantic cognition. Their everyday action sequences were highly fragmented by a tendency to abandon subtasks before their completion and engage, instead, in extended periods of aimless "toying" with objects. The patient group also exhibited recurrent perseverative behaviour. These findings parallel the performance of a recurrent connectionist model of naturalistic action developed by Botvinick and Plaut [Botvinick, M. & Plaut, D. C. (2004). Doing without schema hierarchies: A recurrent connectionist approach to normal and impaired routine sequential action. Psychological Review, 111, 395-429], after the mechanism responsible for controlling action in a temporally sensitive manner was damaged. This study provides converging evidence for a failure of control processes underlying semantic memory impairment in SA, which is reflected not only in patients' performance on language-based tasks, but also in the non-verbal domain of naturalistic object use.


Critical Differences between Microscopic (MIFE) and Macroscopic (MAFE) Fat Embolism during Liposuction and Gluteal Lipoinjection.
Liposuction and gluteal lipoinjection are two of the most frequent surgical procedures in body contouring surgery, and two of the most important complications are microscopic (MIFE) and macroscopic (MAFE) fat embolism. Despite a high index of morbidity and mortality, few reports exist about these complications, and although they have the same causal agent, their etiopathogenesis, clinical evolution, treatment, prognosis, and prevention are totally different. Therefore, the authors performed a comprehensive review of the literature to exhaustively analyze both pathologic conditions and present the differences between them. A detailed search was carried out in PubMed of studies on humans from 1946 to March of 2017 in any language and including the keywords microscopic fat embolism and macroscopic fat embolism with either liposuction or gluteal lipoinjection. The articles found were selected according to the search criteria and were analyzed to provide the final data and recommendations. Of the 1245 and 26 articles that were found on complications related to liposuction and gluteal lipoinjection, respectively, only 41 on liposuction and microscopic fat embolism and seven on gluteal lipoinjection and microscopic fat embolism met the specific criteria for inclusion in the analysis. Only two articles on liposuction and two on gluteal lipoinjection referred to macroscopic fat embolism as a complication. Although microscopic fat embolism and macroscopic fat embolism are pathologic conditions with high morbidity and mortality rates in association with liposuction and gluteal lipoinjection, few reports about them exist; therefore, the authors made recommendations based on this study for their diagnosis, prevention, and treatment.


[Fatigue fractures in the area of the hip joint in joggers].
An increased incidence of fatigue fractures of the lower extremities has been observed as a result of the jogging craze. The authors describe a fatigue fracture of the neck of the femur and a fracture dislocation (not described to date) of the hip joint with fracture of the posterior acetabular margin and avulsion of a femoral head fragment.


A RE-AIM framework analysis of a sports club health promotion MOOC: the PROSCeSS MOOC.
Acquisition of health promotion (HP) skills and knowledge is essential for interventions development in this field. In sports clubs (SC), little HP training exists even though it was requested by SC actors. In response, the PROSCeSS (PROmotion de la Santé au sein du Clubs SportifS) MOOC (Massive Open Online Course) was developed to support actors of HP in the SC in the development of HP interventions. The present study evaluates the MOOC's effectiveness and learning process. The RE-AIM framework, measuring reach, effectiveness, adoption, implementation and maintenance was used to structure this study. Surveys were sent before and after the MOOC to the 2814 learners. Among the 502 (18%) respondents to the pre-survey, 80% reported belonging to a SC as a coach (35%) or manager (25%). The 14% of pre-survey respondents who completed the post-survey increased their HP knowledge score by 42% and their confidence to implement HP actions by 6%. Results present the strategies considered most important and feasible by the learners and the main barriers to the implementation of HP actions in the SC. This study shows that MOOC appears to be an appealing (93% of learners were satisfied) and effective solution (as long as it is followed) to develop HP knowledge and skills of SC actors in HP, meeting their needs and constraints. Although improvements should be made (especially in terms of promoting adoption), this type of educational format should be encouraged to support the HP potential of SC.


Experience of continuity of care of patients with multiple long-term conditions in England.
To examine patients' experiences of continuity of care in the context of different long-term conditions and models of care, and to explore implications for the future organization care of long-term conditions. Qualitative semi-structured interviews were carried out with 33 patients recruited from seven general practices in South London. Patients were selected who had one or more of the following long-term conditions: arthritis, coronary heart disease, stroke, hypercholesterolaemia, hypertension, diabetes mellitus or chronic obstructive pulmonary disease. Multiple morbidity was frequent and experiences of continuity were framed within patients' wider experiences of health care rather than the context of a particular diagnosis. Positive experiences of relational continuity were strongly associated with long-term GP-led or specialist-led care. Management continuity was experienced in the context of shared care in terms of transitions between professionals or organizations. Access and flexibility issues were identified as important barriers or facilitators of continuity. Across a range of long-term conditions, patients' experiences of health care can be understood in terms of nuanced understandings of relational and management continuity. Continuity experiences, meanings and expectations, as well as barriers and facilitators, are influenced by the model of care rather than type of condition.


Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia.
Sirt3, a mitochondrial deacetylase, participates in the regulation of multiple cellular processes through its effect on protein acetylation. The objective of this study was to explore the role of Sirt3 in the mitochondrial autophagy (mitophagy), a process of the specific autophagic elimination of damaged mitochondria. We found that silencing of Sirt3 expression in human glioma cells by RNA interference blunted the hypoxia-induced the localization of LC3 on the mitochondria, and the degradation of mitochondria. These results suggest an important involvement of this protein deacetylase in the induction of mitophagy in cancer cells subjected to hypoxia. Further, we demonstrated that Sirt3 activated the hypoxia-induced mitophagy by increasing the interaction of VDAC1 with Parkin. In the cells subjected to hypoxia, inhibition of Sirt3-mediated mitophagy further decreased the mitochondrial membrane potential, and increased the accumulation of ROS that triggers the degradation of anti-apoptotic proteins Mcl-1 and survivin through the proteasomal pathway. Silencing of Sirt3 expression also promoted apoptosis, and enhanced the sensitivity of cancer cells to hypoxia. The regulatory role of Sirt3 in autophagy and apoptosis was also observed in human breast cancer cells. The results of the current study reveal Sirt3 as a novel regulator coupling mitophagy and apoptosis, two important cellular processes that determine cellular survival and death.


Adaptive Parameter Model for Quasi-Spherical Cell Size Measurement Based on Lensless Imaging System.
Many biological cells appear quasi-spherical, such as red blood cells, white blood cells, egg cells, cancer cells, etc. Cell size is an important basis for medical diagnosis. The traditional method is to use a microscope or flow cytometer to obtain the cell size. Either it depends on professionals and cannot be automated, or it is expensive and bulky, which are not suitable for point-of-care test. Lab-on-a-chip technology using a lensless imaging system gives a better solution for obtaining the cell size. In order to deal with the diffraction in the lensless imaging system, the distance between the light source and the cell, the distance between the cell and the CMOS image sensor and optical wavelength need to be accurately measured or controlled, which will greatly increase the complexity of the system, making it difficult to truly apply to point-of-care test. In this paper, an adaptive parameter model for quasi-spherical cell size measurement based on lensless imaging system is given. First, the diffraction theory used in the model is explained. Then, the adaptive algorithm of the system parameter is given. To illustrate the practicality of the algorithm, a quasi-spherical cell size measurement method and a super-resolution algorithm are given. Finally, the experiment proves that the adaptive parameter model is effective can meet the needs of quasi-spherical cell size measurement.


Bilateral diaphragmatic paralysis in the newborn infant: treatment with nasal continous positive airway pressure.
A newborn infant with severe respiratory distress from bilateral diaphragmatic paralysis caused by birth injury was successfully treated with nasal continuous positive airway pressure (CPAP). Improvement gradually occurred, and CPAP was discontinued after he was 23 days of age. This therapy has advantages over alternative methods.


The use of non-aqueous chloroform/methanol extraction for the delipidation of brain with minimal loss of enzyme activities.
When freeze-dried brain was extracted at -4-0degrees C with dry chloroform/methanol (2:1 v/v), four of the five enzymes examined were recovered in the diethyl ether-washed residue without inactivation. By contrast, extraction with chloroform/methanol (2:1 v/v) in the presence of water destroyed activities of all the enzymes examined. The amounts of major lipids extracted were similar whether extraction was done in the absence or presence of water. The study was carried out with special interest in 2':3'-cyclic nucleotide 3'-phosphodiesterase (EC 220.127.116.11), which is firmly bound to the membrane structures of brain white matter.


Optimization of Neurite Tracing and Further Characterization of Human Monocyte-Derived-Neuronal-like Cells.
Deficits in neuronal structure are consistently associated with neurodevelopmental illnesses such as autism and schizophrenia. Nonetheless, the inability to access neurons from clinical patients has limited the study of early neurostructural changes directly in patients' cells. This obstacle has been circumvented by differentiating stem cells into neurons, although the most used methodologies are time consuming. Therefore, we recently developed a relatively rapid (~20 days) protocol for transdifferentiating human circulating monocytes into neuronal-like cells. These monocyte-derived-neuronal-like cells (MDNCs) express several genes and proteins considered neuronal markers, such as MAP-2 and PSD-95. In addition, these cells conduct electrical activity. We have also previously shown that the structure of MDNCs is comparable with that of human developing neurons (HDNs) after 5 days in culture. Moreover, the neurostructure of MDNCs responds similarly to that of HDNs when exposed to colchicine and dopamine. In this manuscript, we expanded our characterization of MDNCs to include the expression of 12 neuronal genes, including tau. Following, we compared three different tracing approaches (two semi-automated and one automated) that enable tracing using photographs of live cells. This comparison is imperative for determining which neurite tracing method is more efficient in extracting neurostructural data from MDNCs and thus allowing researchers to take advantage of the faster yield provided by these neuronal-like cells. Surprisingly, it was one of the semi-automated methods that was the fastest, consisting of tracing only the longest primary and the longest secondary neurite. This tracing technique also detected more structural deficits. The only automated method tested, Volocity, detected MDNCs but failed to trace the entire neuritic length. Other advantages and disadvantages of the three tracing approaches are also presented and discussed.


Combination of DXA and BIS Predicts Jump Power Better Than Traditional Measures of Sarcopenia.
Traditional diagnostic criteria for sarcopenia use dual-energy X-ray absorptiometry (DXA)-measured appendicular lean mass (ALM), normalized to height (ALM/ht2) or body mass index (ALM/BMI) to define low muscle mass. However, muscle function declines with aging before the loss of muscle mass is detected by ALM. This is likely due, in part, to qualitative muscle changes such as extracellular and intracellular fluid compartment shifts uncaptured by DXA. We propose combining bioimpedance spectroscopy (BIS), which estimates extracellular and intracellular compartment volume, with DXA to more accurately predict muscle function. This combination may help incorporate muscle quality, thereby improving sarcopenia diagnosis. We cross-sectionally analyzed data from 248 Black and White participants aged 25 to 75 years from the Midlife in the United States Refresher Cohort. We proposed two novel muscle measures: ALM corrected by the BIS-derived whole-body extracellular to intracellular fluid ratio (E/I) and leg lean mass (LLM) corrected by leg-specific E/I, creating (ALM/(E/I)W) and (LLM/(E/I)L), respectively. We compared the associations of traditional muscle measures, ALM/(E/I)W, and LLM/(E/I)L, with grip strength and lower limb power using jumping mechanography. LLM/(E/I)L explained jump power best at R 2 = 0.803 compared with ALM/(E/I)W (p < 0.0001) and all other measures. ALM/(E/I)W explained jump power second best (R 2 = 0.759) but not significantly better than traditional muscle measures. No muscle measure performed better than covariates when predicting handgrip strength. LLM/(E/I)L outperformed ALM/ht2 and ALM/BMI when predicting jump power. We propose LLM/(E/I)L is a powerful and clinically relevant method that accounts for muscle quality. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.


β2 glycoprotein I participates in phagocytosis of apoptotic neurons and in vascular injury in experimental brain stroke.
Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the autoimmune anti-phospholipid syndrome, characterized by increased risk of stroke. We here investigated the antibody independent role of β2-GPI after ischemia/reperfusion, modeled in vivo by transient middle cerebral artery occlusion (tMCAo) in male C57Bl/6J mice; in vitro by subjecting immortalized human brain microvascular endothelial cells (ihBMEC) to 16 h hypoxia and 4 h re-oxygenation. ApoH (coding for β2-GPI) was upregulated selectively in the liver at 48 h after tMCAo. At the same time β2-GPI circulating levels increased. β2-GPI was detectable in brain parenchyma and endothelium at all time points after tMCAo. Parenchymal β2-GPI recognized apoptotic neurons (positive for annexin V, C3 and TUNEL) cleared by CD68+ brain macrophages. Hypoxic ihBMEC showed increased release of IL-6, over-expression of thrombomodulin and IL-1α after re-oxygenation with β2-GPI alone. β2-GPI interacted with mannose-binding lectin in mouse plasma and ihBMEC medium, potentially involved in formation of thrombi. We show for the first time that brain ischemia triggers the hepatic production of β2-GPI. β2-GPI is present in the ischemic endothelium, enhancing vascular inflammation, and extravasates binding stressed neurons before their clearance by phagocytosis. Thus β2-GPI may be a new mediator of brain injury following ischemic stroke.


Prostate carcinogenesis and inflammation: emerging insights.
Prostate cancer remains a significant health concern for men throughout the world. Recently, there has developed an expanding multidisciplinary body of literature suggesting a link between chronic inflammation and prostate cancer. In support of this hypothesis, population studies have found an increased relative risk of prostate cancer in men with a prior history of certain sexually transmitted infections or prostatitis. Furthermore, genetic epidemiological data have implicated germline variants of several genes associated with the immunological aspects of inflammation in modulating prostate cancer risk. The molecular pathogenesis of prostate cancer has been characterized by somatic alterations of genes involved in defenses against inflammatory damage and in tissue recovery. A novel putative prostate cancer precursor lesion, proliferative inflammatory atrophy, which shares some molecular traits with prostate intraepithelial neoplasia and prostate cancer, has been characterized. Here, we review the evidence associating chronic inflammation and prostate cancer and consider a number of animal models of prostate inflammation that should allow the elucidation of the mechanisms by which prostatic inflammation could lead to the initiation and progression of prostate cancer. These emerging insights into chronic inflammation in the etiology of prostate carcinogenesis hold the promise of spawning new diagnostic and therapeutic modalities for men with prostate cancer.


Reversal agents for non-vitamin K antagonist oral anticoagulants.
The non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban, and rivaroxaban, which inhibit coagulation factor Xa. Although clinical studies of NOACs were conducted without antidotes, patient outcomes with major bleeding when receiving NOACs were no worse than those in patients treated with a vitamin K antagonist. Nonetheless, in patients with life-threatening bleeding or requiring urgent surgery, the capacity for rapid NOAC reversal is likely to increase patient safety. Three NOAC reversal agents are in various stages of development: idarucizumab, a specific reversal agent for dabigatran; andexanet alfa, which reverses factor Xa inhibitors; and ciraparantag, which is purported to reverse all NOACs. Idarucizumab is licensed in many countries, andexanet is under consideration by regulatory agencies, and ciraparantag is undergoing phase III evaluation. In the absence of licensed reversal agents for the oral factor Xa inhibitors, prothrombin complex concentrates are often used in patients taking these agents who present with life-threatening bleeding. In this Review, we summarize the approved indications for the NOACs, outline how to measure their anticoagulant effects, describe the mechanism of action of the reversal strategies, assess the preclinical and clinical data supporting their use, provide guidance on potential indications for reversal, and offer a management approach for patients treated with NOACs who present with serious bleeding or require urgent surgery.


Maize DBF1-interactor protein 1 containing an R3H domain is a potential regulator of DBF1 activity in stress responses.
The maize dehydration-responsive element (DRE)-binding factor, DBF1, is a member of the Apetala 2/Ethylene Response Factor transcription factors family and is involved in the regulation of the ABA-responsive gene rab17 through the DRE in an ABA-dependent pathway. In this study we analysed the functionality of DBF1 in abiotic stress responses and found that Arabidopsis plants over-expressing DBF1 were more tolerant to osmotic stress than control plants. In yeast two-hybrid analyses, DBF1 interacted with DBF1-interactor protein 1 (DIP1), a protein containing a conserved R3H single-strand DNA-binding domain. Subcellular localization of DIP1 showed that the protein fusion DIP1-Red Flourescent Protein (RFP) was mainly localized in the cytoplasm. However, after co-transformation of DBF1-GFP and DIP1-RFP, both proteins co-localized in the nucleus. Interestingly, when the N-terminal DBF1-GFP was co-expressed with DIP1-RFP, both proteins co-localized predominantly in the cytoplasmic speckles observed for N-terminal DBF1-GFP fusion protein. These results clearly show in vivo interaction of DBF1 with DIP1 in the cell and that this interaction is necessary for the nuclear localization of DIP1 protein. Analysis of the regulatory effect of the DBF1 and DIP1 interaction on the maize rab17 promoter activity indicated that co-transfection of DBF1 with DIP1 enhances promoter activity in the absence of ABA treatment. We suggest that the regulated association of DBF1 and DIP1 may control the levels of target gene expression during stress conditions.


Effects on the monkey, pig and rat pancreas of soy products with varying levels of trypsin inhibitor and comparison with the administration of cholecystokinin.
Raw and heated soy flour and casein diets were compared in rats, pigs, and monkeys with respect to growth, pancreatic changes, fecal trypsin, and nitrogen digestibility. Cholecystokinin injection was compared to feeding raw soy flour and casein in rats and casein in pigs. Several soy protein preparations were fed to rats and monkeys. Neither raw soy flour nor any other soy product produced pancreatic enlargement in pigs or monkeys. Casein and heated soy flour performed similarly. By comparison, other effects of raw soy flour were as follows. Growth was depressed 60% in rats and 84% in pigs, but not at all in monkeys. Nitrogen digestibility was depressed 5, 45, and 9% in rats, pigs, and monkeys, respectively. Pancreatic DNA, RNA, and protein levels were unchanged in monkeys fed raw soy flour. In rats, RNA per milligram pancreas was increased 40%, in pigs 20%. Pancreatic protein was decreased 7% in pigs and increased 47% in rats. Changes in pancreatic trypsin, chymotrypsin, lipase, and amylase were dissimilar in the three species. Fecal trypsin was elevated 300-400% in rats, and decreased approximately 50% in pigs and monkeys. Cholecystokinin injections in pigs and rats produced changes both quantitatively and qualitatively different from those seen with raw soy flour. Feeding of heated soy flour or soy protein isolates was comparable to feeding casein in all three species, and produced no deleterious effects.


Radiological and clinical analysis of Madelung's deformity in children.
Madelung's deformity is a bone dysplasia that occurs predominantly in adolescent females, characterized by early epiphyseal growth arrest in the medial part of the distal radius. This leads to an upward and medial displacement of the radial joint surface, restricting range of motion. The objective of this study was to determine whether there was a link between clinical and radiological data in children with Madelung's deformity and to test the hypothesis of a relation between the deformity and a genetic mutation. A retrospective study recruited 13 patients with Madelung's deformity, with a mean age of 13.2 years (range, 8-18 years). Assessment comprised level of pain, range of motion and grip force, with standard AP and lateral wrist X-rays. Every patient except one underwent molecular genetic screening, adhering to current recommendations. Pronation-supination, radial inclination and grip force were significantly impaired compared to normal results. All X-ray measurements were significantly abnormal, except for the lunate-covering ratio. Genetic mutation (SHOX) was systematic in the 12 patients screened. Radiological deformity did not correlate with functional disturbance or pain. Non-acquired Madelung's deformity requires molecular screening for SHOX or XO mutation, which definitively diagnoses Léri-Weill dyschondrosteosis or Turner syndrome. A larger series is necessary to confirm these preliminary results, which nevertheless suggest that non-acquired Madelung's deformity is not isolated but syndromic. Early detection of Léri-Weill or Turner syndrome is essential, due to their therapeutic specificities. LEVEL: IV.


The TIMPs tango with MMPs and more in the central nervous system.
The matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular proteases that have been implicated in CNS development and disease. Crucial homeostatic regulation of MMPs is mediated through the expression and actions of the tissue inhibitors of metalloproteinases (TIMPs). Although the TIMPs are recognized inhibitors of the MMPs, recent studies have revealed that these proteins also can exhibit biological activities that are distinct from their interactions with or inhibition of the MMPs. With our understanding of the roles of the TIMPs in the CNS continuously emerging, this review examines the current state of knowledge regarding the multifarious and novel functions of this family of proteins, with particular attention to their increasing potential in the development, plasticity, and pathology of the CNS.


Counteracting effects of a non-native prey on the demography of a native predator culminate in positive population growth.
Identifying impacts of non-native species on native populations is central to conservation and ecology. While effects of non-native predators on native prey populations have recently received much attention, impacts of introduced prey on native predator populations are less understood. Non-native prey can influence predator behavior and demography through direct and indirect pathways, yet quantitative assessments of the relative impacts of multiple, potentially counteracting, effects on native predator population growth remain scarce. Using ≈20 years of range-wide monitoring data, we tested for effects of a recently introduced, rapidly spreading non-native prey species (Pomacea maculata) on the behavior and demography of the endangered Snail Kite (Rostrhamus sociabilis). Previous studies found that food-handling difficulties caused by the large size of P. maculata (relative to the native P. paludosa) can lead to energetic deficiencies in juvenile kites, suggesting the potential for evolutionary traps to occur. However, high densities of P. maculata populations could facilitate kites by providing supplemental food resources. Contrary to prior hypotheses, we found that juvenile apparent survival increased ≈50% in wetlands invaded by non-native snails. Breeding rates and number of young fledged/successful nests were also positively associated with non-native snail presence, suggesting direct trophic benefits to kites. We found no direct effects of the invasive snail on adult survival or daily nest survival rates. Kite movements and breeding distribution closely tracked the spread of non-native snail populations. Since 2005, kites have been heavily concentrated in northern regions where non-native snails have established. This geographic shift has had hidden costs, as use of northern regions is associated with lower adult survival. Despite negative impacts to this key vital rate, matrix population modeling indicated that the multifarious effects of the non-native snail invasion on kites culminated in increased population growth rates, likely lowering short-term extinction risks. Results suggest that considering only particular components of behavior or demography may be inadequate to infer the population-dynamic importance of non-native prey on native predators, including their role in creating potential evolutionary traps. Our findings provide information pertinent to Everglades restoration, highlighting potential management trade-offs for non-native species that may aid imperiled species recovery yet disrupt other native communities.


Common Genetic Variation and Age of Onset of Anorexia Nervosa.
Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche. A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h 2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.


Peer-based control in self-managing teams: linking rational and normative influence with individual and group performance.
The authors use a multilevel framework to introduce peer-based control as a motivational state that emerges in self-managing teams. The authors specifically describe how peer-based rational control, which is defined as team members perceiving the distribution of economic rewards as dependent on input from teammates, extends and interacts with the more commonly studied normative control force of group cohesion to explain both individual and collective performance in teams. On the basis of data from 587 factory workers in 45 self-managing teams at 3 organizations, peer-based rational control corresponded with higher performance for both individuals and collective teams. Results further demonstrated that the rational and normative mechanism of peer-based control interacted to explain performance at both the individual and team levels. Increased peer-based rational control corresponded with higher individual and collective performance in teams with low cohesion, but the positive effects on performance were attenuated in cohesive teams.


Comparative study of long, segmented, filamentous organisms in chickens and mice.
No transmission of long, segmented, filamentous organisms (LSFO) from a laboratory mouse strain (Mus musculus) to a domestic broiler chicken strain (Gallus domesticus) occurred by oral dosing with mouse mucosal and fecal preparations, even in hydrocortisone-treated chicks. Transmission of chicken LSFO to laboratory mice was attempted, but the results were confounded by the mice having been already infected with LSFO. However, the morphologic characteristics of the LSFO in the dosed mice suggested that transmission of chick LSFO did not occur. Mouse LSFO, as detected in carbol thionin-stained mucosal smears, are generally wider, longer, and have slightly different morphologic characteristics than chicken LSFO. The results of these studies suggest that the LSFO in mice and chickens may be two distinct species.


Detecting damaged buildings using real-time crowdsourced images and transfer learning.
After significant earthquakes, we can see images posted on social media platforms by individuals and media agencies owing to the mass usage of smartphones these days. These images can be utilized to provide information about the shaking damage in the earthquake region both to the public and research community, and potentially to guide rescue work. This paper presents an automated way to extract the damaged buildings images after earthquakes from social media platforms such as Twitter and thus identify the particular user posts containing such images. Using transfer learning and ~ 6500 manually labelled images, we trained a deep learning model to recognize images with damaged buildings in the scene. The trained model achieved good performance when tested on newly acquired images of earthquakes at different locations and when ran in near real-time on Twitter feed after the 2020 M7.0 earthquake in Turkey. Furthermore, to better understand how the model makes decisions, we also implemented the Grad-CAM method to visualize the important regions on the images that facilitate the decision.


Sabin Vaccine Reversion in the Field: a Comprehensive Analysis of Sabin-Like Poliovirus Isolates in Nigeria.
To assess the dynamics of genetic reversion of live poliovirus vaccine in humans, we studied molecular evolution in Sabin-like poliovirus isolates from Nigerian acute flaccid paralysis cases obtained from routine surveillance. We employed a novel modeling approach to infer substitution and recombination rates from whole-genome sequences and information about poliovirus infection dynamics and the individual vaccination history. We confirmed observations from a recent vaccine trial that VP1 substitution rates are increased for Sabin-like isolates relative to the rate for the wild type due to increased nonsynonymous substitution rates. We also inferred substitution rates for attenuating nucleotides and confirmed that reversion can occur in days to weeks after vaccination. We combine our observations for Sabin-like virus evolution with the molecular clock for VP1 of circulating wild-type strains to infer that the mean time from the initiating vaccine dose to the earliest detection of circulating vaccine-derived poliovirus (cVDPV) is 300 days for Sabin-like virus type 1, 210 days for Sabin-like virus type 2, and 390 days for Sabin-like virus type 3. Phylogenetic relationships indicated transient local transmission of Sabin-like virus type 3 and, possibly, Sabin-like virus type 1 during periods of low wild polio incidence. Comparison of Sabin-like virus recombinants with known Nigerian vaccine-derived poliovirus recombinants shows that while recombination with non-Sabin enteroviruses is associated with cVDPV, the recombination rates are similar for Sabin isolate-Sabin isolate and Sabin isolate-non-Sabin enterovirus recombination after accounting for the time from dosing to the time of detection. Our study provides a comprehensive picture of the evolutionary dynamics of the oral polio vaccine in the field. The global polio eradication effort has completed its 26th year. Despite success in eliminating wild poliovirus from most of the world, polio persists in populations where logistical, social, and political factors have not allowed vaccination programs of sustained high quality. One issue of critical importance is eliminating circulating vaccine-derived polioviruses (cVDPVs) that have properties indistinguishable from those of wild poliovirus and can cause paralytic disease. cVDPV emerges due to the genetic instability of the Sabin viruses used in the oral polio vaccine (OPV) in populations that have low levels of immunity to poliovirus. However, the dynamics responsible are incompletely understood because it has historically been difficult to gather and interpret data about evolution of the Sabin viruses used in OPV in regions where cVDPV has occurred. This study is the first to combine whole-genome sequencing of poliovirus isolates collected during routine surveillance with knowledge about the intrahost dynamics of poliovirus to provide quantitative insight into polio vaccine evolution in the field.


Regulation of Notch Signaling by an Evolutionary Conserved DEAD Box RNA Helicase, Maheshvara in Drosophila melanogaster.
Notch signaling is an evolutionary conserved process that influences cell fate determination, cell proliferation, and cell death in a context-dependent manner. Notch signaling is fine-tuned at multiple levels and misregulation of Notch has been implicated in a variety of human diseases. We have characterized maheshvara (mahe), a novel gene in Drosophila melanogaster that encodes a putative DEAD box protein that is highly conserved across taxa and belongs to the largest group of RNA helicase. A dynamic pattern of mahe expression along with the maternal accumulation of its transcripts is seen during early stages of embryogenesis. In addition, a strong expression is also seen in the developing nervous system. Ectopic expression of mahe in a wide range of tissues during development results in a variety of defects, many of which resemble a typical Notch loss-of-function phenotype. We illustrate that ectopic expression of mahe in the wing imaginal discs leads to loss of Notch targets, Cut and Wingless. Interestingly, Notch protein levels are also lowered, whereas no obvious change is seen in the levels of Notch transcripts. In addition, mahe overexpression can significantly rescue ectopic Notch-mediated proliferation of eye tissue. Further, we illustrate that mahe genetically interacts with Notch and its cytoplasmic regulator deltex in trans-heterozygous combination. Coexpression of Deltex and Mahe at the dorso-ventral boundary results in a wing-nicking phenotype and a more pronounced loss of Notch target Cut. Taken together we report identification of a novel evolutionary conserved RNA helicase mahe, which plays a vital role in regulation of Notch signaling.


The metabolic basis of deoxyuridine cytotoxicity. Studies of cultured human lymphoblasts.
The metabolic consequences of deoxyuridine treatment in four cultured human lymphoblast lines (CCRF-CEM, RPMI-8402, JM, and BALM) were studied by cell growth experiments, flow cytometry, and measurement of 2'-deoxyribonucleoside triphosphate (dNTP) levels. DNA perturbations occurred in all lymphoblast lines, but there was no significant impairment of RNA synthesis. The DNA perturbations in CCRF-CEM, RPMI-8402, and BALM cells reflected inhibition of DNA synthesis, and the associated dNTP changes were consistent with ribonucleotide reductase inhibition or, specifically in BALM cells, with DNA alpha-polymerase inhibition. JM cells treated with an intermediate concentration of deoxyuridine developed a block at the G1/S boundary which was deoxyuridine concentration-dependent, but not specific for deoxyuridine (it was also seen with thymidine treatment) and not related to DNA synthesis inhibition. There were no idiosyncratic dNTP effects accompanying the G1/S boundary block, and the responsible metabolic mechanism remains to be determined.


Toward Bioelectronic Medicine-Neuromodulation of Small Peripheral Nerves Using Flexible Neural Clip.
Neural modulation technology and the capability to affect organ function have spawned the new field of bioelectronic medicine. Therapeutic interventions depend on wireless bioelectronic neural interfaces that can conformally and easily attach to small (few hundred micrometers) nerves located deep in the body without neural damage. Besides size, factors like flexibility and compliance to attach and adapt to visceral nerves associated moving organs are of paramount importance and have not been previously addressed. This study proposes a novel flexible neural clip (FNC) that can be used to interface with a variety of different peripheral nerves. To illustrate the flexibility of the design, this study stimulates the pelvic nerve, the vagus nerve, and branches of the sciatic nerve and evaluates the feasibility of the design in modulating the function of each of these nerves. It is found that this FNC allows fine-tuning of physiological processes such as micturition, heart rate, and muscle contractions. Furthermore, this study also tests the ability of wirelessly powered FNC to enable remote modulation of visceral pelvic nerves located deep in the body. These results show that the FNC can be used with a range of different nerves, providing one of the critical pieces in the field of bioelectronics medicines.


The relationship of antiphospholipid antibodies to thromboembolic disease in systemic lupus erythematosus: a cross-sectional study.
In order to determine whether an association exists between antiphospholipid antibodies (APLA) and thromboembolic events in patients with systemic lupus erythematosus (SLE), we performed a cross-sectional study of consecutive unselected SLE patients. The occurrence of previous thromboembolic events was determined by investigators blinded to the APLA status of the patients by critical review of objective tests that had been performed at the time of symptomatic presentation and by performing venous Doppler ultrasound of the legs to elicit venous reflux as an indication of previous venous thrombosis. The presence of APLA was determined by coagulation assays for the lupus anticoagulant (LA) using five tests with well-defined control ranges and by ELISA assay for anticardiolipin antibodies (ACLA). These tests were measured on two separate occasions. The results of the study demonstrate a statistically significant association between persistently abnormal ACLA assays and thromboembolic events and a non-significant trend between persistently abnormal LA and thromboembolic events. Transient abnormalities of LA and ACLA were less strongly associated with thromboembolic events. We conclude that in patients with SLE, there is a significant association between thromboembolism and APLA.


District Governance and Improved Maternal, Neonatal and Child Health in South Africa: Pathways of Change.
District-level initiatives to improve maternal, neonatal and child health (MNCH) generally do not take governance as their primary lens on health system strengthening. This paper is a case study of a district and sub-district governance mechanism, the Monitoring and Response Unit (MRU), which aimed to improve MNCH outcomes in two districts of South Africa. The MRU was introduced as a decision-making and accountability structure, and constituted of a "triangle" of managers, clinicians and information officers. An independent evaluation of the MRU initiative was conducted, three years after establishment, involving interviews with 89 district actors. Interviewees reported extensive changes in the scope, quality and organization of MNCH services, attributing these to the introduction of the MRU and enhanced support from district clinicians. We describe both the formal and informal aspects of the MRU as a governance mechanism, and then consider the pathways through which the MRU plausibly acted as a catalyst for change, using the institutional constructs of credible commitment, coordination and cooperation. In particular, the MRU promoted the formation of non-hierarchical collaborative networks; improved coordination between community, PHC and hospital services; and shaped collective sense-making in positive ways. We conclude that innovations in governance could add significant value to the district health system strengthening for improved MNCH. However, this requires a shift in focus from strengthening the front-line of service delivery, to change at the meso-level of sub-district and district decision-making; and from purely technical, data-driven to more holistic approaches that engage collective mindsets, widen participation in decision-making and nurture political leadership skills.


Computation of flow and heat transfer in rotating cavities with peripheral flow of cooling air.
Numerical solutions of the Navier-Stokes equations have been used to model the flow and the heat transfer that occurs in the internal cooling-air systems of gas turbines. Computations are performed to study the effect of gap ratio, Reynolds number and the mass flow rate on the flow and the heat transfer structure inside isothermal and heated rotating cavities with peripheral flow of cooling air. Computations are compared with some of the recent experimental work on flow and heat transfer in rotating-cavities. The agreement between the computed and the available experimental data is reasonably good.


The epigenetic network regulating muscle development and regeneration.
This review focuses on our current knowledge of the epigenetic changes regulating gene expression at the chromatin and DNA level, independently on the primary DNA sequence, to reprogram the nuclei of muscle precursors during developmental myogenesis and muscle regeneration. These epigenetic marks provide the blueprint by which the extra-cellular cues are interpreted at the nuclear level by the transcription machinery to select the repertoire of tissue-specific genes to be expressed. The reversibility of some of these changes necessarily reflects the dynamic nature of skeletal myogenesis, which entails the progression through two antagonistic processes--proliferation and differentiation. Other epigenetic modifications are instead associated to events conventionally considered as irreversible--e.g. maintenance of lineage commitment and terminal differentiation. However, recent results support the possibility that these events can be reversed, at least upon certain experimental conditions, thereby revealing a dynamic nature of many of the epigenetic modifications underlying skeletal myogenesis. The elucidation of the epigenetic network that regulates transcription during developmental myogenesis and muscle regeneration might provide the information instrumental to devise pharmacological interventions toward selective manipulation of gene expression to promote regeneration of skeletal muscles and possibly other tissue.