Gramine Derivatives Targeting Ca(2+) Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases.
We describe the synthesis of gramine derivatives and their pharmacological evaluation as multipotent drugs for the treatment of Alzheimer's disease. An innovative multitarget approach is presented, targeting both voltage-gated Ca(2+) channels, classically studied for neurodegenerative diseases, and Ser/Thr phosphatases, which have been marginally aimed, even despite their key role in protein τ dephosphorylation. Twenty-five compounds were synthesized, and mostly their neuroprotective profile exceeded that offered by the head compound gramine. In general, these compounds reduced the entry of Ca(2+) through VGCC, as measured by Fluo-4/AM and patch clamp techniques, and protected in Ca(2+) overload-induced models of neurotoxicity, like glutamate or veratridine exposures. Furthermore, we hypothesize that these compounds decrease τ hyperphosphorylation based on the maintenance of the Ser/Thr phosphatase activity and their neuroprotection against the damage caused by okadaic acid. Hence, we propose this multitarget approach as a new and promising strategy for the treatment of neurodegenerative diseases.


One Step Preparation of Peptide-Coated Gold Nanoparticles with Tunable Size.
Gold nanoparticles (AuNPs) made from self-assembling peptides have been used in many research fields and attracted a great deal of attention due to their high stability, biocompatibility and functionality. However, existing preparation methods for peptide-coated AuNPs are post-synthesis processes, which are complicated and time consuming. Therefore, a one-step preparation method for peptide-coated AuNPs is proposed here. The AuNPs obtained by this method exhibit good stability. Importantly, peptide-coated AuNPs with precise different sizes can be prepared by this method through pH control of reducing reagent tyrosine in range of 10.0~12.7. Thus, the one-step preparation method proposed here provides a significant tool for the research in different fields concerning NP size, stability and biocompatibility.


Interaction of sympathomimetics and insulin with hepatic glucose production by isolated perfused rat livers: effects of continuous versus pulsatile infusion.
To elucidate the efficacy of continuous vs. intermittent exposure to epinephrine, phenylephrine, and insulin, hepatic glucose production was monitored in isolated perfused rat livers (means +/- SE, n = 6 each). To this end livers of fed rats were perfused with 5 mM glucose Krebs-Ringer buffer in a nonrecirculating system. Using this model it was shown that intermittent exposure (3 min on/off period, dose reduction -50%) to epinephrine (0.4 microM, alpha + beta-agonist) and phenylephrine (5 microM, alpha-agonist) elicited an almost identical rise in hepatic glucose production [epinephrine: 0.72 +/- 0.08 mmol/(86 min X 100 g BW); phenylephrine: 0.68 +/- 0.07 mmol/(86 min X 100 g BW) as their continuous administration (epinephrine: 0.78 +/- 0.06 mmol/(86 min X 100 g BW); phenylephrine: 0.74 +/- 0.09 mmol/(86 min X 100 g BW)]. Inhibition by insulin (100 mU/liter) given either continuously or intermittently (3 min on/off intervals; dose reduction -50%) was equipotent for epinephrine- and phenylephrine-stimulated hepatic glucose production. When the off period was doubled to 6 min, thereby reducing the total insulin dose to 33%, no significant suppression of epinephrine- and phenylephrine-stimulated hepatic glucose production was observed. From this we conclude that 1) the effect on hepatic glucose production of pulsatile (3 min on/off, dose reduction 50%) and continuous administration is equipotent for the respective action of epinephrine, phenylephrine as well as of insulin; and 2) insulin is more effective (P less than 0.02) in inhibiting hepatic glucose production stimulated by an alpha-agonist (phenylephrine; 5.0 microM) than in counteracting alpha + beta-agonist action (epinephrine; 0.4 microM). The characteristics of hepatic glucose release as stimulated by alpha- and/or beta-adrenergic agonists and its inhibition by continuously or intermittently infused insulin were simulated and described by a computer model. Thereby, no qualitative difference could be demonstrated in alpha- vs. beta-adrenergic agonists action on stimulated hepatic glucose production.


Diagnosis of arterial occlusive disease of the lower extremities by laser Doppler flowmetry.
Laser Doppler Flowmetry offers the possibility of non-invasive and continuous recording of tissue blood flow. Skin blood flux in resting state and during postocclusive reactive hyperemia was measured at the pulpa of the toe in 21 normal lower limbs and in 58 limbs with arterial occlusive disease. Proper assessment of postischemic flux- and time- parameters (beginning of reactive hyperemia, peak flux, time of peak flux and duration of hyperemic flux) permits accurate separation of healthy and diseased limbs.


Estimates of direct and indirect effects for early juvenile survival in captive populations maintained for conservation purposes: the case of Cuvier's gazelle.
Together with the avoidance of any negative impact of inbreeding, preservation of genetic variability for life-history traits that could undergo future selective pressure is a major issue in endangered species management programmes. However, most of these programmes ignore that, apart from the direct action of genes on such traits, parents, as contributors of offspring environment, can influence offspring performance through indirect parental effects (when parental genotype and phenotype exerts environmental influences on offspring phenotype independently of additive genetic effects). Using quantitative genetic models, we estimated the additive genetic variance for juvenile survival in a population of the endangered Cuvier's gazelle kept in captivity since 1975. The dataset analyzed included performance recording for 700 calves and a total pedigree of 740 individuals. Results indicated that in this population juvenile survival harbors significant additive genetic variance. The estimates of heritability obtained were in general moderate (0.115-0.457) and not affected by the inclusion of inbreeding in the models. Maternal genetic contribution to juvenile survival seems to be of major importance in this gazelle's population as well. Indirect genetic and indirect environmental effects assigned to mothers (i.e., maternal genetic and maternal permanent environmental effects) roughly explain a quarter of the total variance estimated for the trait analyzed. These findings have major evolutionary consequences for the species as show that offspring phenotypes can evolve strictly through changes in the environment provided by mothers. They are also relevant for the captive breeding programme of the species. To take into account, the contribution that mothers have on offspring phenotype through indirect genetic effects when designing pairing strategies might serve to identify those females with better ability to recruit, and, additionally, to predict reliable responses to selection in the captive population.


Prevalence and Factors Associated with Female Sexual Dysfunction in Beijing, China.
Female sexual dysfunction (FSD) is a highly prevalent and often underestimated problem. However, large-scale, population-based epidemiological surveys of FSD are scarce in China. The present study was conducted to evaluate the prevalence and the potential risk factors of FSD across a selection of social groups in Beijing, China, based on the Female Sexual Function Index (FSFI). A cross-sectional study based on the multiple-stage cluster sampling was performed with adult women throughout the Dongcheng and Shunyi districts of Beijing. The Chinese version of FSFI was used, as well as questions on demographic characteristics, the disease-related context, and social relationships. A total of 6000 consecutive women entered this study, with an actual response from 5024 women, corresponding to a response rate of 83.7%. A total of 4697 (78.3%) questionnaires were effective. The prevalence of adult FSD in Beijing was 2973 (63.3%) using a score of 26.55 as the boundary value, whereas the total mean FSFI score was 23.92 ± 6.37. However, 1423 (30.3%) women did not seek help. By multivariate logistic regression analysis, the possible potential risk factors included age (odds ratio [OR] = 1.051), dissatisfaction with the spouse's sexual ability (OR = 3.520), poor marital affection (OR = 2.087), spouse sexual difficulties (OR = 1.720), dissatisfaction with married life (OR = 1.476), living in a rural area (OR = 1.292), chronic pelvic pain (OR = 1.261), chronic disease (OR = 1.534), previous pelvic surgery (OR = 1.605), vaginal delivery (OR = 2.285), lower education (OR = 3.449) and postmenopausal (OR = 3.183). As suggested by the FSFI scores, female sexual problems are highly prevalent in Beijing. Dissatisfaction with the spouse's sexual ability, poor marital affection, sexual difficulties of the spouse, dissatisfaction with the marriage, rural life, CPP, and postmenopausal were conceivable risk factors for FSD in Beijing women.


Protease inhibitors in middle ear effusions.
As the presence of granulocytes in middle ear fluid in serous otitis media implicates a potential risk of extracellular release of granulocyte proteases, the main protease inhibitors in serum, alpha 1-antitrypsin, alpha 1-antichymotrypsin and alpha 2-macroglobulin, were immunochemically quantitated in such effusions. The mean concentration of alpha 1-antitrypsin was found to be higher in middle ear effusion and the mean concentration of alpha 1-antichymotrypsin slightly lower than in plasma. On comparison with albumin, however, lower values than expected were found in the middle ear fluid for the two inhibitors. The high molecular weight alpha 2-macroglobulin was significantly lower than in plasma. Furthermore a low molecular weight protease inhibitor, which is thought to be locally produced in the respiratory epithelium, was demonstrated in the effusion.


Turner syndrome: update on biology and management across the life span.
We review recent understanding of the pathophysiology, molecular biology, and management of Turner syndrome. Sophisticated genetic techniques are able to detect mosaicism in one-third of individuals previously thought to have monosomy X. Prenatal detection using maternal blood should permit noninvasive detection of most fetuses with an X chromosome abnormality. Disproportionate growth with short limbs has been documented in this condition, and a target gene of short stature homeobox, connective tissue growth factor (Ctgf), has been described. Liver disease is more common in Turner syndrome than previously recognized. Most girls have gonadal failure. Spontaneous puberty and menarche is more commonly seen in girls with XX mosaicism. Low-dose estrogen replacement therapy may be given early to induce a more normal onset and tempo of puberty. Oocyte donation for assisted reproduction carries a substantial risk, particularly if the woman has known cardiac or aortic disease. Neurodevelopmental differences in Turner syndrome are beginning to be correlated with differences in brain anatomy. An increased understanding of the molecular basis for aspects of this disorder is now developing. In addition, a renewed focus on health maintenance through the life span should provide better general and targeted healthcare for these girls and women.


Sonographic Markers in the Prediction of Fetal Complex Gastroschisis.
To investigate the ultrasound (US) markers predictive of complex gastroschisis (CG), mortality, and morbidity in fetuses with gastroschisis. This was a retrospective cohort study of 186 pregnancies with isolated fetal gastroschisis. Eight US markers were analyzed. The predictions and associations of US markers with CG, mortality, and morbidity were assessed. Combinations of US markers predictive of CG were investigated. Extra-abdominal bowel dilatation (EABD), intra-abdominal bowel dilatation (IABD), and polyhydramnios were predictive of CG. EABD between 25 and 28 weeks had a sensitivity of 64%, a specificity of 89%, a positive predictive value (PPV) of 56.2%, and negative predictive value (NPV) of 91.8%. The predictions of IABD were sensitivity = 26.7%, specificity = 96.7%, PPV = 61.5%, and NPV = 86.8%. The odds ratios for CG in the presence of 1 and 2 US markers, compared with the absence of a US marker, were 18.3 (95% CI, 3.83-87.64) and 73.3 (95% CI, 6.14-876), respectively. US markers predictive of CG were established. The combination of these markers increases the probability of CG.


Cu2O-promoted degradation of sulfamethoxazole by α-Fe2O3-catalyzed peroxymonosulfate under circumneutral conditions: synergistic effect, Cu/Fe ratios, and mechanisms.
To promote the application of iron oxides in sulfate radical-based advanced oxidation processes, a convenient approach using Cu2O as a catalyst additive was proposed. Composite catalysts based on α-Fe2O3 (CTX%Cu2O, X = 1, 2.5, 5, and 10) were prepared for peroxymonosulfate (PMS) activation, and sulfamethoxazole was used as a model pollutant to probe the catalytic reactivity. The results show that a synergistic catalytic effect exists between Cu2O and α-Fe2O3, which was explained by the promoted reduction of Fe(III) by Cu(I). Iron K-edge X-ray absorption spectroscopy investigations indicated that the promoted reduction probably occurred with PMS acting as a ligand that bridges the redox centers of Cu(I) and Fe(III). The weight ratio between Cu2O and α-Fe2O3 influenced the degradation of sulfamethoxazole, and the optimal ratio depended on the dosage of PMS and catalysts. With 40 mg L-1 PMS and 0.6 g L-1 catalyst, a pseudo-first-order constant of ∼0.019 min-1 was achieved for CT2.5%Cu2O, whereas only 0.004 min-1 was realized for α-Fe2O3. Nearly complete degradation of the sulfamethoxazole was achieved within 180 min under the conditions of 40 mg L-1 PMS, 0.4 g L-1 CT2.5%Cu2O, and pH 6.8. In contrast, less than 20% degradation was realized with α-Fe2O3 under similar conditions. The CT2.5%Cu2O catalyst had the best stoichiometric efficiency of PMS (0.317), which was 4.5 and 5.8 times higher than those of Cu2O (0.070) and α-Fe2O3 (0.054), respectively. On the basis of the products identified, the cleavage of the S-N bond was proposed as a major pathway for the degradation of sulfamethoxazole.


SUBOPTIMAL VIRULENCE OF AN INSECT-PARASITIC NEMATODE.
Recent considerations of parasite virulence have focused on the adverse effects that parasites can have on the survival of their hosts. Many parasites, however, reduce host fitness by an equally deleterious but different means, by causing partial or complete sterility of their hosts. A model of optimal parasite virulence is developed in which a quantity of host resources can be allocated to either host or parasite reproduction. Increases in parasite reproduction thus cause reductions in host fertility. The model shows that under a wide variety of ecological conditions, such parasites should completely sterilize their hosts. Only when opportunities for horizontal transmission are very limited should the parasites appropriate less than all of a host's reproductive resources. Field and laboratory evidence shows that the nematode parasite Howardula aoronymphium is relatively avirulent to one of its principal host species, Drosophila falleni, whereas it is much more virulent to D. putrida and D. neotestacea, suggesting that there may be substantial vertical transmission in D. falleni. However, epidemiological studies in the field and laboratory assays of host specificity strongly suggest that the three host species share a single parasite pool in natural populations, indicating that parasites in all three host species experience high levels of horizontal transmission. Thus, the low virulence of H. aoronymphium to D. falleni is not consistent with the model of optimal parasite virulence. It is proposed that this suboptimal virulence in D. falleni is a consequence of populations of H. aoronymphium being selected to exploit simultaneously several different host species. As a result, virulence may not be optimal in any one host. One must, therefore, consider the full range of host species in assessing a parasite's virulence.


A Method for Predicting Production Costs Based on Data Fusion from Multiple Sources for Industry 4.0: Trends and Applications of Machine Learning Methods.
There is a growing need for manufacturing processes that improve product quality and production rates while reducing costs. With the advent of multisensory information fusion technology, individuals can acquire a broader range of information. Several data fusion and machine learning methods have been discussed in this article within the context of the Industry 4.0 paradigm. Depending on its purpose, a prognostic method can be categorized as descriptive, predictive, or prescriptive. ANN and CNN models are applied to predicting production costs using neural networks based on multisource information fusion, and multisource information fusion theory is examined and applied to ANNs and CNNs. In this study, ANN and CNN predictions have been compared. CNN has demonstrated more remarkable skill in predicting the six cost categories than ANN. When predicting the true value of each cost category, CNN is superior to ANN. As a result, CNN's forecast error for the current month's total income is 0.0234. Because of its improved prediction accuracy and more straightforward training technique, CNN is better suited to incorporating information from several sources. Furthermore, both neural networks overestimate indirect costs, including direct material costs and item consumption prices.


The Inhibitory Effects of Protaetia brevitarsis seulensis Larvae Extract on Human Platelet Aggregation and Glycoprotein IIb/IIIa Expression.
The white-spotted flower chafer, Protaetia brevitarsis seulensis, is used as a traditional remedy against liver cirrhosis, hepatitis, and hepatic cancer. In this study, we investigated if P. brevitarsis extract (PBE) inhibited platelet aggregation via integrin αIIb/β3 regulation. We observed that PBE inhibited αIIb/β3 activation by regulating the cyclic nucleotides, cyclic adenosine monophosphate and cyclic guanosine monophosphate. Additionally, PBE affected phosphatidylinositol-3 kinase, Akt, SYK, glycogen synthase kinase-3α/β, cytosolic phospholipase A2, and p38 expression, which are signal transduction molecules expressed by platelets, and consequently suppressed αIIbβ3 activity and thromboxane A2 generation. Taken together, PBE showed strong antiplatelet effects and may be used to block thrombosis- and platelet-mediated cardiovascular diseases.


Rhoptry neck protein 2 expressed in Plasmodium sporozoites plays a crucial role during invasion of mosquito salivary glands.
Malaria parasite transmission to humans is initiated by the inoculation of Plasmodium sporozoites into the skin by mosquitoes. Sporozoites develop within mosquito midgut oocysts, first invade the salivary glands of mosquitoes, and finally infect hepatocytes in mammals. The apical structure of sporozoites is conserved with the infective forms of other apicomplexan parasites that have secretory organelles, such as rhoptries and micronemes. Because some rhoptry proteins are crucial for Plasmodium merozoite infection of erythrocytes, we examined the roles of rhoptry proteins in sporozoites. Here, we demonstrate that rhoptry neck protein 2 (RON2) is also localized to rhoptries in sporozoites. To elucidate RON2 function in sporozoites, we applied a promoter swapping strategy to restrict ron2 transcription to the intraerythrocytic stage in the rodent malaria parasite, Plasmodium berghei. Ron2 knockdown sporozoites were severely impaired in their ability to invade salivary glands, via decreasing the attachment capacity to the substrate. This is the first rhoptry protein demonstrated to be involved in salivary gland invasion. In addition, ron2 knockdown sporozoites showed less infectivity to hepatocytes, possibly due to decreased attachment/gliding ability, indicating that parts of the parasite invasion machinery are conserved, but their contribution might differ among infective forms. Our sporozoite stage-specific knockdown system will help to facilitate understanding the comprehensive molecular mechanisms of parasite invasion of target cells.


Evaluating the Strange Situation Procedure (SSP) to assess the bond between dogs and humans.
The Strange Situation Procedure (SSP) is increasingly being used to study attachment between dogs and humans. It has been developed from the Ainsworth Strange Situation Procedure, which is used extensively to investigate attachment between children and their parents. In this experiment, 12 female beagle dogs were tested in two treatments to identify possible order effects in the test, a potential weakness in the SSP. In one treatment (FS), dogs participated together with a 'familiar person' and a 'stranger'. In a control treatment (SS), the same dogs participated together with two unfamiliar people, 'stranger A' and 'stranger B'. Comparisons were made between episodes within as well as between treatments. As predicted in FS, dogs explored more in the presence of the familiar person than the stranger. Importantly, they also explored more in the presence of stranger A (who appeared in the same order as the familiar person and followed the same procedure) than stranger B in SS. Furthermore, comparisons between treatments, where a familiar person was present in FS and stranger A was present in SS, showed no differences in exploration. In combination, these results indicate that the effect of a familiar person on dogs' exploratory behaviour, a key feature when assessing secure attachment styles, could not be tested reliably due to the order in which the familiar person and the stranger appear. It is proposed that in the future only counterbalanced versions of the SSP are used. Alternatively, since dogs reliably initiated more contact with the familiar person compared to the strangers, it is suggested that future studies on attachment in dogs towards humans should focus either on the behaviour of the dog in those episodes of the SSP when the person returns, or on reunion behaviour in other studies, specially designed to address dog-human interactions at this time.


Outcome Of 0.2% Glyceryltrinitrate Cream Versus 2% Diltiazem Cream In The Treatment Of Chronic Anal Fissure.
Anal fissure is a linear tear in the distal anal canal resulting from persistent hypertonia and spasm of the internal sphincter which results in mucosal ischemia. We have conducted a study in order to compare the outcome of 0.2% glyceryl trinitrate cream versus 2% diltiazem cream in the treatment of chronic anal fissure. This randomized controlled trial (RCT) was carried out in the Department of Surgical "B" unit, at Ayub Teaching Hospital, Abbottabad, Pakistan from 15th June 2012 to 15th May 2015. One hundred and eighty-four patients who visited the outpatient department for the treatment of chronic anal fissure were included in the study. They were divided into two groups with 92 patients in each group. Patients in group "A" included those patients receiving topical glyceryl trinitrate and group "B" patients were those receiving topical diltiazem cream. Out of 184 patients 66.3% were males, 33.7% were females. Mean age of the patients was 43.84±7.976 and mean duration of symptoms was 10.55±2.524. Overall outcome in terms of healing was 71.2%, among which 80.4% were from diltiazem group while 62% in glyceryl trinitrate group. Complete relief of pain was observed in 67.9%, 26.1% complained of mild pain and 5.4% complained of moderate pain. Only one patient in glyceryl trinitrate group complained with severe pain with no healing after one month of follow up. No statistical association was found between healing outcome and gender as well as age of the patients (p>0.05) although an association was found between healing outcome and duration of symptoms (p<0.05). This study shows that diltiazem has better outcome in terms of healing of chronic anal fissure and reductions in symptoms, i.e., pain compared with glyceryl trinitrate.


Protein undernutrition during development and oxidative impairment in the central nervous system (CNS): potential factors in the occurrence of metabolic syndrome and CNS disease.
Mitochondria play a regulatory role in several essential cell processes including cell metabolism, calcium balance and cell viability. In recent years, it has been postulated that mitochondria participate in the pathogenesis of a number of chronic diseases, including central nervous system disorders. Thus, the concept of mitochondrial function now extends far beyond the common view of this organelle as the 'powerhouse' of the cell to a new appreciation of the mitochondrion as a transducer of early metabolic insult into chronic disease in later life. In this review, we have attempted to describe some of the associations between nutritional status and mitochondrial function (and dysfunction) during embryonic development with the occurrence of neural oxidative imbalance and neurogenic disease in adulthood.


Follicular thyroid carcinoma with an unusual glomeruloid pattern of growth.
We describe an uncommon thyroid tumor in a 56-year-old woman. The widely infiltrating, angioinvasive neoplasm, 5 cm in diameter, exhibited a peculiar architectural growth pattern characterized by follicles with round to oval epithelial tufts growing within, often supported by a fibrovascular core mimicking the renal glomerulus. Colloid-empty follicles, tubular or elongated, were lined by pseudostratified tall, columnar cells with clear cytoplasm. Nuclei were round to oval, with evenly distributed, slightly coarse chromatin. Tumor cells were positive for thyroid transcription factor-1, thyroperoxidase, thyroglobulin, cytokeratin 18, Hector Battifora mesothelial cell, and vimentin. Scattered cells positive for S100, Wilms tumor 1 (WT1), and cytokeratins AE1/AE3 were found, with no reaction detected for cytokeratins 34betaE12, 5/6, 7, 19, or 20. There were PAX8-PPARgamma rearrangement and N-RAS mutation. No mutations were found for APC or BRAF genes, nor were RET/PTC rearrangements detected. Because of the distinctive histologic features, we propose naming this tumor follicular thyroid carcinoma with an unusual glomeruloid pattern of growth.


Renal transplantation in the unimmunosuppressed pig: an abnormal response.
A series of 82 kidney allografts and autografts in unimmunosuppressed pigs surviving for longer than 5 days has been compared with a previously reported series of 24 unimmunosuppressed pig kidney allografts. In the previous series 40 per cent survived for longer than 20 days. In the present series only 2 per cent of 55 transplants performed in cross-bred pigs obtained from different farms survived for longer than 20 days. The major causes of death were unrelated to rejection, prinicipally gastric ulcer bleeding. In the further 16 transplants between different pure-bred animals (thereby ensuring genetic disparity) the ulcer incidence was lowered by a gastro-enterostomy, and 12 per cent survived for longer than 20 days. Histological assessment of rejection in the latter group revealed 20 per cent with minimal rejection, was considered insufficient to account for the death of the animals. Based on the evaluation of 95 unimmunosuppressed pig kidney allografts in both series, it is concluded that a wide and unpredictable range of survival time occurs. Therefore the pig kidney allograft model is an unsatisfactory model in which to study immunosuppressive régimes. Also the unimmunosuppressed pig appears to show less evidence of kidney allograft rejection than the dog, irrespective of genetic disparity. It is tentatively suggested that this might be a lesser manifestation of the unexplained phenomenon of minimal rejection of liver allografts noted in unimmunosuppressed pigs.


Beneficial Effects of Tacrolimus on Brain-Death-Associated Right Ventricular Dysfunction in Pigs.
Right ventricular (RV) dysfunction remains a major problem after heart transplantation and may be associated with brain death (BD) in a donor. A calcineurin inhibitor tacrolimus was recently found to have beneficial effects on heart function. Here, we examined whether tacrolimus might prevent BD-induced RV dysfunction and the associated pathobiological changes. After randomized tacrolimus (n = 8; 0.05 mg·kg-1·day-1) or placebo (n = 9) pretreatment, pigs were assigned to a BD procedure and hemodynamically investigated 1, 3, 5, and 7 h after the Cushing reflex. After euthanasia, myocardial tissue was sampled for pathobiological evaluation. Seven pigs were used as controls. Calcineurin inhibition prevented increases in pulmonary vascular resistance and RV-arterial decoupling induced by BD. BD was associated with an increased RV pro-apoptotic Bax-to-Bcl2 ratio and RV and LV apoptotic rates, which were prevented by tacrolimus. BD induced increased expression of the pro-inflammatory IL-6-to-IL-10 ratio, their related receptors, and vascular cell adhesion molecule-1 in both the RV and LV. These changes were prevented by tacrolimus. RV and LV neutrophil infiltration induced by BD was partly prevented by tacrolimus. BD was associated with decreased RV expression of the β-1 adrenergic receptor and sarcomere (myosin heavy chain [MYH]7-to-MYH6 ratio) components, while β-3 adrenergic receptor, nitric oxide-synthase 3, and glucose transporter 1 expression increased. These changes were prevented by tacrolimus. Brain death was associated with isolated RV dysfunction. Tacrolimus prevented RV dysfunction induced by BD through the inhibition of apoptosis and inflammation activation.


Kinetic Schemes in Open Interacting Systems.
We discuss utilization of kinetic schemes for description of open interacting systems, focusing on vibrational energy relaxation for an oscillator coupled to a nonequilibirum electronic bath. Standard kinetic equations with constant rate coefficients are obtained under the assumption of time scale separation between the system and bath, with the bath dynamics much faster than that of the system of interest. This assumption may break down in certain limits, and we show that ignoring this may lead to qualitatively wrong predictions. Connection with more general, nonequilibrium Green's function (NEGF) analysis is demonstrated. Our considerations are illustrated within generic molecular junction models with electron-vibration coupling.


Nurses are human beings too.
Your story 'Thousands of nurses leave NHS posts to maintain work-life balance' (online news, 3 March) made me think. Maybe it would be better if employers didn't break the Working Time Directive, making us swap from a 12-hour night shift to a 14-hour day with no day off in-between, or two long days in a row with not enough time to go home, shower, sleep and get ready for work between them.


Isolation and Characterization of Acetate-Utilizing Anaerobes from a Freshwater Sediment.
Acetate-degrading anaerobic microorganisms in freshwater sediment were quantified by the most probable number technique. From the highest dilutions a methanogenic, a sulfate-reducing, and a nitrate-reducing microorganism were isolated with acetate as substrate. The methanogen (culture AMPB-Zg) was non-motile and rod-shaped with blunted ends (0.5-1 mm x 3-4 mm long). Doubling times with acetate at 30-35 degrees C were 5.6-8.1 days. The methanogen grew only on acetate. Analysis of the 16S rRNA sequence showed that AMPB-Zg is closely related to Methanosaeta concilii. The isolated sulfate-reducing bacterium (strain ASRB-Zg) was rod-shaped with pointed ends (0.5-0.7 mm x 1.5-3.5 mm long), weakly motile, spore forming, and gram positive. At the optimum growth temperature of 30 degrees C the doubling times with acetate were 3.9-5.3 days. The bacterium grew on a range of organic acids, such as acetate, butyrate, fumarate, and benzoate, but did not grow autotrophically with H2, CO2, and sulfate. The closest relative of strain ASRB-Zg is Desulfotomaculum acetoxidans. The nitrate-reducing bacterium (strain ANRB-Zg) was rod-shaped (0.5-0.7 mm x 0.7-1 mm long), weakly motile, and gram negative. Optimum growth with acetate occurred at 20-25 degrees C. The bacterium grew on a range of organic substrates, such as acetate, butyrate, lactate, and glucose, and did grow autotrophically with H2, CO2, and oxygen but not with nitrate. In the presence of acetate and nitrate, thiosulfate was oxidized to sulfate. Phylogenetically, the closest relative of strain ANRB-Zg is Variovorax paradoxus.


[Male indications of fertilization in vitro].
The place of male indications in FIV remains very limited. However, the best test of sperm fertility is the specific in-vitro fertilization. The search for improvement of the conditions of contact and fusion of the gametes seems well-founded. However, the therapeutic value of FIV in male indications remains debatable.


Hybrid unorganized machines to estimate the number of hospital admissions caused by PM[Formula: see text] concentration.
Air pollution levels exceeding the recommended limit can be the main cause of illnesses that affect human health, mainly diseases of the respiratory system. Consequently, this high exposure can impact public health management, given the increase in hospital admissions. One of the most influential air pollution parameters related to respiratory diseases is particulate matter (PM) concentrations. Thus, this paper proposes to estimate hospital admissions due to respiratory diseases caused by PM concentration with an aerodynamic diameter less than 10 [Formula: see text]m (PM[Formula: see text]), using artificial neural networks. Three hybrid neural network models are developed by combining two architectures denoted unorganized machines: extreme learning machines and echo state networks. These models also comprise extension strategies that seek to improve the generalization capability and the variation in the nonlinear outputs. Case studies explore three cities' datasets from São Paulo state, Brazil: Cubatão, Campinas, and São Paulo, to assess the quality of the hospital admissions estimations obtained by applying the proposed models. Results demonstrate that the hybrid models outperform the previously developed standard approaches in several scenarios. An overall analysis shows that the hybrid models can be a suitable strategy considering the instance particularities, especially in large datasets.


Integration of safety technologies into rheumatology and orthopedics practices: a randomized, controlled trial.
To identify and integrate new safety technologies into outpatient musculoskeletal procedures and measure the effect on outcome, including pain. Using national resources for patient safety and literature review, the following safety technologies were identified: a safety needle to reduce inadvertent needlesticks to heath care workers, and the reciprocating procedure device (RPD) to improve patient safety and reduce pain. Five hundred sixty-six musculoskeletal procedures involving syringes and needles were randomized to either an RPD group or a conventional syringe group, and pain, quality, safety, and physician acceptance were measured. During 566 procedures, no accidental needlesticks occurred with safety needles. Use of the RPD resulted in a 35.4% reduction (95% confidence interval [95% CI] 24-46%) in patient-assessed pain (mean +/- SD scores on a visual analog pain scale [VAPS] 3.12 +/- 2.23 for the RPD and 4.83 +/- 3.22 for the conventional syringe; P < 0.001) and a 49.5% reduction (95% CI 34-64%) in patient-assessed significant pain (VAPS score > or =5) (P < 0.001). Physician acceptance of the RPD combined with a safety needle was excellent. As mandated by the Joint Commission and the Occupational Safety and Health Administration, safety technologies and the use of pain scales can be successfully integrated into rheumatologic and orthopedic procedures. The combination of a safety needle to reduce needlestick injuries to health care workers and the RPD to improve safety and outcome of patients is effective and well accepted by physicians.


[Clinical symptoms of precancerosis].
Clinically, praecancerosis of the oral mucosa may be classified into the following groups: Whitish, flat changes, reddish changes, papillary changes and ulcers. Combination of the various groups and flowing transition between them is often observed. It can be shown that praecancerosis can be neither clearly distinguished from benign tumors or changes, nor can it be differentiated from already existing malignomas. The same picture of a disease can occur in various clinical aspects. On the other hand, histologically very different changes may often hardly be distinguished clinically. A change in the oral mucosa must therefore be regarded as possibly malignous as long as not proven to the contrary. Also, it is important to check, at regular intervals, changes diagnosed benign, since the possibility of malignous change cannot be ignored.


Post-concussion symptom reporting after multiple mild traumatic brain injuries.
The relationship between previous mild traumatic brain injury/injuries (MTBI) and recovery from a subsequent MTBI may be complex. The present study investigated three factors hypothesized to influence this relation: (1) the number of prior MTBIs, (2) the interval between MTBIs, and (3) the certainty level of previous MTBIs. The study design was retrospective cross-sectional. Participants (N=105) were evaluated at a concussion clinic on average 1 month after sustaining an MTBI, defined by World Health Organization diagnostic criteria. Approximately half the sample had at least one previous MTBI. Subgroups with 0, 1, or 2+ previous MTBIs did not differ in levels of current post-concussion symptom reporting on the British Columbia Post-Concussion Symptom Inventory. Time since the most recent previous MTBI was significantly associated with current post-concussion symptom reporting. This relation was best characterized as logarithmic; i.e., the impact of previous MTBI(s) lessens exponentially as time elapses to a subsequent MTBI. Defining previous MTBIs with a higher certainty level (i.e., probable versus possible) was not consistently associated with greater post-concussion symptom reporting. In conclusion, participants with multiple MTBIs did not report more post-concussion symptoms than those with no history of MTBI. Previous MTBI(s), however, were associated with increased symptom reporting from a subsequent MTBI to the extent they occurred closer in time. Having one or two previous remote MTBIs was not associated with worse outcome from subsequent MTBI in this sample.


Effects of a detergent micelle environment on P-glycoprotein (ABCB1)-ligand interactions.
P-glycoprotein (P-gp) is a multidrug transporter that uses energy from ATP hydrolysis to export many structurally dissimilar hydrophobic and amphipathic compounds, including anticancer drugs from cells. Several structural studies on purified P-gp have been reported, but only limited and sometimes conflicting information is available on ligand interactions with the isolated transporter in a dodecyl-maltoside detergent environment. In this report we compared the biochemical properties of P-gp in native membranes, detergent micelles, and when reconstituted in artificial membranes. We found that the modulators zosuquidar, tariquidar, and elacridar stimulated the ATPase activity of purified human or mouse P-gp in a detergent micelle environment. In contrast, these drugs inhibited ATPase activity in native membranes or in proteoliposomes, with IC50 values in the 10-40 nm range. Similarly, a 30-150-fold decrease in the apparent affinity for verapamil and cyclic peptide inhibitor QZ59-SSS was observed in detergent micelles compared with native or artificial membranes. Together, these findings demonstrate that the high-affinity site is inaccessible because of either a conformational change or binding of detergent at the binding site in a detergent micelle environment. The ligands bind to a low-affinity site, resulting in altered modulation of P-gp ATPase activity. We, therefore, recommend studying structural and functional aspects of ligand interactions with purified P-gp and other ATP-binding cassette transporters that transport amphipathic or hydrophobic substrates in a detergent-free native or artificial membrane environment.


Consensus for sclerotherapy.
The American Society for Dermatologic Surgery (ASDS) periodically develops consensus documents for its members concerning various aspects of dermatologic surgery. Unwanted and painful leg veins are a very widespread problem. Many advances in sclerotherapy of varicose and telangiectatic leg veins have occurred since the previous consensus documents. In 2013, the ASDS Board of Directors voted to have a committee of experts in the field to develop consensus documents on sclerotherapy. An expert panel reviewed the literature on sclerotherapy and discussed the findings. A consensus was reached with evidence-based recommendations on diagnostic evaluation and treatment of varicose and telangiectatic leg veins. The consensus documents include discussion of indications for treatment, patient selection, contraindications, diagnostic testing, treatment approaches, use of compression, and expected outcome. Common sclerosants and their mechanisms of action, advantages and disadvantages of foam sclerotherapy, and minimizing and treating complications are presented. The ASDS consensus documents on sclerotherapy will be helpful in educating their members on safe and effective sclerotherapy of varicose and telangiectatic leg veins.


Complement activation in emergency department patients with severe sepsis.
This study assessed the extent and mechanism of complement activation in community-acquired sepsis at presentation to the emergency department (ED) and following 24 hours of quantitative resuscitation. A prospective pilot study of patients with severe sepsis and healthy controls was conducted among individuals presenting to a tertiary care ED. Resuscitation, including antibiotics and therapies to normalize central venous and mean arterial pressure (MAP) and central venous oxygenation, was performed on all patients. Serum levels of Factor Bb (alternative pathway), C4d (classical and mannose-binding lectin [MBL] pathway), C3, C3a, and C5a were determined at presentation and 24 hours later among patients. Twenty patients and 10 healthy volunteer controls were enrolled. Compared to volunteers, all proteins measured were abnormally higher among septic patients (C4d 3.5-fold; Factor Bb 6.1-fold; C3 0.8-fold; C3a 11.6-fold; C5a 1.8-fold). Elevations in C5a were most strongly correlated with alternative pathway activation. Surprisingly, a slight but significant inverse relationship between illness severity (by sequential organ failure assessment [SOFA] score) and C5a levels at presentation was noted. Twenty-four hours of structured resuscitation did not, on average, affect any of the mediators studied. Patients with community-acquired sepsis have extensive complement activation, particularly of the alternative pathway, at the time of presentation that was not significantly reversed by 24 hours of aggressive resuscitation.


Substrate-Mediator Duality of 1,4-Dicyanobenzene in Electrochemical C(sp2 )-C(sp3 ) Bond Formation with Alkyl Bromides.
Electrochemical approaches to form C(sp2 )-C(sp3 ) bonds have focused on coupling C(sp3 ) electrophiles that form stabilized carbon-centered radicals upon reduction or oxidation. Whereas alkyl bromides are desirable C(sp3 ) coupling partners owing to their availability and cost-effectiveness, their tendency to undergo radical-radical homocoupling makes them challenging substrates for electroreductive cross-coupling. Herein, we disclose a metal-free regioselective cross-coupling of 1,4-dicyanobenzene, a useful precursor to aromatic nitriles, and alkyl bromides. Alkyl bromide reduction is mediated directly by 1,4-dicyanobenzene radical anions, leading to negligible homocoupling and high cross-selectivity to form 1,4-alkyl cyanobenzenes. The cross-coupling scheme is compatible with oxidatively sensitive and acidic functional groups such as amines and alcohols, which have proven difficult to incorporate in alternative electrochemical approaches using carboxylic acids as C(sp3 ) precursors.


Standardized screening of elderly patients' needs for social work assessment in primary care: use of the SF-36.
Fewer hospitalizations and decreased lengths of stay in the hospital have resulted in an increased need for extensive support services and continuing care planning for elderly people in primary care. Early identification of elderly patients needing community and hospital nonmedical services is necessary so that timely appropriate services can be delivered. This study addresses the issue of whether a standardized health-related quality of life questionnaire, the SF-36, can be used independently as a screen predicting primary care elderly patients' needs for social work assessment. In addition, the question of what scales on the SF-36 a social worker would use to screen patients in need of assessment is explored.


A phylogenetic approach to the early evolution of autotrophy: the case of the reverse TCA and the reductive acetyl-CoA pathways.
In recent decades, a number of hypotheses on the autotrophic origin of life have been presented. These proposals invoke the emergence of reaction networks leading from CO or CO₂ to the organic molecules required for life. It has also been suggested that the last (universal) common ancestor (LCA or LUCA) of all extant cell lineages was a chemolitho-autotrophic thermophilic anaerobe. The antiquity of some carbon fixation pathways, the phylogenetic basal distribution of some autotrophic organisms, and the catalytic properties of iron-sulfur minerals have been advanced in support of these ideas. Here we critically examine the phylogenetic distribution and evolution of enzymes that are essential for two of the most ancient autotrophic means of metabolism: the reductive tricarboxylic acid (rTCA) cycle and the reductive acetyl-CoA pathway. Phylogenetic analysis of citryl-CoA synthetase and of citryl-CoA lyase, key enzymatic components of the rTCA cycle, and of CO dehydrogenase/acetyl-CoA synthase, a key enzyme in the reductive acetyl-CoA pathway, revealed that all three enzymes have undergone major lateral transfer events and therefore cannot be used as proof of the LCA's metabolic abilities nor as evidence of an autotrophic origin of life.


Haemorrhagic stroke or hyperglycaemia?
A 56-year-old woman with no medical history was admitted with acute onset hemiballistic-choreiform movements of right extremity. On admission, her serum glucose and osmolality were elevated. Her glycosylated haemoblobin (HbA1c) was 17.9 with average blood sugars of 467 mg/dL. A CT scan of the brain revealed unilateral hyperintensities in the basal ganglia. A complete stroke work-up, including MRI and MR angiography of brain was otherwise unrevealing. Subcutaneous insulin was instituted, which led to complete resolution of her symptoms within 48 h of hospital admission. She was readmitted 4 weeks after her initial discharge for similar, but less severe, symptoms. This time her HbA1c was 13.9 with an average blood sugar of 352 mg/dL. A repeat MRI demonstrated a persistent abnormal signal within the left basal ganglia without infarct. She was started on subcutaneous insulin. Her symptoms improved but did not resolve. Haloperidol and gabapentin were initiated and she was again discharged after stabilisation to a rehabilitation centre as per physiotherapy recommendations.


Genetic defects in pregnenolone synthesis.
The pregnenolone synthesis is the first step in the biosynthesis of all steroid hormones. The disruption of this step is known to result in congenital lipoid adrenal hyperplasia (CLAH), a most severe form of congenital adrenal hyperplasia. CLAH was first demonstrated to be caused by mutations in the STAR gene encoding steroidogenic acute regulatory protein (StAR). Now genetic and phenotypic variations have been elucidated in pregnenolone synthesis defects; mutations in the CYP11A1 gene encoding cholesterol side-chain cleavage enzyme (SCC) also cause disordered pregnenolone synthesis, and STAR mutations do not necessarily results in typical CLAH. To define these conditions precisely, pathophysiological diagnoses, such as StAR deficiency and SCC deficiency, are more likely to be appropriate than the histopathological diagnosis like CLAH.


Hypercholesterolemia Increases Colorectal Cancer Incidence by Reducing Production of NKT and γδ T Cells from Hematopoietic Stem Cells.
Obesity will soon surpass smoking as the most preventable cause of cancer. Hypercholesterolemia, a common comorbidity of obesity, has been shown to increase cancer risk, especially colorectal cancer. However, the mechanism by which hypercholesterolemia or any metabolic disorder increases cancer risk remains unknown. In this study, we show that hypercholesterolemia increases the incidence and pathologic severity of colorectal neoplasia in two independent mouse models. Hypocholesterolemia induced an oxidant stress-dependent increase in miR101c, which downregulated Tet1 in hematopoietic stem cells (HSC), resulting in reduced expression of genes critical to natural killer T cell (NKT) and γδ T-cell differentiation. These effects reduced the number and function of terminally differentiated NKT and γδ T cells in the thymus, the colon submucosa, and during early tumorigenesis. These results suggest a novel mechanism by which a metabolic disorder induces epigenetic changes to reduce lineage priming of HSC toward immune cells, thereby compromising immunosurveillance against cancer. Cancer Res; 77(9); 2351-62. ©2017 AACR.


[A case of long-term survival after aggressive surgery for Stage IV gallbladder carcinoma].
A 67-year-old woman was referred to our hospital because of a gallbladder mass. Abdominal computed tomography revealed a protruding mass 34 mm in diameter in the body of the gallbladder with wall thickening and enhancement. Advanced gallbladder carcinoma was diagnosed by image analysis, with liver metastasis in segment 5 and lymph node metastasis in the hepatoduodenal ligament. Subsequently, S4a+S5 hepatic segmentectomy was performed with extrahepatic bile duct resection and regional lymphadenectomy. The final pathological diagnosis was pT2 pN1 pM1, Stage IV,according to the International Union against Cancer classification system. Curative resection was then performed. In addition, we performed adjuvant chemotherapy with 15 courses of 1,000 mg/m2 gemcitabine on days 1, 8, and 15 at every 28 days. At 5 years after the operation, the patient was alive and free of disease. Therefore, in cases of limited liver metastasis (within segments 4a and 5), aggressive surgery should be considered even for Stage IV gallbladder carcinoma. In such cases, long-term patient survival may be expected only when curative resection is achieved.


Preschoolers' comprehension of goal structure in narratives.
Preschool children's understanding and use of goals were studied in two experiments. Children heard stories in the presence of pictures or props. The stories were varied by goal success occurring early or late in the story, with late goal success resulting in more causal connections in the narrative. The results showed that children recalled goals spontaneously and that their recall benefited from goal structure of the stories. Pictures benefited the children when the stories were short. Enactment of the props versus static displays of the props did not enhance recall in the second experiment. Preschool children thus demonstrated ability to infer and use goal and causal information in stories for both picture and object support.


Efficacy of electrolyzed water in the inactivation of planktonic and biofilm Listeria monocytogenes in the presence of organic matter.
The ability of electrolyzed (EO) water to inactivate Listeria monocytogenes in suspension and biofilms on stainless steel in the presence of organic matter (sterile filtered chicken serum) was investigated. A five-strain mixture of L. monocytogenes was treated with deionized, alkaline EO, and acidic EO water containing chicken serum (0, 5, and 10 ml/liter) for 1 and 5 min. Coupons containing L. monocytogenes biofilms were also overlaid with chicken serum (0, 2.5, 5.0, and 7.5 ml/liter) and then treated with deionized water, alkaline EO water, acidic EO water, alkaline EO water followed by acidic EO water, and a sodium hypochlorite solution for 30 and 60 s. Chicken serum decreased the oxidation-reduction potential and chlorine concentration of acidic EO water but did not significantly affect its pH. In the absence of serum, acidic EO water containing chlorine at a concentration of 44 mg/liter produced a > 6-log reduction in L. monocytogenes in suspension, but its bactericidal activity decreased with increasing serum concentration. Acidic EO water and acidified sodium hypochlorite solution inactivated L. monocytogenes biofilms to similar levels, and their bactericidal effect decreased with increasing serum concentration and increased with increasing time of exposure. The sequential 30-s treatment of alkaline EO water followed by acidic EO water produced 4- to 5-log reductions in L. monocytogenes biofilms, even in the presence of organic matter.


Drug repurposing: progress, challenges and recommendations.
Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.


Trophoblasts Modulate the Ca2+ Oscillation and Contraction of Myometrial Smooth Muscle Cells by Small Extracellular Vesicle- (sEV-) Mediated Exporting of miR-25-3p during Premature Labor.
The placenta could transmit information to the maternal circulation via the secretion of small extracellular vesicles (sEVs), but little is known about whether and how these sEVs participate in premature labor (PTL). We speculate that miRNA plays an important role in sEV-mediated fetal-maternal information transmission. The present study was aimed at investigating whether the placenta can regulate the contraction of the maternal myometrium via sEV-mediated transmit of miR-25-3p during PTL. The expression of miR-25-3p and its targets Cav3.2 and SERCA2a in clinical samples, cells, and animal specimens was detected. The role of miR-25-3p was observed in the LPS-induced preterm labor mouse model. The sEVs from HTR-8/SVneo cells were characterized by transmission electron microscopy and nanoparticle tracking analysis. The Ca2+ oscillation in HMSMs was analyzed by an intracellular Ca2+ change tracking assay on a confocal microscope. The contraction of HMSMs was detected by a collagen matrix contraction assay. We found that miR-25-3p can directly bind to the 3'UTR of Cav3.2 and SERCA2a. The miR-25-3p level was decreased, and the expression of its targets Cav3.2 and SERCA2a was increased in the placenta and myometrium tissues of PTL patients. Forced upregulation of miR-25-3p reduced the oxidative stress and inflammation responses and the incidence of PTL in LPS-treated mice. The expression of miR-25-3p was not changed in LPS-stimulated human myometrial smooth muscle cells (HMSMs) but was strongly reduced in the trophoblast cell and its sEVs. Additionally, the trophoblast cell line HTR-8/SVneo could transmit miR-25-3p into HMSMs via sEVs. The sEVs derived from LPS-stimulated trophoblasts upregulated the expression of Cav3.2 and SERCA2a and triggered Ca2+ oscillation as well as the contraction of HMSMs; these effects were partially reversed by the overexpression of miR-25-3p in the trophoblasts. Further, the upregulation of miR-25-3p induced changes of Ca2+ oscillation and contraction of HMSMs mediated by sEVs which were also abrogated by the knockdown of miR-25-3p in HMSMs. The results demonstrated that miR-25-3p plays a crucial role in PTL via Cav3.2- and SERCA2a-mediated Ca2+ oscillation and contraction of HMSMs. PTL seems to be related to the decreased exosomal miR-25-3p content transmitted by the trophoblasts under inflammatory conditions.


Delivery of human mesenchymal adipose-derived stem cells restores multiple urological dysfunctions in a rat model mimicking radical prostatectomy damages through tissue-specific paracrine mechanisms.
Urinary incontinence (UI) and erectile dysfunction (ED) are the most common functional urological disorders and the main sequels of radical prostatectomy (RP) for prostate cancer. Mesenchymal stem cell (MSC) therapy holds promise for repairing tissue damage due to RP. Because animal studies accurately replicating post-RP clinical UI and ED are lacking, little is known about the mechanisms underlying the urological benefits of MSC in this setting. To determine whether and by which mechanisms MSC can repair damages to both striated urethral sphincter (SUS) and penis in the same animal, we delivered human multipotent adipose stem cells, used as MSC model, in an immunocompetent rat model replicating post-RP UI and ED. In this model, we demonstrated by using noninvasive methods in the same animal from day 7 to day 90 post-RP injury that MSC administration into both the SUS and the penis significantly improved urinary continence and erectile function. The regenerative effects of MSC therapy were not due to transdifferentiation and robust engraftment at injection sites. Rather, our results suggest that MSC benefits in both target organs may involve a paracrine process with not only soluble factor release by the MSC but also activation of the recipient's secretome. These two effects of MSC varied across target tissues and damaged-cell types. In conclusion, our work provides new insights into the regenerative properties of MSC and supports the ability of MSC from a single source to repair multiple types of damage, such as those seen after RP, in the same individual.


Cognitive processes and cerebral cortical fundi: findings from positron-emission tomography studies.
Positron-emission tomography (PET) studies of regional cerebral blood flow have provided evidence relevant to localization of cognitive functions. The critical loci identified in these studies are typically described in terms of macroanatomically labeled cortical and subcortical regions. We report the results of a meta-analysis of localization of changes in blood flow, based on nearly 1000 cerebral cortical peaks of activity obtained from groups of subjects in 30 PET studies. The results showed that, on average, 47% of these peaks were localized within the fundus regions of cortical sulci. This is an unexpectedly high proportion because fundal regions compose < 8% of the cortical mantle. Further analysis suggested a coarse correlation between the extent of fundal activation observed in different studies and the estimated cognitive complexity of the tasks used in the studies. These findings are potentially interesting because (i) the preponderance of fundal activation has implications for the interpretation of the PET data, (ii) they suggest that cortical sulcal and fundal regions may play a distinctive role in higher cognitive processing, or (iii) both of the above.


Long-term clinical outcomes after sirolimus-eluting stent implantation in dialysis patients.
There is little information about long-term (> 1 year) outcomes after sirolimus-eluting stent (SES) implantation in dialysis patients. Percutaneous coronary intervention (PCI) using SES was performed in 63 dialysis patients with 77 lesions. A control group for comparison was composed of 45 consecutive dialysis patients with 62 lesions who received PCI using bare metal stents (BMS). Clinical follow-up duration was 21.7 +/- 8.4 months in the SES group and 32.1 +/- 9.2 months in the BMS group (P < 0.01). There was no significant difference in the in-segment restenosis rate (30% versus 40%, P = 0.20) between the 2 groups. The 3-year mortality (22.5% versus 22.2%, P = 0.75), myocardial infarction (3.8% versus 4.9%, P = 0.93), target lesion revascularization (24.7% versus 31.0%, P = 0.61), and stent thrombosis rates (3.8% versus 2.4%, P = 0.73) were not significantly different between the SES and BMS groups. Compared to BMS, SES do not improve long-term clinical outcomes in dialysis patients.


Sonolysis in Prevention of Brain Infarction During Carotid Endarterectomy and Stenting (SONOBUSTER): a randomized, controlled trial.
Previous case series have detected silent brain infarctions in as many as one-third of patients after carotid endarterectomy (CEA) and in up to two-thirds of patients after carotid angioplasty and stenting (CAS). Sonolysis employs ultrasound to facilitate disruption of thrombi and has been shown to be safe and effective for improving long-term outcomes following acute stroke. Here, we examined whether intraoperative sonolysis alters the risk of new brain ischaemic lesions during CEA or CAS. All consecutive patients with internal carotid stenosis ≥70% indicated for CEA/CAS were screened in this prospective study. Patients were allocated randomly to sonolysis and control groups. Neurological examination, cognitive function tests, and brain magnetic resonance imaging (MRI) were conducted before intervention and at 24 and 30 days post-surgery. Of the 487 screened patients, 121 (87 males; mean age, 66.65 ± 7.17 years) were allocated to the sonolysis group and 121 (75; 66.02 ± 8.11 years) to the control group. New brain ischaemic lesions on post-procedure MRI were significantly less frequent in the sonolysis group than in the control group (31.4% of patients vs. 47.1%; P = 0.018). Sonolysis and CEA were identified as independent predictors of reduced brain ischaemic risk [sonolysis: odds ratio (OR) = 0.450 (0.215-0.942), P = 0.034 and CEA: OR = 0.208 (0.087-0.495), P < 0.001]. Stroke or transient ischaemic attack occurred in one sonolysis patient and three control patients (P = 0.372). No significant group differences were found in post-intervention cognitive test scores (P > 0.3). This study provides Class II evidence that sonolysis during CEA or CAS reduces the risk of new brain ischaemic lesions. http://www.clinicaltrials.gov (NCT01591005).


Carfilzomib and dexamethasone induction with lenalidomide, clarithromycin and dexamethasone consolidation and lenalidomide maintenance for newly diagnosed multiple myeloma.
Combination treatment regimens including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and a corticosteroid are standards of care for initial treatment of multiple myeloma (MM). We aimed to evaluate if a sequential treatment program using PI induction followed by IMiD based consolidation and maintenance could achieve similar outcomes with reduced toxicities. This phase 2 study was designed to assess the safety and efficacy of the Car-BiRd regimen: carfilzomib and dexamethasone (Kd) induction until maximum response, followed by lenalidomide, clarithromycin and dexamethasone (BiRd) consolidation until next maximum response, then lenalidomide maintenance in patients with newly diagnosed MM. Seventy-two patients, including both transplant eligible and ineligible patients, were enrolled and evaluated for response. The overall response rate to the Car-BiRd regimen was 94% with 83% of patients achieving a ≥ VGPR and 35% achieving a CR/sCR. The rate of CR/sCR increased from 7% with Kd induction to 21% with BiRd consolidation and 35% with lenalidomide maintenance. These results did not meet the study's target endpoint of a CR rate of 55%. The median PFS using this deferred transplant approach was 37.3 months (95% CI 27.9, 52.7) and median OS was not reached with a median follow-up of 60 months. Toxicities were primarily low grade and manageable. Hematologic toxicities were lower than those expected with a combination PI/IMiD protocol. The sequential Car-BiRd regimen is an effective and safe approach for the upfront treatment of MM including patients unfit for transplant.


Orbital basal cell adenoma: A case report.
Basal cell adenomas are uncommon benign epithelial tumors of the salivary gland. Orbital basal cell adenoma of the orbit has not been described before. The authors report an unusual case of basal cell adenoma that presented in the orbit. Immunohistochemical findings for the tumor are also described.


Outgrowth of CD4low/negCD25+ T cells with suppressor function in CD4+CD25+ T cell cultures upon polyclonal stimulation ex vivo.
CD4(+)CD25(+) regulatory T cells (Tregs) play an essential role in controlling autoimmunity and allograft rejection. Several ex vivo activation and expansion protocols have been developed to amplify cell numbers and suppressor function of murine and human Tregs. We demonstrate in this study that ex vivo activation and expansion of murine Tregs resulted in an enrichment of a CD4(low/neg)CD25(+) T cell population that was more than 20-fold more potent than expanded conventional Tregs in suppressing an in vitro CD4(+)CD25(-) T cell response to allo-Ag. The generation of CD4(low/neg)CD25(+) T cells was independent of the presence of Tregs in the culture, and suppressor function was acquired only after activation and expansion. CD4(low/neg)CD25(+) T cells expressed either an alphabeta or gammadelta TCR, had an activated phenotype, and did not express the transcription factor FoxP3. Despite expressing the cell surface Ags lymphocyte activation gene-3 (CD223) and CD103, neither was essential for suppressor cell function. Suppression by CD4(low/neg)CD25(+) T cells was prevented by a semipermeable membrane and was independent of IL-10 and TGF-beta. In summary, we describe in this study CD4(low/neg)CD25(+) FoxP3(neg) T cells with highly potent suppressor cell function derived from cultures of an enriched population of CD4(+)CD25(+) T cells that may contribute to the suppressor activity of ex vivo expanded bone fide Tregs.


Effect of Moisture Stress on the Development of False Codling Moth Thaumatotibia leucotreta (Lepidoptera: Tortricidae) on Two Tomato Varieties.
False codling moth Thaumatotibia leucotreta (Meyrick) is a pest native to sub-Saharan Africa infesting over 100 plant species including tomato. Its survival and performance are influenced by changes in precipitation and stress-related biochemical changes in the host plant. Water availability for agricultural production continues to decline due to climate change affecting drought-sensitive crops like tomatoes. Little is known on host plant-insect interactions of T. leucotreta and tomato as influenced by moisture stress. Hence, our study tested the impact of different water holding capacities (WHC) (40%, 50%, 60%, 70%, and 90%) of plant growing media on the growth of Anna F1 and Yaye tomato varieties and the infestation rate and development of T. leucotreta on the two varieties. WHC significantly influenced the growth of Anna F1 and Yaye tomato varieties. WHC significantly affected stem girth of Anna F1 variety and leaf length, leaf width, stem girth, and plant height of the Yaye variety. For Yaye variety, T. leucotreta laid a significantly high number of eggs when grown at 70% WHC and had the highest pupation when grown at 60% WHC. The development of T. leucotreta as observed on wing growth was highest at 40% and 50% WHC for both Anna F1 variety and Yaye variety. Our study shows that the infestation of tomato by T. leucotreta is likely to be high when grown in water-scarce media. The results are useful for predicting possible future T. leucotreta trends with increasing water scarcity due to climate change and in designing pest management programmes.


Treatment and early intervention in psychosis program (TIPP-Lausanne): Implementation of an early intervention programme for psychosis in Switzerland.
In a survey conducted in the Lausanne catchment area in 2000, we could estimate on the basis of file assessment that first-episode psychosis (FEP) patients had psychotic symptoms for more than 2 years before treatment and that 50% did not attend any outpatient appointment after discharge from hospital. In this paper, we describe the implementation of a specialized programme aimed at improving engagement and quality of treatment for early psychosis patients in the Lausanne catchment area in Switzerland. The Treatment and Early Intervention in Psychosis Program-Lausanne is a comprehensive 3-year programme composed of (i) an outpatient clinic based on assertive case management; (ii) a specialized inpatient unit; and (iii) an intensive mobile team, connected for research to the Center for Psychiatric Neuroscience. Eight years after implementation, the programme has included 350 patients with a disengagement rate of 9% over 3 years of treatment. All patients have been assessed prospectively and 90 participated in neurobiological research. Based on this experience, the Health Department funded the implementation of similar programmes in other parts of the state, covering a total population of 540,000 people. Programmes for early intervention in psychosis have a major impact on patients' engagement into treatment. While development of mobile teams and assertive case management with specific training are crucial, they do not necessitate massive financial support to be started. Inclusion of a research component is important as well, in terms of service planning and improvement of both quality of care and impact of early intervention strategies.


Electrical stimulation of the auditory nerve via cochlear implants in patients with auditory neuropathy.
Auditory neuropathy (AN) is a term used to describe an auditory disorder in which there is evidence of normal outer hair cell function (otoacoustic emissions and/or cochlear microphonics) and poor function of the auditory nerve (absent or highly distorted auditory brain stem response starting with wave I). Many of these patients have evidence of generalized peripheral nerve disease, leading to an assumption that the peripheral portion of the auditory nerve is the most likely site of lesion. A small group of these patients has received cochlear implants, and the majority of them achieve average to above-average performance. Although this outcome may seem incongruous with neural disease, average performance by patients with AN may be a result of the reintroduction of neural synchrony by electrical stimulation and/or the fact that most deaf patients have poor nerve survival. Although cochlear implants are promising for deaf patients with AN, more study of the disorder is needed.


[Tuberculosis challenge to medicine in 21st century].
Although, since discovering Koch's bacilli over 130 years have passed, and 70 since the invention of the first antituberculous drug, the epidemic of this illness has not been brought under control. It is still an important health problem of the contemporary world. In the 21st century co-infection with the Koch's bacillus and HIV, as well as multidrug-resistance, will be a challenge for medicine. In countries with a good epidemiological situation the prevalence of the disease is becoming a problem in particular populations, such as immigrants, homeless, prisoners, elderly persons and people with immunodeficiency. A tighter control of infection in these groups is necessary.


Free oxygen radicals are not detectable by chemiluminescence during human natural killer cell cytotoxicity.
Mononuclear cells isolated from peripheral blood of normal donors produce free oxygen radicals (FR), detectable by chemiluminescence (CL), when interacting with target cells during natural killer (NK) cell lysis. FR-producing cells were found to have monocyte characteristics and gave a positive CL reaction when mixed at low concentration (0.5%) with purified NK cells. No correlation was found between susceptibility to NK cell lysis and capacity to induce CL with different target cell lines. Using high and low molecular FR scavengers, no NK cell inhibition was seen with superoxide dismutase, cytochrome c, and catalase, whereas some inhibition was seen with 4,5-dihydroxy-m- benzenedisulphonic acid (Tiron) and 2,3-dihydroxybenzoate. These compounds, however, required higher concentrations than used for inhibition of CL, suggesting an alternative action of these compounds. Normal levels of NK cell activity were found in two patients with chronic granulomatous disease, who were genetically incapable of producing detectable amounts of FR. As a result, it is concluded that human NK cells do not produce large amounts of FR during killing and that FR are unlikely to be the lytic end product. Nevertheless, neither a low degree of FR formation in NK cells nor a more subtle signal-transmitting role of FR during NK cell triggering can be excluded.


Amyloid-Related Imaging Abnormalities in an Aged Squirrel Monkey with Cerebral Amyloid Angiopathy.
Amyloid-related imaging abnormalities (ARIA) in magnetic resonance imaging scans have emerged as indicators of potentially serious side effects in clinical trials of therapeutics for Alzheimer's disease. These anomalies include an edematous type (ARIA-E) that appears as hyperintense (bright) regions by T2-weighted MRI, and a type characterized by the deposition of hemosiderin (ARIA-H) that elicits a hypointense signal, especially in T2* susceptibility weighted images. ARIA in general has been linked to the presence of amyloid-β (Aβ)-type cerebral amyloid angiopathy, an accumulation of misfolded Aβ protein in the vascular wall that impairs the integrity of brain blood vessels. However, the pathobiology of ARIA remains poorly understood, in part due to the absence of an animal model of the disorder that would enable a contemporaneous analysis of tissue integrity in the affected region. Here we describe both ARIA-E and ARIA-H in an aged squirrel monkey (Saimiri sciureus), a nonhuman primate model of naturally occurring cerebral amyloid angiopathy. Histopathologic examination of the anomalous region revealed reactive astrocytosis and microgliosis, infiltration of systemic inflammatory/immune cells, damage to axons and myelin, and hemosiderin deposition. The disruption of axons in particular suggests that ARIA-E could have functional consequences for affected regions. The squirrel monkey model can be useful for studying the pathogenesis and long-term effects of ARIA, and for testing the safety and efficacy of emerging therapies for Alzheimer's disease.


[Pharmacodynamic effect and virulent effect of Tripterygium wilfordii based on network pharmacology].
To investigate the pharmacodynamic effect and virulent effect of the main components of the toxic Chinese medicine Tripterygium wilfordii,such as triptolide,tripchlorolide,tripterine,demethylzeylasteral,wilfotrine and euonine,the admet SAR online assessment system was used to calculate the properties of the main components of T. wilfordii. The potential targets of the components were mined and collected through multiple databases,and the potential targets were enriched by the bioinformatics database DAVID.Cytoscape software was used to establish a " target-pathway" network and perform topology analysis on the network. The main chemical components of T. wilfordii were able to penetrate the blood-brain barrier and had intestinal permeability. A total of 65 targets were predicted,including pathways in cancer,hepatitis B,rheumatoid arthritis,and chagas disease( American trypanosomiasis),Toll-like receptor signaling pathway,apoptosis,colorectal cancer,NF-kappa B signaling pathway,etc. T. wilfordii mainly plays a role in the treatment of immune diseases and cancer by regulating inflammatory signaling pathways and cancer signaling pathways. Its action on apoptosis pathway and drug metabolism enzymes may be the mechanism of its toxicity.


Role of "diseased" root cementum in healing following treatment of periodontal disease. A clinical study.
This clinical trial was undertaken to examine whether root debridement in the treatment of periodontal disease must include the removal of the exposed cementum in order to achieve periodontal health. The study included 11 adult patients with moderate to advanced periodontal disease. In a split-mouth design, the dentition of each patient was by random selection divided into test- and control quadrants comprising the incisors, canines and premolars. Following a baseline examination, all patients were given a case presentation and a detailed instruction in self-performed oral hygiene measures. The patients were then subjected to periodontal surgery. Following reverse bevel incisions, buccal and lingual mucoperiosteal flaps were elevated and all granulation tissue was removed. In 2 jaw quadrants (control quadrants) in each patient, the denuded root surfaces were carefully scaled and planed in order to remove soft and hard deposits as well as all cementum, using hand instruments and flame-formed diamond stones. In the contralateral quadrants (test quadrants) the roots were not scaled and planed but soft microbial deposits were removed by polishing the root surfaces with the but soft microbial deposits were removed by polishing the root surfaces with the use of rubber cups, interdental rubber tips and a polishing paste. Calculus in the test quadrants was removed by the use of a curette, but precaution was taken to avoid the removal of cementum. The flaps were repositioned to their original level and sutured. The patients were following active treatment enrolled in a supervised maintenance care program including "professional tooth cleaning" once every 2 weeks for a 3-month period.(ABSTRACT TRUNCATED AT 250 WORDS)


Predictors of emotional outcomes of intensive care.
Negative emotional outcomes (anxiety, depression and post-traumatic stress) have been identified in patients discharged from intensive care. The aims of this prospective, longitudinal study were to assess levels of and changes in emotional outcome after intensive care, and to explore how these relate to objective and subjective indicators of the intensive care experience. Emotional outcome was assessed using the Hospital Anxiety and Depression and Impact of Event Scales. Anxiety (p = 0.046) and depression (p = 0.001) were reduced subsequently, but not avoidance (p = 0.340) or intrusion (p = 0.419). Most objective (age, gender, length of ICU and hospital stay) and subjective indicators (as measured by the Intensive Care Experience Questionnaire) of the intensive care experience were related to negative emotional outcome. Subjective interpretation of the intensive care experience emerged as a consistent predictor of adverse emotional outcome, in both the short- and the long-term.


Evidence for a defect in "switch" T cells in patients with immunodeficiency and hyperimmunoglobulinemia M.
Immunodeficiency with hyperimmunoglobulinemia M is a syndrome characterized by normal to elevated serum levels of IgM and low levels or absence of IgG and IgA. The defect in this syndrome is thought to reside within the B lymphocyte, which may be unable to undergo a "switch" in immunoglobulin class from IgM to IgG or IgA. To address this question more directly, we cultured B cells from nine patients with this syndrome with pokeweed mitogen and either "switch" T cells or normal control T cells. In cultures with normal T cells, only IgM was secreted, whereas in cultures with switch T cells, IgG as well as IgM, or IgM, IgG, and IgA were secreted. Furthermore, analysis of the immunoglobulin heavy-chain genes in these B cells by means of genetic probes of constant and switch regions revealed normal gene patterns. These data suggest that B cells from patients with hyperimmunoglobulinemia M may not be abnormal, as previously proposed, and that, at least in some patients with this syndrome, a defect in switch T cells may be pathogenic.


[Comparative morphometric study of the ultrastructure of cells in vivo and in vitro].
A morphometrical study of the fine structure of normal and malignant cells, both taken immediately from the organism (in vivo) or previously cultured (in vitro) was carried out. A high level on the mitochondrial morphological coefficient -- Km was discovered in normal and malignant cells in vitro. Unlike, the ergastoplasmic morphological coefficient -- Ke was high in the in vivo cells and low in the in vitro cells. The in vitro factor causes considerable changes in the fine structure of cells, which are more important than distinctions between normal and malignant cells. This fact must be taken into account in morphological studies of cells in vitro.


Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer's agents.
Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults. Pathogenic factors, such as oxidative stress, an increase in acetylcholinesterase activity, mitochondrial dysfunction, genotoxicity, and neuroinflammation are present in this syndrome, which leads to neurodegeneration. Neurodegenerative pathologies such as Alzheimer's disease are considered late-onset diseases caused by the complex combination of genetic, epigenetic, and environmental factors. There are two main types of Alzheimer's disease, known as familial Alzheimer's disease (onset < 65 years) and late-onset or sporadic Alzheimer's disease (onset ≥ 65 years). Patients with familial Alzheimer's disease inherit the disease due to rare mutations on the amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) genes in an autosomal-dominantly fashion with closely 100% penetrance. In contrast, a different picture seems to emerge for sporadic Alzheimer's disease, which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology. Importantly, the fundamental pathophysiological mechanisms driving Alzheimer's disease are interfaced with epigenetic dysregulation. However, the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer's disease or following injury or stroke in humans. In recent years, there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer's disease. Through epigenetic mechanisms, such as DNA methylation, non-coding RNAs, histone modification, and chromatin conformation regulation, natural compounds appear to exert neuroprotective effects. While we do not purport to cover every in this work, we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer's disease-related genes.


Amyotrophic lateral sclerosis: effects of acute intravenous and chronic subcutaneous administration of thyrotropin-releasing hormone in controlled trials.
We performed double-blind crossover trials to assess the effects of thyrotropin-releasing hormone (TRH) on amyotrophic lateral sclerosis patients. For acute intravenous trials, 500 mg TRH or placebo with norepinephrine was given at 1-week intervals (16 patients). CSF TRH concentration increased, and clinical side effects appeared with TRH. For chronic studies, 25 mg TRH and a saline placebo were given subcutaneously every day for 3 months (25 patients). CSF TRH level increased 29-fold after a single TRH injection, and mild transient side effects occurred. Vital signs, respiratory function, semiquantitative and quantitative neurologic function, muscle strength by manual and dynamometer testing, and EMG were studied. With daily TRH, 10 patients noted subjective improvement without objective evidence, and 10 patients complained of worsening of the disease with objective decline after TRH was stopped. Statistical analysis, however, showed no beneficial effects from either acute or chronic TRH trials.


Phytochemical compositions of extract from peel of hawthorn fruit, and its antioxidant capacity, cell growth inhibition, and acetylcholinesterase inhibitory activity.
Hawthorn fruit (HF) is a well-known traditional medicine in China with the effects of improving digestion and regulating qi-flowing for removing blood stasis. Modern pharmacological experiments showed that HF extract has various pharmaceutical properties and flavonoids are considered as the main bioactive compounds. In this paper, Diaion HP-20 adsorption chromatography was used to enrich flavonoids in PHF, and the phytochemical composition of EPHF was analyzed by high performance liquid chromatography (HPLC) and liquid chromatography tandem mass spectrometry (LC-MS). In addition, EPHF's antioxidant capacity, acetylcholinesterase (AChE) inhibitory activity and cytotoxic activity were evaluated. EPHF was obtained by Diaion HP-20 adsorption chromatography. Phytochemical composition of EPHF was analyzed qualitatively and quantitatively using HPLC and LC-MS. Radical scavenging capacity of EPHF was estimated using 2,2-diphenyl-1-picryhydrazyl (DPPH) assay and oxygen radical absorbance capacity (ORAC) assay. The AChE inhibitory activity of EPHF was evaluated by Ellman method. Cytotoxic activity of EPHF was assessed by means of MTT assay. Eight kinds of components were identified, in which ideain with the value of 179.4 mg/g was identified to be present in the highest level in EPHF, followed by (-)-epicatechin, chlorogenic acid, cyanidin 3-arabinoside, hyperoside and isoquercitrin at the concentrations of 40.9, 10.0, 1.4, 0.4 and 0.2 mg/g, respectively. The contents of these compounds in EPHF were much higher than those in PHF and HF. In addition, EPHF exhibited strong antioxidant and AChE inhibitory activity (ORAC value: 11.65 ± 2.37 μM Trolox equivalents (TE)/mg, DPPH IC50 value: 6.72 μg/mL, anti-AChE activity IC50 value: 11.72 μg/mL) compared with PHF and HF. Moreover, EPHF exhibited high levels of cytotoxicity on MCF-7 and SKOV-3 human tumour cell lines in a dose-dependent manner with the IC50 of 2.76 and 80.11 μg/mL, respectively. Macroporous resin is useful for the extraction and separation of the total flavonoids from PHF. The contents of flavonoids especially anthocyanin in EPHF were increased significantly compared with the PHF, and EPHF exhibited strong antioxidant, AChE inhibitory activity and cytotoxicity on human tumour cells.


Drivers of calcium oxalate stone formation in the octogenarian population.
American Urological Association (AUA) guidelines suggest metabolic testing via 24-h urine studies in high-risk, interested first-time stone formers, and recurrent stone formers. If metabolic testing is not available or otherwise not feasible, clinicians may need to utilize empiric therapy. Debility and social barriers, particularly in the elderly population, may limit the practicality of metabolic testing, and therefore, empiric therapy is of particular importance. The aim of this study is to identify whether unique urinary metabolic abnormality profiles exist for octogenarians with calcium oxalate kidney stones, as this may guide empiric stone prevention therapy more precisely in this population. Patients with calcium oxalate stones from a single academic kidney stone center in New York, NY, were retrospectively identified in our prospectively managed database. Patient data, including demographic, clinical information, and baseline 24-h urine studies, were collected before initiating any treatment. Subjects were stratified by age (≤ 40, 41-59, 60-79, and ≥ 80 years) to compare the metabolic urinary abnormality profiles between octogenarians and other age groups. Subgroup analyses were also performed to compare results by gender and by the presence of underlying kidney dysfunction. Comparative statistical analysis was carried out using Chi-square tests, Mann-Whitney U tests, and t-tests where appropriate. Hypocitraturia, low urine pH, and low urine volume were most common in older patients, particularly in octogenarians. Hypercalciuria, hypernatriuria, and hyperuricosuria were more apparent in younger groups. With increasing age, hypocitraturia, low urine pH, and low urine volume were more prevalent on 24-h urine metabolic testing. We hypothesize increased comorbidity, including medical renal disease, polypharmacy, and dehydration are possible factors contributing to this unique profile. We suggest that empiric therapy targeted towards this profile is important in very elderly stone formers in whom 24-h urine testing may not be possible. Increased hydration, increased fruit and vegetable intake, and low-dose alkali therapy are easy measures to accomplish this.


Studying critical values: adverse event identification following a critical laboratory values study at the ohio state university medical center.
No study to date has used laboratory critical values to evaluate variations in patient adverse events. We retrospectively analyzed a database of critical values to determine their distribution by hospital unit over time. The data were drawn from the Ohio State University Medical Center Information Warehouse (Columbus) for a 58-month period. Critical values were plotted over time on statistical control charts and analyzed for unusual peaks in monthly occurrence rates. Chart review of individual patient results yielded several predictor variables for the unusual peaks. Of these, occurrence of patient adverse events was the most relevant independent predictor variable for a month with an unusual number of critical values vs a normal month. This result epidemiologically confirms the basic premise of critical value reporting and suggests that the control-chart method of this type could be a new statistical tool to compare clinical activity of different hospital locations at different times.


A trial of oral nifedipine and oral labetalol in preeclampsia hypertensive emergency treatment.
This observational retrospective cohort study was conducted to compare oral nifedipine and labetalol for emergency treatment of hypertension in preeclamptic patients. Time (minutes) and necessary doses were outlined to achieve blood pressure lower than 150/95 mmHg. In 14 patients with preeclampsia, 55 hypertensive emergencies were identified (BP >150/95). Of these emergencies, 43 were treated with oral nifedipine 10 mg (10 patients) and 12 with oral labetalol 100 mg (4 patients). To achieve a target blood pressure under 150/95, these doses were repeated as necessary every 20 min, up to a maximum of 4 doses. Oral nifedipine reduced BP more rapidly (31.30 vs. 53.50 min, p = .03). No maternal or foetal adverse events were observed and no major differences were found according to the type of delivery. Oral nifedipine is faster than and at least as safe as labetalol in pre-eclampsia hypertensive emergency treatment.


Hypoglycemic and hypolipidemic effects of blueberry anthocyanins by AMPK activation: In vitro and in vivo studies.
Blueberries are rich in bioactive anthocyanins, with a high level of malvidin, which is associated with antioxidant benefits that contribute to reducing the risk of diabetes. The objective of this study was to investigate the hypoglycemic and hypolipidemic effects of blueberry anthocyanin extract (BAE), malvidin (Mv), malvidin-3-glucoside (Mv-3-glc), and malvidin-3-galactoside (Mv-3-gal) in both human hepatocarcinoma cell line HepG2 and in a high-fat diet combining streptozotocin-induced diabetic mice. High glucose treatment significantly increased hepatic oxidative stress up to 6-fold and decreased HepG2 cell viability. Pretreatment with BAE, Mv, Mv-3-glc and Mlv-3-gal significantly mitigated these damages by lowering the reactive oxygen species (ROS) by 87, 80, 76, and 91%, and increasing cell viability by 88, 79, 73, and 98%, respectively. These pretreatments also effectively inhibited hyperglycemia and hyperlipidemia, respectively by reducing the expression levels of enzymes participating in gluconeogenesis and lipogenesis and enhancing those involved in glycogenolysis and lipolysis, via adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in HepG2 cells. To determinate the role of AMPK in BAE-induced reaction of glucose and lipid metabolism in vivo, doses of 100 mg/kg (blueberry anthocyanin extracts - low concentration, BAE-L) and 400 mg/kg (blueberry anthocyanin extracts - high concentration, BAE-H) were administrated per day to diabetic mice for 5 weeks. BAE treatments had a significant (P < 0.05) effect on body weight and increased the AMPK activity, achieving the decrease of blood- and urine-glucose, as well as triglyceride and total cholesterol. This research suggested that anthocyanins contributed to the blueberry extract-induced hypoglycemia and hypolipidemia effects in diabetes and BAE could be a promising functional food or medicine for diabetes treatment.


[Transurethral echography in the staging of bladder neoplasms].
Forty vesical neoplasias in various stages and which were treated through transurethral resection followed by chemotherapy, in accordance to the currently accepted approach, were studied using transurethral ultrasound techniques. A histochemical correlation is established based on the proposed U.I.C.C. grading (T.N.M.). Such correlation coincides in 88.2% of cases for the "unified" Ta-T1 stage; 70% for T2; 88.8% for T3; and 100% for T4.


Repeated dose 28-day oral toxicity study of DEAE-Dextran in mice: An advancement in safety chemotherapeutics.
Cancer has emerged as a global threat with challenges for safe chemotherapeutics. Most of the currently available anti-cancer drugs exhibit significant toxicity. Amongst novel agents, interferons have exhibited anti-proliferative and cytoprotective roles. However, due to stability drawbacks of interferons, we have identified an interferon inducer DEAE-Dextran, which resolves the stability issues. Based on the previous history of toxicity pertaining to the current chemotherapeutic agents, it is equally essential to determine the safety of DEAE-Dextran. In the present study, repeated dose 28 day oral toxicity of DEAE-Dextran has been evaluated in accordance to OECD-407. We found absence of any CNS behavioral changes related to self-mutilation, walking backwards, aggressiveness on handling or tonic-clonic seizures during the 28 day study. Neither the motor activity nor grip strength was altered during the treatment duration with DEAE-Dextran implying absence of any effect on the skeletal muscles. Interestingly, we also found that treatment with DEAE-Dextran did not present any significant cardiac, hepatic, renal, gastrointestinal, lymphatic or reproductive system toxicity or alteration in the body's normal physiology based upon the various organ function tests. Henceforth, it may be concluded that DEAE-Dextran is a safe anti-cancer agent devoid of any sub-acute toxicity.


Functional veloplasty in bilateral palatal palsy.
A new technique for the treatment of bilateral palatal palsy involves the submucosal transposition of the tensor palati muscles of both sides to form an active muscular sling for the elevation of the paralyzed soft palate. The effect of the rerouted tensor palati muscle on Eustachian tube function and its efficacy as a substitute for the levator palati muscle in lifting the soft palate was evaluated by animal experimentation. Subsequently, two patients with bilateral palatal palsy, who failed to show improvement during a six-month period, were treated successfully with this new surgical technique, "functional veloplasty", without complication.


Comparison of clinical characteristics of opium-induced and independent major depressive disorder.
Psychiatric disorders and among them depression are common in substance dependent patients. The aim of this study is to compare the clinical characteristics of those that appear to have substance-induced depression and those that have independent major depression. One-hundred eighty-four independent and 187 opium-induced (OID) depressed male patients that met the DSM-IV criteria for major depressive disorder were randomly selected. Standard demographic data, including age, marital, employment and education status, were collected. The primary measure of depressive signs and symptoms was Hamilton Depression Scale (HAMD-21). The two groups were compared with each other for the HAMD total and subscales scores. The two groups were matched regarding age, educational level and marital status. Opium-induced depressed patients were more severely depressed and motor retarded and also they had more social and occupational problems. Gastrointestinal, sexual and somatic complaints were more common among them too. MDD patients had better insight than the other group. The results demonstrate that it is possible to differentiate between substance-induced and independent depression. Such differentiation might be important for establishing prognosis and optimal treatment.


New cembranoid diterpenes from the Vietnamese soft coral Sarcophyton mililatensis stimulate osteoblastic differentiation in MC3T3-E1 cells.
Chemical investigation of the Vietnamese soft coral Sarcophyton mililatensis resulted in the isolation of four new cembranoid diterpenes, namely (-)-7beta-hydroxy-8alpha-methoxydeepoxysarcophytoxide (1), (+)-7beta,8beta-dihydroxydeepoxysarcophytoxide (2), (-)-17-hydroxysarcophytonin A (3) and sarcophytol V (4), along with two known compounds, (+)-sarcophine (5) and sarcophytoxide (6). The NMR spectral data of the new compounds were completely assigned by using a combination of 2D NMR experiments including (1)H-(1)H COSY, HSQC, HMBC, and ROESY. To investigate the bioactivities of compounds, which act on bone metabolism, we studied the effects of compounds on the function of osteoblastic MC3T3-E1 cells. Compound 1 caused a significant elevation of alkaline phosphatase activity, collagen content, and nodules mineralization compared to those of the control (p<0.05). These results suggest that newly isolated compound 1 has a direct stimulatory effect on bone formation in vitro and may contribute to the prevention for osteoporosis.