Cardiac Magnetic Resonance Imaging Versus Invasive-Based Strategies in Patients With Chest Pain and Detectable to Mildly Elevated Serum Troponin: A Randomized Clinical Trial.
The optimal diagnostic strategy for patients with chest pain and detectable to mildly elevated serum troponin is not known. The objective was to compare clinical outcomes among an early decision for a noninvasive versus an invasive-based care pathway. The CMR-IMPACT trial (Cardiac Magnetic Resonance Imaging Strategy for the Management of Patients with Acute Chest Pain and Detectable to Elevated Troponin) was conducted at 4 United States tertiary care hospitals from September 2013 to July 2018. A convenience sample of 312 participants with acute chest pain symptoms and a contemporary troponin between detectable and 1.0 ng/mL were randomized early in their care to 1 of 2 care pathways: invasive-based (n=156) or cardiac magnetic resonance (CMR)-based (n=156) with modification allowed as the patient condition evolved. The primary outcome was a composite including death, myocardial infarction, and cardiac-related hospital readmission or emergency visits. Participants (N=312, mean age, 60.6 years, SD 11.3; 125 women [59.9%]), were followed over a median of 2.6 years (95% CI, 2.4-2.9). Early assigned testing was initiated in 102 out of 156 (65.3%) CMR-based and 110 out of 156 (70.5%) invasive-based participants. The primary outcome (CMR-based versus invasive-based) occurred in 59% versus 52% (hazard ratio, 1.17 [95% CI, 0.86-1.57]), acute coronary syndrome after discharge 23% versus 22% (hazard ratio, 1.07 [95% CI, 0.67-1.71]), and invasive angiography at any time 52% versus 74% (hazard ratio, 0.66 [95% CI, 0.49-0.87]). Among patients completing CMR imaging, 55 out of 95 (58%) were safely identified for discharge based on a negative CMR and did not have angiography or revascularization within 90 days. Therapeutic yield of angiography was higher in the CMR-based arm (52 interventions in 81 angiographies [64.2%] versus 46 interventions in 115 angiographies [40.0%] in the invasive-based arm [P=0.001]). Initial management with CMR or invasive-based care pathways resulted in no detectable difference in clinical and safety event rates. The CMR-based pathway facilitated safe discharge, enriched the therapeutic yield of angiography, and reduced invasive angiography utilization over long-term follow-up. URL: https://www. gov; Unique identifier: NCT01931852.


CUL4B promotes aggressive phenotypes of renal cell carcinoma via upregulating c-Met expression.
Cullin 4B (CUL4B), encoding a scaffold protein in Cullin RING ubiquitin-ligase complexes (CRL4B), is overexpressed and serves as an oncogene in various solid tumors. However, the roles and the underlying mechanisms of CUL4B in renal cell carcinoma (RCC) are still unknown. In this study, we demonstrated that CUL4B was significantly upregulated in RCC cells and clinical specimens, and its overexpression was correlated with poor survival of RCC patients. Knockdown of CUL4B resulted in the inhibition of proliferation, migration and invasion of RCC cells. Furthermore, we found that the expression of CUL4B is positively correlated with c-Met expression in RCC cells and tissues. Konckdown of c-Met or treatment with c-Met inhibitor, SU11274, could block the increase in cell proliferation, migration and invasion induced by CUL4B-overexpression. We also showed that CUL4B overexpression significantly accelerated xenograft tumor growth, and administration of SU11274 could also abrogate the accelerated tumor growth induced by CUL4B overexpression in vivo. These findings shed light on the contribution of CUL4B to tumorigenesis in RCC via activating c-Met signaling and its therapeutic implications in RCC patients.


Gestural praxis in young adults with mild to moderate intellectual disabilities.
Praxis functioning in the population with intellectual disabilities (ID) has been poorly studied. The goal of this research was to look for a starting point to study the praxic functioning in young adults with mild to moderate ID. Thirty young adults with ID and 30 young adults without ID, between the ages of 18 and 35 years, participated in this study. All participants completed tests that assessed gestural praxis. It was possible to observe similar praxis behaviour in the group with ID in almost all domains studied, albeit showing statistical values lower than those of the group without ID. Despite the high number of errors committed, the sample of participants with ID was able to reach the goal of praxic tasks performed; such errors may be associated with a deficit in the development of various brain functions and not only with praxis functioning, mainly related to a lower yield in terms of planning, monitoring and correcting intentional movement.


The effects of Lichtenstein tension-free mesh hernia repair on testicular arterial perfusion and sexual functions.
Lichtenstein tension-free mesh hernia repair has been gold standard for treatment of inguinal hernia. Studies have demonstrated that the complication rate is low. However, because the structures in spermatic cord pass through a narrow space, there has been concern about injury to testicular artery, vein, and vas deferens. The aim of this study was to evaluate the effects of Lichtenstein tension-free mesh hernia repair on testicular arterial perfusion and sexual functions in early phase after the operation. Forty male patients underwent tension-free mesh hernia repair. All of them underwent Lichtenstein tension-free mesh hernia repair under spinal anesthesia. Patients were evaluated for local wound complications such as seroma, hematoma, and infection on days 1 and 7. To evaluate the effects of surgery on sexual activity, pain was graded on a scale of 1 to 10 by visual analog scale (VAS). International Index of Erectile Dysfunction (IIEF-5) questionnaire was used in our study to evaluate sexual dysfunction. Testicular arterial flow was reevaluated by Doppler ultrasound. Patients were questioned about erectile dysfunction and sexual satisfaction as well as pain limiting their daily activities and sexual function. Mean operation time was 38 ± 5 (23-122) minutes. Preoperative/postoperative mean flow velocity for operation side (ipsilateral) was 5.13 ± 2.7 ml/min and 6.3 ± 2.3 ml/min respectively and the difference was statistically significant (p = 0.008). VAS scores in preoperative and postoperative periods were compared and had mean values of 0.6 ± 1.4 and 0.8 ± 1.7 respectively and the difference was not statistically significant. Lichtenstein tension-free mesh hernia repair does not have any negative effects on testicular perfusion and sexual function; it can be performed safely for treatment of inguinal hernia.


[Internet resources for radiologists : a positive selection].
In radiology the use of internet resources is part of the daily routine. The critical selection of but not the access to radiologically relevant information is the key topic in internet use. We offer a selection of reviewed internet sources for radiologists. We present sources that offer guidance in decision-making in daily routine as well as internet sources on technical topics in radiology. Case selection and radiological search engines are helpful sites to begin an internet research. Online anatomy sites can be of assistance for interpretation of findings in radiology. Writing and publishing scientific works in radiology requires access to numerous internet services, a positive selection of which are reviewed in the present article. A variety of freeware is available on the internet, some of which may be a substantial benefit to projects in radiology.


Intravascular Renal Denervation Reduces Ambulatory and Office Blood Pressure in Patients with Essential Hypertension: A Meta-Analysis of Randomized Sham-Controlled Trials.
This meta-analysis was designed to evaluate the antihypertensive efficacy of intravascular renal denervation (RDN) in patients with essential hypertension, especially to determine the magnitude of blood pressure (BP) reduction with RDN therapy using second-generation catheters. PubMed was searched to identify randomized sham-controlled trials from inception through August 2021. The endpoints were changes in 24-h ambulatory BP or office BP. This meta-analysis was performed by calculating the weighted mean difference (WMD) with 95% confidence interval (CI) using the random-effects model when the I2 index was <50%. A fixed-effects model was used when the I2 index was ≥50%. A total of 1,297 patients were included in 8 randomized, sham-controlled trials in this meta-analysis. Intravascular RDN reduced 24-h ambulatory systolic BP (SBP) -3.02 (WMD, 95% CI: -4.95, -1.10, p < 0.01) and diastolic BP (DBP) -1.66 (WMD, 95% CI: -2.44, -0.88, p < 0.001) mm Hg, respectively. In the studies using first-generation catheters, the WMDs of 24-h ambulatory SBP and DBP changes between intravascular RDN and sham control were -2.67 (95% CI: -5.08, -0.27; p < 0.05; I2 = 0%, p = 0.53) and -0.82 (95% CI: -2.19, 0.56; p > 0.05; I2 = 0%, p = 0.64) mm Hg. In the studies using second-generation catheters, the WMDs of 24-h ambulatory SBP and DBP changes between intravascular RDN and sham control were -3.14 (95% CI: -5.94, -0.33, p < 0.05; I2 = 71%, p = 0.008) and -2.06 (95% CI: -3.02, -1.11, p < 0.001; I2 = 50%, p = 0.09) mm Hg. Intravascular RDN using second-generation catheters reduced office SBP -6.30 (WMD, 95% CI: -7.67, -4.93, p < 0.001; I2 = 43%, p = 0.14) and DBP -3.88 (WMD, 95% CI: -4.44, -3.33, p < 0.001; I2 = 42%, p = 0.14) mm Hg, respectively. Intravascular RDN using second-generation catheters reduces ambulatory and office BP in patients with essential hypertension. The selection of appropriate hypertensive patients may be the major challenge for the performance of intravascular RDN in routine clinical practice.


Effect of the interfacial tension and ionic strength on the thermodynamic barrier associated to the benzocaine insertion into a cell membrane.
The insertion of local anaesthetics into a cell membrane is a key aspect for explaining their activity at a molecular level. It has been described how the potency and response time of local anaesthetics is improved (for clinical applications) when they are dissolved in a solution of sodium bicarbonate. With the aim of gaining insight into the physico-chemical principles that govern the action mechanism of these drugs at a molecular level, simulations of benzocaine in binary lipid bilayers formed by DPPC/DPPS were carried out for different ionic strengths of the aqueous solution. From these molecular dynamic simulations, we observed how the thermodynamic barrier associated with benzocaine insertion into the lipid bilayers diminished exponentially as the fraction of DPPS in the bilayer increased, especially when the ionic strength of the aqueous solution increased. In line with these results, we also observed how this thermodynamic barrier diminished exponentially with the phospholipid/water interfacial tension.


Systemic lupus erythematosus and small vessel coronary infarction: who's to blame?
Systemic lupus erythematosus (SLE) with or without accompanying antiphospholipid antibody syndrome (APLS) is known to cause myocardial ischemia via multiple mechanisms, including accelerated coronary atherosclerosis, impaired coronary vasomotor function, spontaneous intracoronary thrombus formation, or endothelial dysfunction in the context of cardiac syndrome X (CSX). We present the case of a young woman with SLE and APLS who presented with myocardial ischemia and peculiar echocardiographic evidence of multiple small septal perforator infarcts despite a normal coronary angiogram, a rare combination.


Colonic varices due to intestinal cavernous hemangiomas.
Colonic varices are an unusual cause of rectal bleeding. Occurring most often in the setting of portal hypertension, colonic varices have also been linked to congenital vascular lesions. One such vascular lesion, the cavernous hemangioma, is rarely found in the bowel. We report a patient with cavernous hemangiomas involving skin, lower extremities, and gastrointestinal tract, who presented with chronic rectal bleeding from colonic varices. The progression of his hemangiomatous lesions over an 18-year course is documented. The association of colonic varices and hemangiomas of the bowel is discussed.


Correlation between scaffold in vivo biocompatibility and in vitro cell compatibility using mesenchymal and mononuclear cell cultures.
The aim of this study was to compare the cell compatibility of silk and polyglycolic acid (PGA) scaffolds cultured in vitro with mesenchymal stem cells (MSCs) and peripheral blood mononuclear cells (PBMCs) to their biocompatibility in vivo following implantation. Scaffolds were knitted with silk or PGA thread and the average efficiency of cell attachment was 35 +/- 4% and 17 +/- 2% in the PGA and silk scaffold groups. Thus, the initial attachment of the MSC cells to the PGA scaffold was superior to the initial attachment of the cells on the silk scaffold. After 21 days in culture, the average cell density on the silk scaffold was 5.8 +/- 0.5 x 10(5) cells, and the average cell density of the PGA scaffolds was 6.34 +/- 0.5 x 10(5) cells. In addition, there was no cell cytoxicity observed with either scaffold. However, the immune response of in vitro cultured PBMCs was significantly higher with the PGA scaffold than with the silk scaffold. The proliferation of the PBMCs cultured on the PGA scaffold was two times greater than that of those cultured on the silk scaffold after 3 days of culture. In addition, the secretion of IL-1 by the PBMCs cultured on the PGA scaffold was superior to that of the PBMCs cultured on the silk scaffold. The secretion of IL-1beta and IFN-gamma was increased by about 50% when the PBMCs were cultured with the PGA scaffold. Silk and PGA scaffolds were also implanted subcutaneous in rats. Histological evaluation of the scaffold explants revealed the presence of monocytes and macrophages in PGA scaffold. The inflammatory tissue reaction was more conspicuous on the PGA scaffold than on the silk scaffold. These results suggest that the results of in vitro PBMC cultures were more closely related to the in vivo results of implantation than the results of in vitro MSC cultures.


Political dimensions of 'the psychosocial': The 1948 International Congress on Mental Health and the Mental Hygiene Movement.
The Foucauldian sociologist Nikolas Rose has influentially argued that psychosocial technologies have offered means through which the ideals of democracy can be made congruent with the management of social life and the government of citizens in modern Western liberal democracies. This interpretation is contested here through an examination of the 1948 International Congress on Mental Health held in London and the mental hygiene movement that organised it. It is argued that, in Britain, this movement's theory and practice represents an uneasy and ambiguous attempt to reconcile visions of 'the modern' with 'the traditional'. The mental hygienist emphasis on the family is central. Here it appears as a forcing-house of the modern self-sustaining individual. Mental hygienists cast the social organisation of 'traditional' communities as static, with rigid authority frustrating both social progress and the full emergence of individual personality. Yet mental hygienists were also concerned about threats to social cohesion and secure personhood under modernity. If the social organisation of 'traditional' communities was patterned by the archetype of the family, with its personal relations of authority, mental hygienists compressed these relations into the 'private' family. Situated here they became part of a developmental process of mental adjustment through which 'mature', responsible citizens emerged. This reformulation of the family's centrality for the social order informed mental hygienist critiques of the growth of state power under existing forms of democracy, as well as suspicion of popular political participation or protest, and of movements towards greater egalitarianism.


The sound of blood: photoacoustic imaging in blood analysis.
Blood analysis is a ubiquitous and critical aspect of modern medicine. Analyzing blood samples requires invasive techniques, various testing systems, and samples are limited to relatively small volumes. Photoacoustic imaging (PAI) is a novel imaging modality that utilizes non-ionizing energy that shows promise as an alternative to current methods. This paper seeks to review current applications of PAI in blood analysis for clinical use. Furthermore, we discuss obstacles to implementation and future directions to overcome these challenges. Firstly, we discuss three applications to cellular analysis of blood: sickle cell, bacteria, and circulating tumor cell detection. We then discuss applications to the analysis of blood plasma, including glucose detection and anticoagulation quantification. As such, we hope this article will serve as inspiration for PAI's potential application in blood analysis and prompt further studies to ultimately implement PAI into clinical practice.


An immunocytochemical study of lymphocyte and macrophage populations in the bone marrow of patients with non-Hodgkin's lymphoma.
Pairs of bone marrow trephine samples from 67 patients with known or suspected non-Hodgkin's lymphoma (NHL) were collected. One sample was processed for morphological examination, the other for frozen section immunohistology, using a panel of monoclonal antibodies (MAB) reacting with lymphocyte and macrophage determinants, detected by the immuno-alkaline-phosphatase (APAAP) method. Forty-one cases showed definite (36) or suspected (5) involvement of the marrow by NHL. Most were examples of lymphocytic or centroblastic/centrocytic NHL. The pattern of immunostaining confirmed the presence of NHL in these cases: the phenotype of the neoplastic cells was broadly consistent with nodal histology, where available. In ten cases, the marrow showed no evidence of involvement by NHL, and in 15, the eventual diagnosis was an abnormality of the myeloid series. These two groups of marrows not involved by NHL both showed a 'reactive' pattern of immunostaining, comprising polyclonal B-cells, T-helper and suppressor/cytotoxic cells and macrophages. We conclude that immunohistological examination of the bone marrow is useful in cases where the specimen shows morphological evidence of NHL, including those that are only 'suspect', but does not detect lymphoma where there is no morphological evidence of involvement.


A proteasome inhibitor produced by Burkholderia pseudomallei modulates intracellular growth.
The NRPS/PKS cluster encodes the enzymes necessary for glidobactin synthesis it is partially conserved in various members of the Burkholderia genus including B. pseudomallei. In this study we have shown that the insertional inactivation or deletion of glbC in this cluster in B. pseudomallei could reduce the ability of the bacterium to survive or grow in murine macrophages or in human neutrophils. Exogenously added proteasome inhibitors were able to chemically complement the mutation. The insertional inactivation or deletion of glbC increased virulence in an acute model of infection in Balb/c or C57BL/6 mice but virulence in a chronic model of infection was similar to that of the wild type. Our findings contrast with the previous finding that inactivation of the glb gene cluster in B. pseudomallei strain 1026b resulted in marked attenuation, and provides evidence of differential roles for some genes in virulence of different strains of B. pseudomallei.


Absolute and relative grip strength as predictors of cancer: prospective cohort study of 445 552 participants in UK Biobank.
Reduced muscular strength, as measured by absolute grip strength, has been associated with increased risk of some site-specific cancers. The ability of grip strength to predict other diseases may be affected by whether it is expressed in absolute or relative terms, but the evidence for cancer is scarce. This study compared the associations of absolute and relative grip strength with all-cause and 15 site-specific cancers. A prospective cohort study was undertaken using data from the UK Biobank. The exposure variable was grip strength, in absolute form (kilogrammes) and relative to weight, body mass index (BMI), height. and body fat mass. The outcome was incident cancer, at 15 sites and overall. Cox proportional hazard models were performed to study the associations. This study included 445 552 participants, where 53.8% of the participants were women, with a mean (SD) age of 56.3 (8.11) years. During a median of 8.8 years follow-up period, 48 886 (11.0%) patients were diagnosed with cancer. After adjusting for sociodemographic and lifestyle factors, as well as multiple testing, absolute grip strength was inversely and linearly associated with endometrial [hazard ratio (HR): 0.74, 95% confidence interval (CI): 0.69; 0.79, P value <0.001], gallbladder (HR: 0.81, 95% CI: 0.72; 0.92, P value = 0.001), liver (HR: 0.86, 95% CI: 0.79; 0.93, P value <0.001), kidney (HR: 0.93, 95% CI: 0.88; 0.99), and breast (HR: 0.93, 95% CI: 0.91; 0.96, P value = 0.031), as well as all-cause cancer (HR: 0.97, 95% CI: 0.95; 0.98, P value <0.001). Eight cancer sites were inversely associated with HGS relative to weight and BMI: endometrium, liver, gallbladder, kidney, oesophagus, pancreas, colorectal, breast, and all-cause cancer. Compared with absolute grip strength, grip strength relative to body fat mass had better discriminatory power for head and neck and breast cancer. Grip strength relative to BMI was marginally better than absolute grip strength in predicting stomach cancer. Grip strength was associated with risk of several site-specific cancers and all-cause cancer. Head and neck and breast cancers might be better predicted by relative grip strength.


Correlation of p53 mutations with epidermal growth factor receptor overexpression and absence of mdm2 amplification in human esophageal carcinomas.
Esophageal carcinomas from 24 patients, most of whom were smokers and consumed alcoholic beverages daily, were analyzed for mutations in exons 5-8 of the p53 tumor suppressor gene. Mutations were identified by polymerase chain reaction amplification and direct sequencing in 12 of 24 (50%) of the samples; almost half of the mutations were at A:T base pairs. Nuclear accumulation of p53 protein, determined by immunohistochemistry with the CM-1 polyclonal antibody, was observed in all cases in which a missense mutation in the p53 gene was detected. None of the 24 carcinomas had amplification of the mdm2 gene, an alternate pathway to p53 loss of function. Alterations involving three other cancer-related genes associated with human esophageal carcinogenesis, c-erbB-1/epidermal growth factor receptor (EGFR), c-myc, and retinoblastoma (Rb), were examined by Southern blot or immunohistochemical analysis in the same sample set to explore the possibility of a link between oncogene activation and loss of tumor suppressor function. While no associations were observed between amplification of the c-myc or EGFR genes and p53 abnormalities, a significant correlation (P < 0.01) was seen between the presence of p53 mutation and EGFR overexpression. Absence of Rb protein, measured immunohistochemically, was observed in four tumors, none of which had aberrations of the p53 gene.


The geographic pattern of Belgian mortality: can socio-economic characteristics explain area differences?
Country averages for health outcomes hide important within-country variations. This paper probes into the geographic Belgian pattern of all-cause mortality and wishes to investigate the contribution of individual and area socio-economic characteristics to geographic mortality differences in men aged 45-64 during the period 2001-2011. Data originate from a linkage between the Belgian census of 2001 and register data on mortality and emigration during the period 2001-2011. Mortality rate ratios (MRRs) are estimated for districts and sub-districts compared to the Belgian average mortality level using Poisson regression modelling. Individual socio-economic position (SEP) indicators are added to examine the impact of these characteristics on the observed geographic pattern. In order to scrutinize the contribution of area-level socio-economic characteristics, random intercepts Poisson modelling is performed with predictors at the individual and the sub-district level. Random intercepts and slopes models are fitted to explore variability of individual-level SEP effects. All-cause MRRs for middle-aged Belgian men are higher in the geographic areas of the Walloon region and the Brussels-Capital Region (BCR) compared to those in the Flemish region. The highest MRRs are observed in the inner city of the BCR and in several Walloon cities. Their disadvantage can partially be explained by the lower individual SEP of men living in these areas. Similarly, the relatively low MRRs observed in the districts of Halle-Vilvoorde, Arlon and Virton can be related to the higher individual SEP. Among the area-level characteristics, both the percentage of men employed and the percentage of labourers in a sub-district have a protective effect on the individual MRR, regardless of individual SEP. Variability in individual-level SEP effects is limited. Individual SEP partly explains the observed mortality gap in Belgium for some areas. The percentage of men employed and the percentage of labourers in a sub-district have an additional effect on the individual MRR aside from that of individual SEP. However, these socio-economic factors cannot explain all of the observed differences. Other mechanisms such as public health policy, cultural habits and environmental influences contribute to the observed geographic pattern in all-cause mortality among middle-aged men.


Prevention of cadmium-induced sterility by zinc in the male rat.
The potential of zinc (Zn) to antagonize the adverse effects of cadmium (Cd) on the male reproductive processes was studied. A significant reduction in the weights of the testis and epididymis, the testicular sperm population and oligospermia to azoospermia in the epididymis was recorded in rats treated once s.c. with 2 mg/kg Cd and sacrificed 20 days later. This was accompanied by a significantly reduced serum T and a loss of fertility. Administration of a single s.c. injection of Zn (80 mg/kg) did not alter significantly any of the reproductive parameters studied. On the other hand, Zn given 1/2 to 2 h after Cd resulted in partial recovery. Organ weights and sperm population in these groups were maintained and the fertility rate was 67% and 50% at 5 and 20 days as compared to 67% and 0% at corresponding period in Cd-exposed males. The protective effect diminished when Zn was given more than 2 h after Cd exposure. The most effective regimen of Zn therapy was an administration of a total dose of 80 mg/kg Zn given in 3 injections (15 mg/kg before, 50 mg/kg at the time and 15 mg/kg 2 h after Cd). The results provide evidence that Zn, if given before or within 2 h of Cd exposure, is capable of at least partially reversing its deleterious effects on spermatogenesis, steroidogenesis and fertility of the male rat.


Prevention of peridural fibrosis using a cyclooxygenase-2 inhibitor (nonsteroidal anti-inflammatory drug) soaked in absorbable gelatin sponge: an experimental comparative animal model.
Experimental study. To evaluate the efficacy and safety of peridural parecoxib-soaked absorbable gelatin sponge, and cellulose membrane on peridural fibrosis prevention in an animal model. Postoperative peridural fibrosis is one of the causes of failed back surgery syndrome. Nonsteroidal anti-inflammatory drugs inhibit the inflammatory response, while an absorbable gelatin sponge or cellulose membrane interposes between the dura and the paraspinal muscle to staunch the surgical bleeding. These mechanisms may prevent peridural fibrosis. Forty L5-L6 laminectomized adult Sprague-Dawley rats were randomly allocated into 4 groups. The high parecoxib group received 6 mg of parecoxib soaked into an absorbable gelatin sponge placed over the dura. The low parecoxib group was given 2 mg of parecoxib soaked into an absorbable gelatin sponge. The dura in the cellulose group was covered with a cellulose membrane, while the control group received normal saline drip before surgical wound closure. All rats were killed at 6 weeks for histopathological assessment. The fibroblast density, inflammatory cell density, fibrous adherence, and adverse events were quantified. The obtained results were analyzed statistically. The respective mean fibroblast density in the high parecoxib, low parecoxib, cellulose, and control groups was 217.77 ± 51.76, 317.51 ± 126.92, 321.80 ± 90.94, and 328.48 ± 73.41 cells/mm², while the respective mean inflammatory cell density was 539.65 ± 236.52, 910.17 ± 242.59, 1011.84 ± 239.30, and 1261.78 ± 319.68 cells/mm². The mean fibroblast and inflammatory cell densities of the high parecoxib group were significantly lower than the control. The high parecoxib group also showed statistically less fibrous adherence than low parecoxib, cellulose, and control groups. The high-dose parecoxib-soaked absorbable gelatin sponge can prevent peridural fibrosis without complications. The low-dose parecoxib and cellulose membrane provided no significant benefit vis-à-vis prevention of peridural fibrosis, as adduced from the lack of any statistically significant difference between the test and control rats.


Molecular bases and clinical spectrum of early infantile epileptic encephalopathies.
Epilepsy can be a challenging diagnosis to make in the neonatal and infantile periods. Seizures in this age group may be due to a serious underlying cause that results in an epileptic encephalopathy. Early infantile epileptic encephalopathy (EIEE) is a progressive neurologic condition that exhibits concomitant cognitive and motor impairment, and is often associated with severe intellectual disability. This condition belongs to the group of age-dependent epileptic encephalopathies, and thus the clinical and electro-encephalographic features change with age as the central nervous system evolves. The molecular bases and the clinical spectrum associated with the early infantile epileptic encephalopathies continue to expand as new genetic discoveries are made. This review will highlight the molecular etiologies of early infantile epileptic encephalopathy, and the clinical and electro-encephalographic changes that take place in these epileptic phenotypes as the brain develops.


Can Neuroscience Change the Way We View Morality?
Neuroscience has cast new light on the nature of human morality by exploiting simplified paradigms. To enhance our understanding of everyday moral decisions, the field should complement computational approaches with naturalistic paradigms and a focus on narratives and stories.


Carbamazepine induced pitch shift and octave space representation.
Octave-circular pitch perception, the repetition of pitch scale qualities when surpassing the octave interval, has been observed in behavioral data from humans and monkeys, but the underlying anatomy and physiology is still unknown. Here we analyze octave circularity in a concert pianist with absolute pitch, both under medication with the neurotropic drug carbamazepine (CBZ) and without medication. Analysis of 4619 responses in a pitch identification task revealed an internal tone-scale representation, based on the norm-tone scale re A4=440 Hz, with an octave-circular pattern of strongly and weakly represented tones. CBZ caused a global down-shift of pitch (ca. 1 semitone at 500 Hz), but no down-shift of the octave-circular pattern of tone characteristics. This pattern was similar in the six tested octave ranges (32.7-2093 Hz), both under the control and the CBZ condition. Pattern repetition always occurred at octave intervals and did not reflect the stretched octaves of piano tuning. The results indicate that CBZ influences pitch detection peripheral of an octave-circular pitch representation. Thus they support previous evidence for pitch detection in the auditory midbrain and for octave-circular pitch mapping in the auditory thalamus.


Overexpression of Fos-related antigen-1 in head and neck squamous cell carcinoma.
The activating protein-1 (AP-1) family of transcription factors has been implicated in the control of proliferation and differentiation of keratinocytes, but its role in malignant transformation is not clear. The aim of this study is to assess the pattern of mRNA expression of jun-fos AP-1 family members in 45 samples of head and neck squamous cell carcinomas (HNSCC) and matched adjacent mucosa by means of Northern blot analysis. Transcripts of all family members were identified, except for JunB that was detected only by means of reverse transcription polymerase chain reaction. Neither c-Fos nor JunD or FosB mRNA differed between tumours and normal tissues. We observed a strong Fos-related antigen-1 (Fra-1) and Fra-2 expression, but only Fra-1 mRNA densitometric values were higher in tumour, compared to normal adjacent mucosa (t-test, P = 0.006). A direct relationship between the positive expression of Fra-1 mRNA, above tumour median, was associated with the presence of compromised lymph nodes (Fischer exact test, P = 0.006). In addition, Fra-1 protein staining was assessed in a collection of 180 tumours and 29 histologically normal samples adjacent to tumours in a tissue array. Weak reactivity, restricted to the basal cell layer, was detected in 79% of tumour adjacent normal tissues, opposed to the intense reactivity of cancer tissues. In the subgroup of oral cancers, we have observed a shift in Fra-1 immunoreactivity, as long as the number of patients in each category, cytoplasmic or nuclear/cytoplasmic staining, was analysed (Fischer exact test, P = 0.0005). Thus, Fra-1 gene induction and accumulation of Fra-1 protein may contribute to the neoplastic phenotype in HNSCC.


An improved scheme on decoy-state method for measurement-device-independent quantum key distribution.
Quantum key distribution involving decoy-states is a significant application of quantum information. By using three-intensity decoy-states of single-photon-added coherent sources, we propose a practically realizable scheme on quantum key distribution which approaches very closely the ideal asymptotic case of an infinite number of decoy-states. We make a comparative study between this scheme and two other existing ones, i.e., two-intensity decoy-states with single-photon-added coherent sources, and three-intensity decoy-states with weak coherent sources. Through numerical analysis, we demonstrate the advantages of our scheme in secure transmission distance and the final key generation rate.


Case report: 3D intracranial vessel wall MRI in Susac syndrome: potential relevance for diagnosis and therapeutic management.
Susac syndrome (SS) is a rare immune-mediated vasculitis affecting retina, inner ear and brain. Assessment of central nervous system (CNS) involvement is currently based on standard brain magnetic resonance imaging (MRI) sequences. Accuracy of three dimensional (3D)-vessel wall imaging (VWI) was compared to standard sequences and contrast-enhanced-3D T2-fluid attenuated inversion recovery (CE-FLAIR) to assess CNS disease activity in two cases of definite SS. Brain MRI scan and retinal fluorescein angiogram (RFA) were performed at disease onset and at 1, 3, and 6 months after induction therapy start. CE-FLAIR and VWI based on 3D black-blood proton density weighted (PDW) with and without gadolinium were added to standard sequences on a 3 Tesla MRI scanner. Contrast enhanced-VWI (CE-VWI) detected an abnormal diffuse leptomeningeal enhancement (LME) in both cases at onset and during follow-up. Pathological enhancement on CE-VWI persisted at 6-month brain MRI, despite absence of new lesions and disappearance of LME on CE-FLAIR. Follow-up RFA revealed new arterial wall hyperfluorescence in both cases. VWI may represent a useful tool for diagnosing and monitoring CNS disease activity in SS patients, as confirmed by concordance with RFA, leading treatment's choice and timing. Moreover, CE-VWI seemed at least as sensitive as CE-FLAIR in detecting LME, possibly being superior to the latter in posterior fossa. LME remission might be not accurate in predicting suppression of CNS inflammation in SS.


Integrating network pharmacology, transcriptomics, and molecular simulation to reveal the mechanism of tert-butylhydroquinone for treating diabetic retinopathy.
Diabetic retinopathy (DR), a common microvascular complication of diabetes mellitus, is a significant cause of blindness. As one of the crucial factors in the pathogenesis of DR, oxidative stress provides new insights for the treatment of DR. Tert-butylhydroquinone (TBHQ), an efficient phenolic antioxidant, has been proved to inhibit diabetic retina injury. However, the mechanism of TBHQ for DR treatment is still unclear. The present study was designed to investigate the potential mechanism of TBHQ for treating DR. Firstly, the potential targets of TBHQ and DR were selected to construct protein-protein interaction network, which was applied to illustrate the potential mechanism of TBHQ against DR. Combined with transcriptomics and molecular simulation, the potential mechanisms were systematically verified. The results showed that TBHQ inhibited retinal microvascular injury by regulating oxidative stress, inflammation, cell proliferation-death regulation, and vascular system development. The mechanisms of these activities were associated with hypoxia-inducible factor-1 (HIF-1), nuclear factor-erythroid 2 related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), forkhead box O (FoxO), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and rhoptry-associated protein1 (Rap1) signaling pathways and their related targets nitric oxide synthase 3 (NOS3), mitogen-activated protein kinase 8 (MAPK8), prostaglandin-endoperoxide synthase 2 (PTGS2), and heme oxygenase 1 (HMOX1). In conclusion, a systematic perspective for the mechanism of TBHQ against DR was revealed by present study which lays a foundation for the application of TBHQ in treating DR.


The case against the case against group studies.
We challenge the position that only the analysis of single patients can allow us to infer normal function from impaired performance. We claim that the focus on group vs. single case studies is unprofitable and that a more useful question is how best to form abstractions of relevance to cognitive theory. In this context, we consider issues concerning the category of "agrammatism."


Highly multiplexed bioactivity screening reveals human and microbiota metabolome-GPCRome interactions.
The human body contains thousands of metabolites derived from mammalian cells, the microbiota, food, and medical drugs. Many bioactive metabolites act through the engagement of G-protein-coupled receptors (GPCRs); however, technological limitations constrain current explorations of metabolite-GPCR interactions. Here, we developed a highly multiplexed screening technology called PRESTO-Salsa that enables simultaneous assessment of nearly all conventional GPCRs (>300 receptors) in a single well of a 96-well plate. Using PRESTO-Salsa, we screened 1,041 human-associated metabolites against the GPCRome and uncovered previously unreported endogenous, exogenous, and microbial GPCR agonists. Next, we leveraged PRESTO-Salsa to generate an atlas of microbiome-GPCR interactions across 435 human microbiome strains from multiple body sites, revealing conserved patterns of cross-tissue GPCR engagement and activation of CD97/ADGRE5 by the Porphyromonas gingivalis protease gingipain K. These studies thus establish a highly multiplexed bioactivity screening technology and expose a diverse landscape of human, diet, drug, and microbiota metabolome-GPCRome interactions.


BF175 inhibits endometrial carcinoma through SREBP-regulated metabolic pathways in vitro.
Elevated lipogenesis is an important metabolic hallmark of rapidly proliferating tumor such as endometrial carcinoma (EC). The sterol regulatory element-binding protein 1 (SREBP1) is a master regulator of lipogenesis and involved in EC proliferation. BF175 is a novel chemical inhibitor of SREBP pathway, and has shown potent anti-lipogenic effects. However, the effect of BF175 on EC cells are yet to be determined. In the present study, we found that BF175 decreased cell viability, colony formation and migratory capacity, inducing autophagy and mitochondrial related apoptosis in EC cell line AN3CA. Z-VAD-FMK partially attenuated the effect of BF175 on AN3CA. In addition, BF175 significantly downregulated SREBPs and their downstream genes. The levels of free fatty acids and total cholesterol were also inhibited. Microarray analysis suggested BF175 treatment obviously affected lipid metabolic pathways in EC. Taken together, we validated BF175 exhibited anti-tumor activity by targeting SREBP-dependent lipogenesis and inducing apoptosis which mitochondrial pathway involved in, suggesting that it's potential as a novel therapeutic reagent for EC.


Decreased Serum Hepatocyte Growth Factor (HGF) in Individuals with Anxiety Increases After Zinc Therapy.
To assess serum Hepatocyte Growth Factor (HGF) levels in individuals with anxiety and to test the hypothesis that there is a relationship between HGF levels and zinc therapy. Serum from 19 individuals with anxiety and 19 controls were tested for serum HGF using ELISAs. HGF serum concentration in individuals with anxiety before zinc and anti-oxidant therapy was compared to levels after therapy. Zinc and copper levels in anxiety patients, pre and post therapy, were also measured and compared. Individuals with anxiety had significantly lower serum levels of HGF compared to controls (P = 0.0005). HGF concentration rose significantly (normalized) after zinc therapy (P = 0.04) and zinc levels increased significantly in these same patients (P = 0.0002). These results suggest an association between HGF serum levels and individuals with anxiety and demonstrate that zinc therapy is associated with increasing HGF levels.


Genetic Polymorphisms in Antioxidant Enzymes Modulate the Susceptibility of Idiosyncratic Antituberculous Drug-Induced Liver Injury and Treatment Outcomes in Patients with Tuberculosis.
The pathogenic mechanism of antituberculous drug-induced liver injury (ATDILI) is associated with antioxidant enzymes. The objective of the present study was to investigate the associations of ATDILI susceptibility with genetic polymorphisms of antioxidant enzyme genes including nitric oxide synthase 2 (NOS2), thioredoxin reductase 1 (TXNRD1), superoxide dismutase 2 (SOD2), BTB domain and CNC homolog 1 (BACH1), and MAF bZIP transcription factor K (MAFK). Thirty tag single nucleotide polymorphisms (tag-SNPs) from the all candidate genes were genotyped in a 2-stage cohort study including an initial discovery stage with 461 ATDILI patients and 466 controls and a replication stage with 216 ATDILI patients and 432 controls. The frequencies and distributions of genotypes and haplotypes were compared between the case and control groups. Three different genetic models including dominant, recessive, and additive models were used to determine the associations with susceptibility to ATDILI. The SNPs rs9906835, rs944725, and rs3794764 of the NOS2 gene were significantly associated with an increased risk of ATDILI. The MAFK rs3735656 SNP was significantly associated with a decreased risk for ATDILI. The AAA haplotype of the NOS2 gene was associated with susceptibility to ATDILI. The treatment outcomes of patients with tuberculosis were further affected by genetic variants of the NOS2 and MAFK genes. Genetic polymorphisms of NOS2 and MAFK are associated with ATDILI susceptibility in Chinese patients with tuberculosis. The variants in NOS2 and MAFK affect treatment outcomes of tuberculosis patients. Further studies are needed to better understand the molecular mechanisms of ATDILI susceptibility via regulation of the expression of ATDILI-susceptibility genes and proteins.


Improving Medical Students' Application of Knowledge and Clinical Decision-Making Through a Porcine-Based Integrated Cardiac Basic Science Program.
Despite the concerted effort of modern undergraduate curriculum designers, the ability to integrate basic sciences in clinical rotations is an ongoing problem in medical education. Students and newly qualified doctors themselves report worry about the effect this has on their clinical performance. There are examples in the literature to support development of attempts at integrating such aspects, but this "vertical integration" has proven to be difficult. We designed an expert-led integrated program using dissection of porcine hearts to improve the use of cardiac basic sciences in clinical medical students' decision-making processes. To our knowledge, this is the first time in the United Kingdom that an animal model has been used to teach undergraduate clinical anatomy to medical students to direct wider application of knowledge. Action research methodology was used to evaluate the local curriculum and assess learners needs, and the agreed teaching outcomes, methods, and delivery outline were established. A total of 18 students in the clinical years of their degree program attended, completing precourse and postcourse multichoice questions examinations and questionnaires to assess learners' development. Student's knowledge scores improved by 17.5% (p = 0.01; students t-test). Students also felt more confident at applying underlying knowledge to decision-making and diagnosis in clinical medicine. An expert teacher (consultant surgeon) was seen as beneficial to students' understanding and appreciation. This study outlines how the development of a teaching intervention using porcine-based methods successfully improved both student's knowledge and application of cardiac basic sciences. We recommend that clinicians fully engage with integrating previously learnt underlying sciences to aid students in developing decision-making and diagnostic skills as well as a deeper approach to learning.


Characteristics of cardiac action potentials in marsupials.
Standard microelectrode techniques were used to record action potentials from single atrial, ventricular and Purkinje fibers of hearts taken from three species of marsupial (Macropus rufus, Macropus robustus and Macropus eugenii) and from dogs, sheep and guinea-pigs. The major electrophysiological parameters of marsupial potentials were qualitatively similar to the values for placental mammals. The grouped data for ventricular action potentials from studies on 6 adult male red kangaroos (Macropus rufus) were (mean +/- SD): Resting potential -69.5 +/- 5.0 mV; action potential amplitude 92.7 +/- 5.7 mV; action potential duration (to 90% repolarization): 182.5 +/- 17.5 ms; maximum rate of depolarization: 196.5 +/- 80.1 V/s. The major point of difference was the short duration of the red kangaroo ventricular action potential compared to those of the placental mammals, and compared to atrial cells from the kangaroos. It is suggested that this explains the short QT interval reported by others for kangaroo electrocardiograms, and that it may also be implicated in the high frequency of sudden death previously noted in these animals.


Impact of fermentable fiber, xylo-oligosaccharides and xylanase on laying hen productive performance and nutrient utilization.
This study evaluated the impact of feeding xylo-oligosaccharides (XOS), fermentable fiber in the form of wheat bran (WB), and xylanase (XYL) on laying hen productive performance and nutrient digestibility. The hypothesis was that the WB would provide the microbiota in the hindgut with fermentable dietary xylan, and the XOS and XYL would further upregulate xylan fermentation pathways, resulting in improved nutrient utilization. Isa Brown hens (n = 96) were obtained at 39 wk of age. They were fed 12 dietary treatments, 8 hens per treatment, for 56 d. A commercial laying hen ration was fed, and for half of the treatments 10% of this ration was directly replaced with WB. The diets were then supplemented with either 1) no supplements; 2) XOS 50 g/t; 3) XOS 2000 g/t; 4) XYL (16,000 BXU/kg); 5) XYL + XOS 50 g/t, or 6) XYL + XOS 2,000 g/t. Hen performance and egg quality were measured every 14 d. On d56, ileum digesta samples were collected for determination of starch, nonstarch polysaccharide (NSP), XOS, protein, energy, and starch digestibility. Ceca digesta samples were also collected for analysis of XOS, short chain fatty acid (SCFA), xylanase and cellulase activity and microbial counts. Feeding 2,000 g/t XOS increased ileal protein digestibility. Combined 2,000 g/t XOS and XYL increased cecal Bifidobacteria concentration. This combination also increased cecal xylanase activity in birds fed the control diet. Cecal cellulase activity was improved by feeding WB, XYL, and 2,000 g/t XOS. XYL increased cecal lactate production. Feeding 2,000 g/t XOS with WB increased insoluble NSP degradability and shell breaking strength at d56. In summary, supplementing laying hen diets with fermentable fiber, XYL and XOS increases utilization of dietary xylan, improving nutrient utilization, performance, and gastrointestinal health.


Eating disorders and irritable bowel syndrome: is there a link?
The relationship between eating disorders (ED) and irritable bowel syndrome (IBS) is poorly understood. We wanted to determine the prevalence of IBS in a large sample of eating disordered individuals, examine the timing of onset of these disorders and assess whether there are any predictors of IBS symptoms in ED sufferers. Participants with a current or past ED were recruited from a volunteer register. Two hundred thirty-four respondents completed a questionnaire on IBS devised for the study. ED symptoms were assessed using the Eating Disorders Examination-Questionnaire (EDE-Q). Sixty-four percent currently met the widely used Manning criteria for IBS. The majority of participants (87%) had developed their ED before the onset of IBS, with a mean of 10 years between the onset of ED and IBS. All EDE subscales were associated with current IBS symptoms, whereas ED duration was not. Preliminary findings suggest that EDs may increase the risk of developing IBS.


Ultrasound Measurement of Local Deformation in the Human Free Achilles Tendon Produced by Dynamic Muscle-Induced Loading: A Systematic Review.
Achilles tendinopathy is the most prevalent lower limb tendinopathy, yet it remains poorly understood, with mismatches between observed structure and reported function. Recent studies have hypothesised that Achilles tendon (AT) healthy function is associated with variable deformation across the tendon width during use, focusing on quantifying sub-tendon deformation. Here, the aim of this work was to synthesise recent advances exploring human free AT tissue-level deformation during use. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, PubMed, Embase, Scopus and Web of Science were systematically searched. Study quality and risk of bias were assessed. Thirteen articles were retained, yielding data on free AT deformation patterns. Seven were categorised as high-quality and six as medium-quality studies. Evidence consistently reports that healthy and young tendons deform non-uniformly, with the deeper layer displacing 18%-80% more than the superficial layer. Non-uniformity decreased by 12%-85% with increasing age and by 42%-91% in the presence of injury. There is limited evidence of large effect that AT deformation patterns during dynamic loading are non-uniform and may act as a biomarker of tendon health, risk of injury and rehabilitation impact. Better considered participant recruitment and improved measurement procedures would particularly improve study quality, to explore links between tendon structure, function, aging and disease in distinct populations.


Poverty modeling in the Islamic Republic of Iran using an ANFIS optimized network with the differential evolution algorithm (ANFIS_DE).
Poverty is a multifaceted phenomenon that its study and analysis from all dimensions requires accurate knowledge. In the past, poverty was measured only by the income approach. That is, only people's incomes were compared to the poverty line. But this approach does not identify other dimensions of poverty. Given the importance of discussing poverty in the economies of developing countries, this article examines and models poverty in the Islamic Republic of Iran. This article presents the internal and external dimensions of poverty in the period 1996-2017. In this paper, to model the poverty in Iran, the ANFIS method optimized with a differential evolution algorithm was used. In this method, a differential evolution algorithm was used to train the ANFIS system instead of the FIS system. To evaluate the strength of the model, mean squared error (MSE), root mean squared error (RMSE), Mean absolute error (MAE), STD_error, Mean_error criteria have been used. The data used in this paper are from the World Development Index (WDI) Database, the World Bank Good Governance Indices, the Heritage Foundation's Economic Freedom Indices, and the United Nations data. This information is related to Iran and in the period (1996-2017). The purpose of this paper is to train the ANFIS network with DE algorithm using time series data and to model the data related to the Iran Multidimensional Poverty Index using the trained network. Multidimensional Poverty Index is a very suitable index for monitoring data. Poverty is in society. With the help of this data, we can assess the trend of poverty and income distribution and welfare in this country. The results of this study showed that training the ANFIS system by differential evolution algorithm, can make a very good improvement in the modeling process and reduce error criteria and improve the accuracy of this method.•This article has been compiled with the aim of modeling poverty in the Islamic Republic of Iran.•The method used in this paper is ANFIS network training using the differential evolution algorithm•The use of evolutionary algorithms to train fuzzy systems and artificial neural networks leads to improved performance.


Intranasal desmopressin (DDAVP) by spray in mild hemophilia A and von Willebrand's disease type I.
Desmopressin acetate (1-desamino-8-D-arginine vasopressin, DDAVP) has mostly been given by the parenteral route for the treatment of mild hemophilia A and von Willebrand's disease type I. In the present study the hemostatic effects of desmopressin acetate administered intranasally by spray in a dose of 300 micrograms and intravenously 0.3-0.4 micrograms/kg were assessed and compared in 8 patients with hemophilia A and 22 patients with von Willebrand's disease type I. A bioequivalent response to intravenous and intranasal desmopressin acetate was found in Factor VIII coagulant activity (VIII:C) in the hemophilia patients. In the von Willebrand patients, an equivalent shortening of the bleeding time was seen after the two modes of administration, even though intravenous injection gave a higher increase in plasma levels of VIII:C and vWF:Ag. In five patients with von Willebrand's disease the duration of the spray effect on VIII:C and vWF:Ag was followed for 24 h. After 12 h the mean level of VIII:C was 1.4, and of vWF:Ag 1.5, times the basal level. The findings suggest that the spray can be recommended for home or prophylactic treatment of patients with mild hemophilia A and von Willebrand's disease.


Gender Differences in Left Ventricular Ejection Fraction and Outcomes Among Patients Hospitalized for Acute Decompensated Heart Failure.
In patients with acute decompensated heart failure (HF), the association of gender and left ventricular ejection fraction (LVEF) with clinical outcomes has not been fully investigated. The aim of this study was to evaluate gender differences in LVEF and adverse outcomes across the full spectrum of LVEF in patients hospitalized for acute decompensated HF. Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes registry, 4,231 patients (2,461 men and 1,770 women) discharged alive after hospitalization for acute decompensated HF were investigated to assess the association of gender and LVEF with the primary end point (all-cause death and readmission for HF). Men or women were divided into 5 groups based on the LVEF at hospital discharge (<30%, 30% to <40%, 40% to <50%, 50% to <60%, and ≥60%). The median follow-up period after discharge was 523 (384 to 791) days. The frequency of the primary end point did not differ between men and women (36.5% vs 38.1%, p = 0.291). After adjustment for multiple comorbidities, male patients with an LVEF <30%, 30% to <40%, 40% to <50%, or 50% to <60% had a significantly higher risk of the primary end point than those with an LVEF ≥60%, indicating an inverse association between LVEF and adverse outcomes. In contrast, the adjusted risk of the primary end point was similar for all 5 LVEF groups of female patients. In conclusions, the association between LVEF and outcomes differs markedly between men and women hospitalized for acute decompensated HF, although event-free survival is similar for both genders.


Dysphagia in children: an overview.
Swallowing is a vital body function. It is important in maintaining optimal nutritional status. Dysphagia is any disturbance in swallowing. Dysphagia in children most commonly presents as feeding or respiratory difficulty. Dysphagia may be for solid foods or liquids or both. A careful history and examination are important in determining the etiology. Both, neurologic or non-neurologic conditions may cause dysphagia in children. Evaluation is often multidisciplinary in nature. A definitive diagnosis is possible in most cases and facilitates management and prognosis.


Haplotype analysis and LD detection at DM1 locus.
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy affecting adults and is due to trinucleotide sequence (CTG) in the 3' UTR region of DMPK gene located at 19q13.3 chromosome. Several neighboring genes (markers) located on the same chromosomes that are statistically associated and transmitted together (haplotype), influence the disease pathogenesis as caused by mutated DMPK. The intention of the study was to investigate the population genetic characteristics and to identify founder haplotypes from Northern India. Clinically diagnosed and molecularly confirmed DM1 patients (=27) and their family members (=76) were included in the study. PCR-RFLP analysis was performed for intron 5 (C/T)/HhaI, DMPK (G/T) intron 9/HinfI, Bpm1 and CKMM genetic polymorphism. The SNP Stat Online Software was used to construct haplotype group and for linkage-disequilibrium analysis. In all DM chromosomes: allele 2 had higher frequency in HhaI and HinfI while allele 1 had higher frequency in BpmI and CKMM. Total 11, 7, 10 and 11 haplotype groups had been formed in proband (patients), proband's father, proband's mother and in combined group respectively. Haplotype combination 2 (HhaI)/2 (HinfI)/1 (BpmI)/1 (CKMM TaqI)/1 (CKMM Nco1) had higher frequency, 0.4096 and 0.2867 in patients and combined group respectively. The haplotype combination 1/1/1/1/1 and 2/1/1/1/1 was most common for patient's father and mother respectively. The polymorphic markers HhaI & HinfI; HinfI & BpmI; and HinfI & CKMM TaqI showed significant LD. In comparison to other population, HhaI and HinfI have common origin of mutation.


Discovery of pyridine-2-ones as novel class of multidrug resistance (MDR) modulators: first structure-activity relationships.
A novel facile synthesis led to pyridine-2-one target structures of which first series with varying substituents have been yielded and biologically characterized as novel multidrug resistance (MDR) modulators inhibiting P-glycoprotein (P-gp). Structure-activity relationships prove a dependency of the MDR-modulating properties from the kind and positioning of hydrogen bond acceptor functions within the molecular skeleton. Cyano functions turned out as biologically effective substituents for a potential hydrogen bonding to the protein target structure.


Analysis of metabolism and genotoxicity of 5-nitro-3-thiophenecarboxanilides in bacterial, mammalian and human cells.
5-nitro-3-thiophenecarboxanilide (NTCA3) was clearly mutagenic in Salmonella typhimurium strains TA98, YG1021 (the strain with elevated nitroreductase) and YG1024 (the strain with elevated O-acetyltransferase) and only slightly mutagenic at the gpt locus in AS52 cells. Clastogenic activity in human lymphocytes was dependent on the length of exposure: detectable chromosome aberrations were observed following a 24 h treatment period, but not after 3 h exposure. S9 increased genotoxicity in both mammalian cells and human lymphocytes. Metabolites formed by incubation of NTCA3 with the different cell systems were examined. A time-course study in cell whole extracts showed that bacterial and mammalian cells can acetylate NTCA3 forming 5-acetylamino-3-thiophene-carboxanilide. The formation of this metabolite in human lymphocyte extracts was not confirmed. These data support the conclusions that: (i) both bacterial and mammalian activation pathways play a role in mutations by NTCA3; (ii) the N-acetylated derivative is generated by acyl-transferase after reduction and is the end product of the metabolism in both bacterial and mammalian cells; and (iii) different levels of reductase and acetyltransferase activity may contribute to the differential sensitivity of the different cellular species to the genotoxicity of NTCA3. The fact that NTCA3 serves as substrate for enzymatic activities of importance also in human metabolism needs consideration in assessing the potential risk posed by NTCAs.


Substance use and HIV risk behavior among men who have sex with men: the role of sexual compulsivity.
The relationship between substance use, sexual compulsivity and sexual risk behavior was assessed with a probability-based sample of men who have sex with men (MSM). Stimulant, poppers, erectile dysfunction medication (EDM), alcohol use, and sexual compulsivity were independently associated with higher odds of engaging in any serodiscordant unprotected anal intercourse (SDUAI). The association of sexual compulsivity with SDUAI was moderated by poppers and EDM use. Behavioral interventions are needed to optimize biomedical prevention of HIV among substance using MSM.


Assessment of the effects of phenylpropanolamine on appetite and food intake.
Single 37.5 mg doses of phenylpropanolamine (PPA) were given on each of two separate, nonconsecutive days to each of twelve nonobese women. PPA's effects on reported appetite and food intake were compared to those of a placebo also given on two nonconsecutive days. To control for possible effects on appetitive behavior of knowledge about the drug's putative role as an appetite suppressant, the subjects were told that PPA was a nasal decongestant which was expected to affect their sensitivity to flavors. Hunger rating before eating was significantly lower on trials after PPA than on trials after placebo (carry-over effect), but the direct effect of PPA on hunger was not significant. Although food intake was 26 g less under the PPA condition (407 g) than under placebo (433 g), this difference was not significant. However, because of insufficient power, the null hypothesis could not be accepted. The true effect of PPA on intake remains inconclusive. Either more subjects must be tested at this dose or the effect must be made larger by changing the dose, in order to obtain conclusive results.


Removing the infected aortofemoral graft using a two-stage procedure with a delay between the stages.
This study describes the results of a procedure for removing the infected aortofemoral graft using a two-stage procedure with a delay between the stages. The objective was to lessen the morbidity and mortality associated with removing an infected graft through a single operation. Eight consecutive patients were treated in this manner over a 6-year span. The indications for surgery were infected groin false aneurysms in three, chronic draining sinuses involving the prosthetic graft in four, and an open groin infection involving graft in one. There were five males and three females, with ages ranging 47-83 years (mean = 63). The mean operative time of the first-stage operation was 5.1 hr (range 3.0-7.7), and the mean blood transfusion requirement was 1.7 units. The mean operative time of the second stage operation was 3.5 hr (range 3.5-7.6), and the mean blood transfusion requirement was 2.5 units. In six patients, the hospital course was uncomplicated, with a mean hospital stay of 8.4 days for the initial stage and 9.2 days for the second stage. Two patients had complicated postoperative courses with hospital stays of >30 days. There was no operative or graft-related late mortality. No patients were lost to follow-up. One patient died of unrelated causes with a patent graft at 22 months postsurgery. All other patients remain well with patent grafts, without requiring revisions at a mean follow-up of 33 months (range 6-73). A two-stage approach with a delay between the stages may reduce the morbidity and mortality associated with the removal of an infected aortobifemoral graft.


Head and neck squamous cell carcinoma in patients aged > or = 80 years: patterns of care and survival.
Scarce data exist concerning the outcome of very elderly patients with head and neck squamous cell carcinoma (HNSCC). The clinical files of 316 patients aged > or = 80 years with HNSCC who were included in the authors' hospital database between 1987 and 2006 were reviewed retrospectively. Approximately 88% of patients received locoregional treatment, 31% of patients underwent surgery, and 57% of patients received definitive radiotherapy. The median disease-specific survival (DSS) was 21.3 months, and a plateau was observed after 5 years. The median overall survival (OS) was 13.0 months. Both the median DSS and the median OS were longer for patients with stage I/II HNSCC than for patients with stage III/IV HNSCC (median DSS, not reached vs 11.4 months; P < .001; median OS, 41.9 months vs 7.9 months; P < .001). On multivariate analysis, stage I/II disease, treatment with curative intent, and evidence of locoregional control were independent predictors of improved survival. The outcome of patients with stage I/II HNSCC aged > or = 80 years was similar to that of younger patients, and the current results indicated that age should not be used to deny them optimal treatment. Elderly patients with stage III/IV HNSCC had poor survival. Geriatric tools should be used to identify elderly patients who are eligible for optimal locoregional treatment.


Expression of cancer testis antigens in pancreatic carcinoma cell lines, pancreatic adenocarcinoma and chronic pancreatitis.
In order to define antigens that might be suitable as vaccines for pancreatic carcinoma, we investigated the composite expression of 10 cancer testis (CT) antigens (SCP-1, NY-ESO-1, SSX-1, SSX-2, SSX-4, GAGE, MAGE-3, MAGE-4, CT-7 and CT-8) by Reverse Transcriptase-PCR (RT-PCR) in fresh biopsies of human pancreatic adenocarcinoma, chronic pancreatitis and pancreatic carcinoma cell lines. While all CT genes were frequently expressed in cell lines derived from pancreatic cancer, no expression of MAGE-3, SSX-1, SSX-2, NY-ESO-1 and CT-7 was detected in fresh tumor biopsies, and MAGE-4 (1/52), SSX-4 (1/39) and CT-8 (2/41) were only rarely expressed. In contrast, HOM-TES-14/SCP-1 was expressed in 48% (29/61) and GAGE in 21% (13/61) of cases, respectively. One CT gene was expressed by 59% (75% in male, 46% in female patients; p = 0.05) and 2 or more CT genes by 15% of the samples. SCP-1 protein expression correlated well with mRNA expression. While SCP-1 and GAGE were absent in normal pancreas, they were found in 2/8 (SCP-1) and 1/8 (GAGE) samples of chronic pancreatitis, respectively, supporting the concept of chronic pancreatitis as a premalignant condition. SCP-1 and GAGE represent promising candidates for vaccine development in pancreatic carcinoma. Whether SCP-1 and GAGE expression identify cases of chronic pancreatitis with a high risk of malignant transformation remains to be shown.


Aggregation and cell cycle dependent retinoic acid receptor mRNA expression in P19 embryonal carcinoma cells.
Differentiation of P19 EC cells along different pathways into derivatives resembling cells of the three embryonic germ layers is accompanied by characteristic differences in modulation of expression of each of the three retinoic acid receptor genes, RAR alpha, -beta and -gamma. Differentiation induced by addition of RA to P19 EC cells cultured in monolayer is accompanied by a rapid increase in expression of both RAR alpha and -beta. Induction of RAR beta occurs in a characteristic biphasic manner, suggesting that multiple factors and/or different mechanisms are involved in controlling its expression. RAR beta mRNA is induced to a far higher level during early aggregation in the presence of RA than during early differentiation in monolayer, suggesting that the direction of differentiation depends on the number and/or ratio of alpha and beta type of RA receptors. Aggregation of P19 EC cells in the presence of RA, but not DMSO, is accompanied by repression of RAR gamma, suggesting that the expression of RAR beta and RAR gamma during neuroectodermal differentiation is mutually exclusive. The effects of RA on RAR expression are significantly greater in G1 than in S-phase of the cell cycle. These results extend previous observations that commitment to differentiation is cell cycle dependent and indicates that critical target gene regulation in response to RA has to take place in G1 for differentiation to occur.


[Role of abortion and ectopic pregnancies in maternal mortality rate at three university hospitals in Yaoundé].
The World Health Organization (WHO) estimates that 585.000 women die every year in the world as a result of complications related to pregnancy, delivery, postpartum period and abortion (the latter contributing to 13% of maternal deaths). Ectopic pregnancies are responsible for 10% of maternal mortality in the first quarter of pregnancy. Maternal mortality rate is high in Cameroon, estimated at 782 per 100.000 live births according to EDS-MICS 2011. AS the role of these two conditions in maternal mortality is little documented in our country, we conducted this study to assess the role of abortions and ectopic pregnancies in maternal mortality rate in Cameroon. We conducted a retrospective and analytic study. We collected data from all the medical records of pregnant patients and pregnant patients died before the 28thweek of pregnancy at three university hospitals: Central Hospital of Yaoundé (HCY), Yaoundé Gynaecology, Obstetrics and Pediatrics Hospital (HGOPY), University Hospital (CHU), over a period of five years, from 1 June 2011 to 31 May 2016. Data were recorded on a pre-established and tested technical sheet, collected using CS Pro 6.2 software and analyzed using SPSS software 20. The statistical tests for comparison used were Khi 2 and Fischer test according to the effective sample. The threshold significance level was set at p <0.05. We recorded 524 maternal deaths per 31116 live births, reflecting a maternal mortality rate (MMR) of 1538,9/100 000 live births. Out of 524 maternal deaths, 414 medical records were workable, including 100 (24.2%)abortions and 24 (5.8%) ectopic pregnancies. These 2 conditions contributed together to 30% of maternal deaths (124 medical records out of 414). The analysis of 124 medical records showed that the average age was 27.58 +/- 6 years, ranging from 18 to 48 years. The age group 20-24 years was the most represented (33.1%), followed by that 25-29 years (24.19%). The singles constituted 75%, housewives 36.7%, with level of secondary education in 62.5% and multigestes constituted 36.1% of our sample. 73.4% of patients didn't undergo any prenatal consultation and only 2.4% had undergone at least 4 consultations. Complications resulting in deaths were dominated by hemorrhage and infections. Abortions and ectopic pregnancies are the major causes of maternal mortality in our country. We recommend strengthening of family planning to limit unwanted pregnancies and socio-economic support for patients at risk.


Use of a custom designed external fixator system to treat ballistic injuries to the mandible.
The authors describe a custom designed mandibular external fixator II system that can be used to treat complex, comminuted fractures. The system is adjustable and lightweight, quick, robust, simple to apply, and allows mouth opening during healing, It is well suited to use in the modern war surgery environment. The authors present a case of successful treatment of a ballistic fracture of the mandible using this device.


Center practice drives variation in choice of US kidney transplant induction therapy: a retrospective analysis of contemporary practice.
To assess factors that influence the choice of induction regimen in contemporary kidney transplantation, we examined center-identified, national transplant registry data for 166 776 US recipients (2005-2014). Bilevel hierarchical models were constructed, wherein use of each regimen was compared pairwise with use of interleukin-2 receptor blocking antibodies (IL2rAb). Overall, 82% of patients received induction, including thymoglobulin (TMG, 46%), IL2rAb (22%), alemtuzumab (ALEM, 13%), and other agents (1%). However, proportions of patients receiving induction varied widely across centers (0-100%). Recipients of living donor transplants and self-pay patients were less likely to receive induction treatment. Clinical factors associated with use of TMG or ALEM (vs. IL2rAb) included age, black race, sensitization, retransplant status, nonstandard deceased donor, and delayed graft function. However, these characteristics explained only 10-33% of observed variation. Based on intraclass correlation analysis, "center effect" explained most of the variation in TMG (58%), ALEM (66%), other (51%), and no induction (58%) use. Median odds ratios generated from case-factor adjusted models (7.66-11.19) also supported large differences in the likelihood of induction choices between centers. The wide variation in induction therapy choice across US transplant centers is not dominantly explained by differences in patient or donor characteristics; rather, it reflects center choice and practice.


Intrinsic muscle advancement to treat chronic palmar instability of the metacarpophalangeal joint of the thumb.
Chronic palmar instability of the metacarpophalangeal joint of the thumb can result in a significant disability. Grasp, particularly pinch, is painful and weak because the thumb goes into hyperextension. Stabilization of the metacarpophalangeal joint can be achieved by distal advancement of the conjoined tendon of the abductor pollicis brevis and lateral fibers of the flexor pollicis brevis.


In situ temperature-jump dynamic nuclear polarization: enhanced sensitivity in two dimensional 13C-13C correlation spectroscopy in solution.
Dynamic nuclear polarization is combined with temperature-jump methods to develop a new 2D 13C-13C NMR experiment that yields a factor of 100-170 increase in sensitivity. The polaization step is performed at 100 K, and the sample is subsequently melted with a 10.6 microm laser pulse to yield a sample with highly polarized 13C spins. 13C detected 2D 13C-13C spectroscopy is performed in the usual manner.


Infections during extracorporeal life support.
Little data exist on the type of infections patients acquire during extracorporeal life support. Through a retrospective analysis of 109 patients who underwent 115 episodes of venoarterial extracorporeal life support, it was determined that nosocomial infections developed in 18 patients (16%). Patients with nosocomial infections were supported for longer periods of time (230 versus 140 hours; P < .05) and were more likely to have an open chest (P = .02) than those who did not have infectious complications. Blood-borne infections occurred most often while patients were cannulated for extracorporeal life support, with urinary tract and wound infections more commonly occurring after decannulation. Fungal organisms were isolated in 50% of nosocomial infections. Patients with blood or wound fungal infections had a higher case-fatality rate than those patients with bacterial complications (P = .03). Because it is unlikely that the duration of extracorporeal life support can be shortened significantly, the authors recommend an increased level of awareness of nosocomial infections in patients on prolonged extracorporeal life support. Further research is needed to assess the effects of antifungal prophylaxis or immune modulation to prevent nosocomial infections.


What is known about parents' treatment decisions? A narrative review of pediatric decision making.
With the increasing complexity of decisions in pediatric medicine, there is a growing need to understand the pediatric decision-making process. To conduct a narrative review of the current research on parent decision making about pediatric treatments and identify areas in need of further investigation. Articles presenting original research on parent decision making were identified from MEDLINE (1966-6/2011), using the terms "decision making," "parent," and "child." We included papers focused on treatment decisions but excluded those focused on information disclosure to children, vaccination, and research participation decisions. We found 55 papers describing 52 distinct studies, the majority being descriptive, qualitative studies of the decision-making process, with very limited assessment of decision outcomes. Although parents' preferences for degree of participation in pediatric decision making vary, most are interested in sharing the decision with the provider. In addition to the provider, parents are influenced in their decision making by changes in their child's health status, other community members, prior knowledge, and personal factors, such as emotions and faith. Parents struggle to balance these influences as well as to know when to include their child in decision making. Current research demonstrates a diversity of influences on parent decision making and parent decision preferences; however, little is known about decision outcomes or interventions to improve outcomes. Further investigation, using prospective methods, is needed in order to understand how to support parents through the difficult treatment decisions.


Control of plasma aldosterone in a patient with Conn's syndrome before and during spironolactone medication.
In a patient suffering from Conn's syndrome analysis of short-time fluctuations of plasma aldosterone, plasma cortisol and plasma renin activity were performed before and after a 9-months therapy period with spironolactone. Under the former conditions aldosterone was secreted episodically and a highly significant correlation was found between plasma aldosterone and plasma cortisol (r=0.817, p is less than 0.001) while plasma renin activity was undetectable (is less than 0.16 ng/ml/3hr). Following a 9-month therapy with spironolactone episodic secretion of aldosterone and the significant correlation between aldosterone and cortisol persisted (r=0.819, p less than 0.001) in the presence of an abnormally high plasma renin activity. First when the secretion of ACTH was suppressed by dexamethasone a weak correlation was found between renin activity and aldosterone (r=0.517, p is less than 0.05). Our results show that both before and after a 9-months therapy with spironolactone episodic aldosterone release of an aldosterone producing adrenal adenoma was mediated through ACTH and that endogeneous angiotensin II had no or only little influence.


The extent to which the recommendations issued after the periodic evaluation of university programs are targeted, specific, measurable and unequivocal: An exploratory analysis.
Each year, Quebec universities conduct a periodic evaluation of their study programs and issue recommendations to improve the quality and relevance of these latter. Although these evaluations are commonplace in higher education institutions, there is little information about them and the resulting recommendations. To compensate this lack of convincing data, our exploratory analysis will look at the quality of expression of these recommendations. Experts were solicited to evaluate whether the recommendations were targeted, specific, measurable and unequivocal, four strategic characteristics of good formulations. Our results reveal major issues. Almost all of the recommendations do not indicate who is to carry them out. Also, the desired improvement is not clearly identified, thus leaving unanswered major questions about how they should be implemented. Another weak point was the absence of indicators for measuring the accomplishment of the recommendations. The last part of this study presents the best practices for issuing better recommendations, since these latter are key in the improvement process and the development of action plans. This study opens the way for research that will examine the root causes of the problem and make it possible to establish best practices for writing recommendations.


Influence of mannitol on maintaining coronary flows and salvaging myocardium during ventriculotomy and during prolonged coronary artery ligation.
We investigated whether prolonged infusion of hypertonic mannitol results in a sustained increase in coronary flow and reduces myocardial necrosis after ventriculotomy or two hours of circumflex coronary artery occlusion. Cardiac outputs, intracardiac pressures, and heart rates did not differ between mannitol and control animals. Those receiving mannitol after ventriculotomy had coronary flows to myocardium near the incision which did not differ from controls. During coronary occlusion, mannitol did increase flow to ischemic and peri-ischemic regions by one hour, but this increase was not sustained at two hours. On histologic examination, myocardial necrosis involving the right ventricular free wall in the ventriculotomy animals and the posterior papillary muscle and subadjacent free wall in the coronary occlusion animals, did not differ between the mannitol treated and control groups. The data obtained in the present study, combined with those from earlier evaluations of the influence of mannitol during ventriculotomy and myocardial ischemia, suggest that mannitol's ability to increase coronary flow to injured areas of myocardium is relatively short-lived.


Protective role of heat shock protein 27 in gastric mucosal injury.
Heat shock protein 27 (HSP27) mediates cytoprotective effects through its function as a molecular chaperone and through the phosphorylation-dependent stabilization of actin filaments. The role of HSP27 in gastric ulcer formation and healing is, however, unknown. The expression of HSP27 was studied in human gastric tissue specimens obtained from patients with gastric ulcers and from healthy Helicobacter pylori-negative individuals, who received low-dose aspirin, rofecoxib, and the combination in a prospective study. The susceptibility of the gastric mucosa to indomethacin-induced lesions was further studied in transgenic mice overexpressing human HSP27 (Tg(huHSP27)) and compared with wild-type mice (Wt). The expression of HSP27, COX-1, and COX-2 was investigated in Tg(huHSP27) mice and Wt mice by immunohistochemistry and western blot analysis. While no specific changes in HSP27 expression were found following exposure of healthy human gastric mucosa to oral administration of aspirin or refocoxib, chronic gastric ulcers showed strong HSP27 expression at the ulcer base and margins. Here it was expressed by granulation tissue and regenerating surface epithelium. In Tg(huHSP27) mice, overexpression of HSP27 led to a significant decrease of indomethacin-induced erosions and ulcers compared with Wt mice. COX-1 and COX-2 levels did not change. HSP27 is involved in chronic gastric ulcer repair mechanisms in humans, while overexpression of human HSP27 in gastric epithelial cells in mice reduces the susceptibility to non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulceration. This indicates that HSP27 expression is critical for mucosal protection in the stomach.


Structural and functional study in the rhizosphere of Oryza sativa L. plants growing under biotic and abiotic stress.
A structural and functional study has been carried out in the rice production area of the Guadalquivir marshes in southern Spain aiming to increase knowledge of rice rhizosphere structure and function for further application on integrated management practices. Rhizosphere bacterial structure (analysis of 16S rRNA partial sequences from total soil DNA), metabolic diversity (analysed by Biolog FF for fungal community and GN for microbial community) and a screening for putative plant growth-promoting rhizobacteria (PGPR) to identify potential isolates for development of local biofertilizers, and biodiversity of culturable micro-organisms (analysis of 16S rRNA partial sequences) from four areas differing in salinity and Magnaporthe oryzae incidence in two moments of the crop cycle were studied. Results indicate that the dominant taxon in libraries from the four areas was Proteobacteria. Metabolic diversity was higher in areas affected only by salinity or incidence of Magnaporthe than in the control or area affected by both stresses. It seems that rice plants selected, in their rhizosphere, micro-organisms able to affect plant hormonal balance under all conditions, and this activity relied in different bacterial genera depending on the environmental stress. Bacterial genera for each stress, as well as generalist strains, were found present in all the studied areas. Potential molecular markers and taxonomic markers (Sphingobacteria for salt and Thermococci for Magnaporthe) of the different stress situations have been highlighted, and Class Verrucomicrobiae could be a marker for nonstressed areas. In addition, putative PGPR strains isolated in this study could be used as biofertilizers. Rice paddies are great ecologically important ecosystems. The results are very relevant as they may be included in the process of rice production, improving crop conditions with less environmental impact.


Cytotoxic and pro-apoptotic effects of novel ganoderic acid derivatives on human cervical cancer cells in vitro.
Ganoderic acid T, a triterpenic acid produced by Ganoderma lucidum, has demonstrated therapeutic potential for tumor disease. In the current work, ganoderic acid T was modified to produce more effective small-molecule inhibitors of cancer cell proliferation. Moreover, the anticancer effects of three new ganoderic acid T derivatives, i.e., (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid ethyl ester (TLTO-Ee), (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid propyl ester (TLTO-Pe), and (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid amide (TLTO-A), and one known derivative, (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid methyl ester (TLTO-Me), on the cervical cell line HeLa were investigated and compared. MTT assay indicated that, among the tested compounds, TLTO-A displayed the highest inhibitory effect on the growth of HeLa cells, whereas it showed less cytotoxicity to the non-tumorous cell line MCF-10A than ganoderic acid T. Flow cytometry analysis revealed that all the compounds caused cell cycle arrest at the G1 phase and induced apoptosis. Furthermore, they decreased the mitochondrial membrane potential and enhanced the activities of pro-apoptotic factors caspase-3 and caspase-9 in a dose-dependent manner. Accordingly, the apoptosis induction was presumed to occur through the endogenous pathway. The following order ranks both cytotoxic and pro-apoptotic effects of the compounds against HeLa cells: TLTO-A>ganoderic acid T≈TLTO-Me≈TLTO-Ee≈TLTO-Pe. This study suggests that the carboxyl group of ganoderic acid T is not the main active group and is suitable for its further structural modification. The current work presents valuable information on the design of ganoderic acid T derivatives to develop potential chemotherapy agents.


Deep Learning-Based Estimation of Implantable Collamer Lens Vault Using Optical Coherence Tomography.
To develop and validate a deep learning neural network for automated measurement of implantable collamer lens (ICL) vault using anterior segment optical coherence tomography (AS-OCT). Cross-sectional retrospective study. A total of 2647 AS-OCT scans were used from 139 eyes of 82 subjects who underwent ICL surgery in 3 different centers. Using transfer learning, a deep learning network was trained and validated for estimating the ICL vault on OCT. A trained operator separately reviewed all OCT scans and measured the central vault using a built-in caliper tool. The model was then separately tested on 191 scans. A Bland-Altman plot was constructed and the mean absolute percentage error (MAPE), mean absolute error (MAE), root mean squared error (RMSE), Pearson correlation coefficient (r), and determination coefficient (R2) were calculated to evaluate the strength and validity of the model. On the test set, the model achieved a MAPE of 3.42%, an MAE of 15.82 µm, a RMSE of 18.85 µm, a Pearson correlation coefficient r of +0.98 (P < .00001), and a coefficient of determination R2 of +0.96. There was no significant difference between the vaults of the test set labeled by the technician vs those estimated by the model: 478 ± 95 µm vs 475 ± 97 µm, respectively, P = .064). Using transfer learning, our deep learning neural network was able to accurately compute the ICL vault from AS-OCT scans, overcoming the limitations of an imbalanced data set and limited training data. Such an algorithm can assist the postoperative assessment in ICL surgery.


A new picorna-like virus identified in populations of the potato psyllid Bactericera cockerelli.
The potato/tomato psyllid Bactericera cockerelli (Hemiptera: Triozidae) is a pest of Solanaceae plants and a vector of the pathogenic bacterium 'Candidatus Liberibacter solanacearum', which is associated with zebra chip disease in potato. This disease is controlled through insecticide treatments, and more environmentally friendly management options are desirable. The objective of this study was to identify viruses present in potato psyllid populations that might be used as biocontrol agents for this insect pest. A new picorna-like virus, tentatively named "Bactericera cockerelli picorna-like virus" (BcPLV), was discovered in B. cockerelli populations maintained in greenhouses, through the use of high-throughput sequencing data and subsequent confirmation by RT-PCR and Sanger sequencing. BcPLV has a positive-sense 9,939-nt RNA genome encoding a single 2,947-aa polyprotein and is related to the Diaphorina citri picorna-like virus (DcPLV) found in Asian citrus psyllid Diaphorina citri populations. Based on their genome organization and the phylogeny of their RNA-dependent RNA polymerase domains, BcPLV and DcPLV together are proposed to comprise a new genus, provisionally named "Psylloidivirus", within the family Iflaviridae.


Epidemiology and risk factors for (tardive) dyskinesia.
Dyskinesia can develop in patients with schizophrenia in the course of the disease with or without the use of antipsychotics.In patients with psychiatric disorders other than schizophrenia Tardive Dyskinesia (TD) can develop in patients treated with antipsychotics or other drugs with dopamine D2 blocking properties. Spontaneous Dyskinesia in antipsychotic naive patients with schizophrenia ranges from 4 to 40%, depending on the age and duration of the illness. Moreover, siblings of patients with schizophrenia have higher prevalence rates of dyskinesia than matched controls. Incidence rates of TD due to dopamine blocking properties vary due to the sample population and the affinity for the dopamine blocker to the D2 dopamine receptor. Once developed, TD seems very persistent, the course of TD might be mediated by the affinity for the dopamine D2 receptor. Risk factors for TD in the literature are numerous, in this chapter only replicated and risk factors from longitudinal studies will be reported limiting the amount of risk factors. Furthermore only meta-analyses on genetic factors related to TD will be discussed due to inconsistency of genetic effects because of sample heterogeneity, small effects of multiple genes, (epi)genetic interactions,pleiotropy and small sample size. Finally the concept "Tardive Dyskinesia" will be discussed and the influence hereof on the above mentioned factors.


Radon Exposure Assessment and Relative Effective Dose Estimation to Inhabitants of Puglia Region, South Italy.
Indoor radon concentrations were measured in dwellings of the Puglia region in Southern Italy using LR-115 passive detectors. The results show that the radon concentrations varied from 15 ± 2 to 2166 ± 133 Bq/m³ with a geometric mean of 114 Bq/m³ and a geometric standard deviation of 2.3. An analysis on the factors affecting radon concentration such as age of the dwellings, floors, and stories, was performed. The mean effective dose to inhabitants has been calculated and found to be 8.2 mSv/y. Finally, for estimation of cancer risks, the lifetime risk and lung cancer cases per years per million have been calculated.


Management options for refractory chronic myeloid leukemia: considerations for the elderly.
Despite the excellent results obtained with standard-dose imatinib as first-line therapy for chronic myeloid leukemia in the chronic phase, one third of patients do not achieve an optimal response and require alternative therapies due to the emergence of drug resistance. Studies of resistance mechanisms, first tested in vitro and then in vivo, have driven the development of second-generation tyrosine kinase inhibitors (TKIs), dasatinib and nilotinib. These agents have been proven effective in a large number of patients resistant to imatinib and are also effective in older patients. The use of second-generation TKIs in first-line treatment has increased the rate of cytogenetic and molecular responses and reduced the number of patients experiencing disease progression. In this review, we detail the various mechanisms of resistance and management options for refractory patients, in particular in older patients. No differences in terms of efficacy were reported in this subset of patients when treated with nilotinib or dasatinib after imatinib resistance. Results of trials that tested second-generation TKIs as first-line treatment showed similar results in older and younger patients.


Spatial and temporal distribution of Tie-1 and Tie-2 during very early development of the human placenta.
Vasculogenesis in the human placenta comprises differentiation and growth of newly forming blood vessels derived from hemangiogenic stem cells within the mesenchymal core of villi. In a second stage, angiogenesis leads to the expansion and remodeling of the already existing vessels. At present, relatively little is known about the regulatory mechanisms of vasculogenesis and angiogenesis during very early placentation. Using placental villous tissues from days 22 to 48 of pregnancy, we analyzed the spatial and temporal expression of Tie-1 and Tie-2 in parallel to vascular maturation in the human placenta. In immunohistochemistry both receptors, Tie-1 and Tie-2 show a cell and villous type specific expression during this early phase of placental development. Especially, cytotrophoblast and hemangiogenic cell cords in mesenchymal villi and Hofbauer cells in immature intermediate villi have the strongest immunoreactivities. Western blot analysis showed that no significant changes were detected for Tie-1 and Tie-2 as pregnancy advanced. Moreover, phospho-Tie-2 levels did not change significantly in parallel to pregnancy ages. We conclude that both receptors are involved in angiogenesis as well as vascular modulation of early vessels. Due to their spatial distribution we speculate on an additional role in regulation of villous and extravillous trophoblastic behavior.


Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1).
Tricyclic isoxazoles were identified from a screen as a novel class of selective multidrug resistance protein (MRP1) inhibitors. From a screen lead, SAR efforts resulted in the preparation of LY 402913 (9h), which inhibits MRP1 and reverses drug resistance to MRP1 substrates, such as doxorubicin, in HeLa-T5 cells (EC(50)=0.90 microM), while showing no inherent cytotoxicity. Additionally, LY 402913 inhibits ATP-dependent, MRP1-mediated LTC(4) uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC(50)=1.8 microM). LY 402913 also shows selectivity ( approximately 22-fold) against the related transporter, P-glycoprotein, in HL60/Adr and HL60/Vinc cells. Finally, when dosed in combination with the oncolytic MRP1 substrate vincristine, LY 402913 delays the growth of MRP1-overexpressing tumors in vivo.