Two-Stage anaerobic digestion in agroindustrial waste treatment: A review.
The anaerobic digestion is a process widely recognized as an interesting alternative for the treatment and stabilization of residual organic substrates. However, several technical limitations were observed based on the characteristics of the organic matter submitted to the process, such as the presence of high concentrations of soluble sugars or fats. The technology of anaerobic digestion in multiple stages is described as a viable option in the control of variables, optimizing the environmental conditions of the main microorganisms involved in the process, assuring high solid removal and methane production, besides allowing a higher energy yield through the generation of molecular fuel hydrogen. Several studies reviewed the process of anaerobic digestion in multiple stages in the treatment of food waste, although few report its use applied directly to agroindustrial residues. Thus, the present work aims to review the literature evaluating the scenario and viability of the multi-stage anaerobic digestion process applied to agroindustrial effluents. Effluents such as manipueira, vinasse, and dairy wastewater are substrates that present high yields when treated by AD processes with stage separation. The high concentration of easily fermentable sugars results in a high production of molecular hydrogen (co-product of the production of volatile acids in the acid phase) and methane (methanogenic phase). The great challenges related to the development of the sector are focused on the stability of the composition and yield of hydrogen in the acid phase, besides the problems resulting from the treatment of complex residues. Thus, the present study suggests that future works should focus on the technologies of new microorganisms and optimization of process parameters, providing maturation and scale-up of the two-stage anaerobic digestion technique.


Automatic segmentation of white matter hyperintensities by an extended FitzHugh & Nagumo reaction diffusion model.
To evaluate the efficiency and reproducibility of the extended FitzHugh & Nagumo (FHN) reaction-diffusion model proposed in this study for white matter hyperintensities (WMH) segmentation. Five types of magnetic resonance T2-weighted fluid-attenuated inversion-recovery (T2FLAIR) images of 127 patients with different scanning parameters from five clinical scanner systems were selected for this study. After skull and scalp removal and denoise, the T2FLAIR images were processed by the proposed extended FHN model to obtain WMH. This new technique replaced the global threshold constant with a local threshold matrix. There was no significant difference between the segmentation results of the training set and the manual contouring against those between the test set and the manual contouring based on similarity index (SI) values (P = 0.5217). The SI values of the five types of T2FLAIR images were 86.0% ± 15.4%, 85.8% ± 10.5%, 84.1% ± 14.8%, 87.2% ± 14.6%, 86.3% ± 12.7%, respectively, comparing the segmentation results using the proposed method to the manual delineations. The overall SI value of the images was 86.5% ± 14.5%. This approach also demonstrated a better WMH segmentation performance over its classic form (P < 0.001). The proposed approach is efficient and could provide a more effective and convenient tool for clinical quantitative WMH analysis.


Direct recognition of LPS drive TLR4 expressing CD8+ T cell activation in patients with rheumatoid arthritis.
Aberrant immune responses characterize autoimmune disorders like Rheumatoid Arthritis (RA) wherein lymphocytes are recognized as key players. Role of CD8+ T cells in RA has been less defined however we found that these cells are activated in RA patients with increased expression of cytolytic granules and inflammatory mediators thereby modulating immune responses contributing to disease severity. Though unconventional expression of different Toll Like Receptors (TLRs) on CD8+ T cells has been proposed but their expression and role in T cell activation and differentiation in RA still remains obscure. Herein we report, for the first time, an increased expression of TLR4 on peripheral CD8+ T cells of RA patients and its role in skewing CD8+ T cells towards activated and inflammatory phenotype thereby playing a significant role in pathogenesis and progression of RA. We found that the surface expression of TLR4 on CD8+ T cells directly correlates with disease severity. Moreover, these CD8+ T cells respond to the TLR4 ligand LPS and express robust amounts of cytotolytic and inflammatory molecules including TNFα and IFNγ. Our study hence identifies an important role for CD8+ T cells in orchestrating RA through TLR4 mediated activation and differentiation.


The occult head and neck primary: to treat or not to treat?
In patients with cervical node metastases from an unknown primary malignancy, there is unresolved controversy regarding the utility of elective irradiation of putative pharyngeal primary sites as part of the management plan. We analysed the experience of the Peter MacCallum Cancer Institute to assess the risk of withholding mucosal irradiation in relation to the diagnostic algorithm used to exclude a primary lesion at the time of initial presentation. Between 1983 and 1992, 69 patients were seen with metastatic squamous or undifferentiated carcinoma in cervical nodes from an unknown primary site. Neck nodal stage was NX or N1 13%; N2 52%; N3 35%. Nodal disease was bilateral in 12% of patients. Investigations included examination under anaesthesia, with or without random biopsies, in 84%, and CT scanning of the head and neck in 55%. Treatment was by surgery alone in four patients, by radiotherapy alone in 23, and by combined modalities in 40. Two patients received no treatment. Seventeen were treated with palliative intent. The radiotherapy fields provided comprehensive coverage of the pharynx in only eight patients and partial coverage in five. The estimated overall 5-year survival was 36%. Eleven primary tumours were detected between 7 months and 7 years after the initial treatment, of which nine were in head and neck sites. This yielded an estimated incidence of 30% at 10 years, which is similar to the risk of the development of a second primary after the successful treatment of a known head and neck cancer. Only three patients (none of whom had a CT scan as part of their initial evaluation) manifested a primary in an unirradiated pharyngeal site within 2 years of treatment. As the accuracy of imaging improves, the risk of missing an occult primary lesion will decrease further. We conclude that the use of standardized diagnostic investigations incorporating modern imaging substantially eliminates the indication for comprehensive elective mucosal irradiation with its consequent morbidity. The overriding priority in patients who present with advanced neck disease is to secure regional control.


Olivo-cortico-nuclear localizations within crus I of the cerebellum.
Retrograde and anterograde tracers were microinjected into the folia of crus I of the cat cerebellum to investigate spatial localization in olivo-cerebellar and cortico-nuclear projections. The folia were shown to be mainly occupied in rostrocaudal succession by three zones receiving their olivo-cerebellar climbing fiber afferents from parts of, respectively, the dorsal lamella of the principal olive, the ventral lamella of the principal olive, and the rostral half of the medial accessory olive. These zones are presumably parts of the D(2), D(1), and C(2) cerebellar cortical zones, as earlier proposed by Rosina and Provini ([1982] Neuroscience 7:2657-2676). Their respective nuclear target territories were found to be in the rostroventral quadrant of nucleus lateralis, the caudoventral quadrant of nucleus lateralis, and the ventral half of nucleus interpositus posterior. The medial-to-lateral width of each zone was shown to be innervated by different groups of olive cells and to project respectively to medial and lateral parts of the nuclear territory for that zone, consistent with the existence in crus I of olivo-cortico-nuclear microcomplexes (cf. Ito [1984] New York: Raven Press). Parts of the length of each zone located within different folia were also shown to relate to different groups of olive cells and to different regions of the zone's overall nuclear territory. Interfolial localizations, which were heavily overlapping in nature, intersected orthogonally with those for zone width. The fine-grain topography implies that individual microzones exist within each of the zones present within crus I. The results also have implications for the possibility that lateral cerebellar pathways are involved in cognition.


Sepsis-induced acute lung injury in young rats is relieved by calycosin through inactivating the HMGB1/MyD88/NF-κB pathway and NLRP3 inflammasome.
Sepsis is the primary cause for children's death worldwide. Calycosin (CAL) is an astragalus extract with anti-inflammatory, antioxidant and anti-tumor functions. This study aims to probe the role of CAL in alleviating sepsis-induced acute lung injury (ALI). Cecal ligation and puncture (CLP) was carried out in young rats to induce sepsis model, which were then treated with CAL. The histopathological changes of the lung were observed, and the dry/wet (W/D) weight ratio of the lung was calculated to analyze pulmonary edema. Apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, and the contents of PaO2, PaCO2 and PaO2/FiO2 in the aortic blood of the rats were monitored by blood-gas analysis. In addition, lipopolysaccharide (LPS) was applied to treat Type II alveolar epithelial cells (AEC-II) to establish an in-vitro sepsis model. Cell viability was detected by the (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was examined by flow cytometry. The expression of apoptosis-related proteins Bax, Bcl2 and Caspase3, as well as the HMGB1/MyD88/NF-κB axis and NLRP3 inflammasome were measured by Western Blot. The profiles of inflammatory factors (TNF-α, IL-1β, and MCP-1) and oxidative stress markers (MDA, SOD, and CAT) in rat serum and AEC-II cells were also detected. CLP induced remarkable lung injury in the young rats. The administration of CAL significantly mitigated pathological injuries of rat lung, reduced lung edema and the apoptosis (labeled by TUNEL). In vitro, CAL treatment improved the damage of LPS-treated AEC-II cells. In addition, CAL dampened inflammation and oxidative stress both in vitro and in vivo, repressed the HMGB1/MyD88/NF-κB pathway and NLRP inflammasome activation induced by CLP or LPS. Interestingly, inhibiting HMGB1 (by ethyl pyruvate, EP) enhanced CAL-mediated protective effects against LPS in AEC-II cells. CAL alleviates sepsis-induced ALI in young rats by inhibiting the HMGB1/MyD88/NF-κB pathway and NLRP3 inflammasome activation.


[Unusual antenatal gestational choriocarcinoma].
Choriocarcinoma is a rare and aggressive tumor that occurs mainly after a molar pregnancy, and exceptionally during a diploid viable pregnancy. We report a case of a 30 years old primipare that revealed a choriocarcinoma at 37 weeks by a generalized seizure. This unusual event did not, however, delay the early introduction of chemotherapy even in the absence of histological diagnosis. This diagnosis must be evoked in woman with genital activity presenting an unknown tumor. Treatment can be started without waiting for the histological evidence, due to the important feature of the hCG assay, significantly improving the prognosis.


Migration does not enlarge inequalities in health between rich and poor neighbourhoods in The Netherlands.
We estimate to what extent migration contributes to inequalities in health between rich and poor neighbourhoods in The Netherlands. We used a sample from the survey WoonOnderzoek Nederland 2006. Using multilevel logistic regression analyses, we assessed the magnitude of health differences between poor vs. rich areas for the migrant and total population. Next, we compared the health of migrants to non-migrant populations and we assessed the role of sociodemographic characteristics. For most health indicators, area inequalities in health were much smaller in the migrant population than in the total population. The health of migrants was generally in-between the health of non-migrants who lived in areas of origin and destination. The differences in health with the population in the areas of origin were almost completely explained by sociodemographic characteristics. Health is related to risk of migration between poor and rich areas, mostly through sociodemographic selection instead of a direct effect of health. Despite the relationship with health, migration does not enlarge inequalities in health between poor and rich neighbourhoods but possibly attenuates the health differences.


Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells.
Blockade of colony-stimulating factor-1 (CSF-1) limits macrophage infiltration and improves response of mammary carcinomas to chemotherapy. Herein we identify interleukin (IL)-10 expression by macrophages as the critical mediator of this phenotype. Infiltrating macrophages were the primary source of IL-10 within tumors, and therapeutic blockade of IL-10 receptor (IL-10R) was equivalent to CSF-1 neutralization in enhancing primary tumor response to paclitaxel and carboplatin. Improved response to chemotherapy was CD8(+) T cell-dependent, but IL-10 did not directly suppress CD8(+) T cells or alter macrophage polarization. Instead, IL-10R blockade increased intratumoral dendritic cell expression of IL-12, which was necessary for improved outcomes. In human breast cancer, expression of IL12A and cytotoxic effector molecules were predictive of pathological complete response rates to paclitaxel.


Synergistic roles of BMP15 and GDF9 in the development and function of the oocyte-cumulus cell complex in mice: genetic evidence for an oocyte-granulosa cell regulatory loop.
Bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) are oocyte-specific growth factors that appear to play key roles in granulosa cell development and fertility in most mammalian species. We have evaluated the role(s) of these paracrine factors in the development and function of both the cumulus cells and oocytes by assessing cumulus expansion, oocyte maturation, fertilization, and preimplantation embryogenesis in Gdf9+/-Bmp15-/- [hereafter, double mutant (DM)] mice. We found that cumulus expansion, as well as the expression of hyaluronon synthase 2 (Has2) mRNA was impaired in DM oocyte-cumulus cell complexes. This aberrant cumulus expansion was not remedied by coculture with normal wild-type (WT) oocytes, indicating that the development and/or differentiation of cumulus cells in the DM, up to the stage of the preovulatory luteinizing hormone (LH) surge, is impaired. In addition, DM oocytes failed to enable FSH to induce cumulus expansion in WT oocytectomized (OOX) cumulus. Moreover, LH-induced oocyte meiotic resumption was significantly delayed in vivo, and this delayed resumption of meiosis was correlated with the reduced activation of mitogen-activated protein kinase (MAPK) in the cumulus cells, thus suggesting that GDF9 and BMP15 also regulate the function of cumulus cells after the preovulatory LH surge. Although spontaneous in vitro oocyte maturation occurred normally, oocyte fertilization and preimplantation embryogenesis were significantly altered in the DM, suggesting that the full complement of both GDF9 and BMP15 are essential for the development and function of oocytes. Because receptors for GDF9 and BMP15 have not yet been identified in mouse oocytes, the effects of the mutations in the Bmp15 and Gdf9 genes on oocyte development and functions must be produced indirectly by first affecting the granulosa cells and then the oocyte. Therefore, this study provides further evidence for the existence and functioning of an oocyte-granulosa cell regulatory loop.


Statistical analysis of comparative tumor growth repeated measures experiments in the ovarian cancer patient derived xenograft (PDX) setting.
Repeated measures studies are frequently performed in patient-derived xenograft (PDX) models to evaluate drug activity or compare effectiveness of cancer treatment regimens. Linear mixed effects regression models were used to perform statistical modeling of tumor growth data. Biologically plausible structures for the covariation between repeated tumor burden measurements are explained. Graphical, tabular, and information criteria tools useful for choosing the mean model functional form and covariation structure are demonstrated in a Case Study of five PDX models comparing cancer treatments. Power calculations were performed via simulation. Linear mixed effects regression models applied to the natural log scale were shown to describe the observed data well. A straight growth function fit well for two PDX models. Three PDX models required quadratic or cubic polynomial (time squared or cubed) terms to describe delayed tumor regression or initial tumor growth followed by regression. Spatial(power), spatial(power) + RE, and RE covariance structures were found to be reasonable. Statistical power is shown as a function of sample size for different levels of variation. Linear mixed effects regression models provide a unified and flexible framework for analysis of PDX repeated measures data, use all available data, and allow estimation of tumor doubling time.


The data debate. CIOs weigh issues, obstacles to information networks. Panel discussion.
CEOs are looking toward the development of provider networks in a post-reform environment, as envisioned in the AHA's proposal for Community Care Networks. But CIOs face conceptual and technical challenges on the path to true information networking. An exclusive Hospitals panel discussion.


Mechanism of ribonucleoside diphosphate reductase from Escherichia coli. Evidence for 3'-C--H bond cleavage.
Incubation of the pyrimidine [3'-3H]UDP with ribonucleotide reductase resulted in an isotope effect on the conversion to dUDP which varied as a function of pH and allosteric effectors (pH, kH/kT, effector): 6.6, 4.7, ATP; 7.6, 3.3, ATP; 7.6, 2.6, dATP; 7.6, 2.0, TTP; 8.4, 2.8, ATP. During this reaction 3H2O was also released. The lower the pH of the reaction, the larger the isotope effect, and the smaller the amount of 3H2O produced. At 50% conversion of UDP to dUDP and at pH 7.6, approximately 0.5% of total 3H present in solution was volatilized, while at pH 8.4, approximately 0.9% was volatilized. Similar experiments in which the purine [3'-3H]ADP was incubated with ribonucleotide reductase also resulted in an isotope effect on its conversion to dATP which varied as a function of pH (pH, kH/kT with dGTP as an effector); 6.6, 1.9; 7.6, 1.7; 8.6, 1.4. Furthermore, 3H2O was also released as a function of the extent of the reaction. At 50% turnover and pH 7.6, approximately 0.6% of 3H2O was volatilized, while at pH 8.6 approximately 1.25% was released. Two control experiments in which either the B1 subunit of ribonucleotide reductase was inactivated with 2'-chloro-2'-deoxyuridine 5'-diphosphate or the B2 subunit of ribonucleotide reductase was inactivated with 2'-azido-2'-deoxyuridine 5'-diphosphate and then the enzyme incubated with [3'-3H]ADP or [3'-3H]UDP indicated that in neither case was 3H released. Both B1 and B2 subunits are required for cleavage of the 3'-C--H bond. Incubation of [3'-3H]dADP or [3'-3H]dUDP with ribonucleotide reductase produced no measurable release of 3H. These data clearly indicate that conversion of a purine or pyrimidine diphosphate to a deoxynucleotide diphosphate by Escherichia coli ribonucleotide reductase requires cleavage of the 3'-C--H bond of the substrate. The fate of the 3'-H of the substrate was also determined. Incubation of [3'-2H]UDP with ribonucleotide reductase resulted in the production of [3'-2H]dUDP.


Point mutations in mitochondrial DNA in patients with hypertrophic cardiomyopathy.
Recent advances suggest that mutations in nuclear DNA are involved in the etiology of autosomal dominant hypertrophic cardiomyopathy. Mitochondria have their own DNA, and mutations in mitochondrial DNA have been shown to contribute to the genesis of various diseases. In this study, we developed rapid sequencing methods with the use of a fluorescence-based sequencing system and analyzed total mitochondrial DNA of seven patients with nonautosomal dominant hypertrophic cardiomyopathy. Multiple point mutations were observed in all patients with hypertrophic cardiomyopathy, although some of them were common among the subjects examined and the others are unique to each subject. Point mutations in transfer RNA genes were observed in five of the seven patients, and point mutations that replaced conserved amino acids were also observed. These mutations may result in the impairment of mitochondrial function. According to these results, mutations in mitochondrial DNA may contribute to the genesis of some cases of nonautosomal dominant hypertrophic cardiomyopathy, and our methods may be useful for the detection of point mutations in mitochondrial DNA.


[Brain stimulation for treating stroke-related motor deficits].
Functional recovery of stroke-related deficits is mainly achieved through neural reorganization. Neurorehabilitative approaches, therefore, aim at supporting positive processes while suppressing maladaptive neuronal processes. This review summarizes the main findings of studies using non-invasive and invasive brain stimulation with respect to the benefits of the treatment for motor deficits after stroke. In addition, the article discusses possible approaches to enhance the effectiveness of neuromodulatory approaches and thus improve the outcome of patients.


Resistant hypertension due to unilateral renal artery occlusion as the first presentation of antiphospholipid syndrome.
Resistant hypertension in the setting of renal artery occlusion should prompt further investigation for secondary causes in a young patient. We present renal artery occlusion in the setting of antiphospholipid syndrome as the initial presentation successfully treated with percutaneous intervention. This case is followed by review of the literature.


Advances in understanding the molecular causes of diabetes-induced birth defects.
To review the current understanding of the molecular causes of birth defects resulting from diabetic pregnancy, with a focus on neural tube defects. A mouse model of diabetic pregnancy is described, in which embryo gene expression associated with neural tube defects is examined. Chemical, physiologic, or genetic manipulations are employed to elucidate critical pathways affected by increased glucose metabolism, and how abnormal gene expression disrupts neural tube closure. Increased glucose delivery to embryos, or activation of pathways that are stimulated by high glucose, such as the hexosamine biosynthetic pathway or hypoxia, increase oxidative stress in embryos, inhibit expression of Pax3, a gene that encodes a transcription factor that is required for neural tube closure, and increase neural tube defects. Conversely, blocking these pathways, or providing the antioxidants, reduced glutathione or vitamin E, suppress the adverse effects of excess glucose. Pax3 decreases steady-state levels of the p53 tumor-suppressor protein, such that when Pax3 is deficient, p53 protein increases, leading to increased neuroepithelial apoptosis prior to completion of neural tube closure. Embryos that lack both functional Pax3 protein and p53 do not display neuroepithelial apoptosis or neural tube defects. Excess glucose metabolism by embryos resulting from maternal hyperglycemia disturbs a complex network of biochemical pathways, leading to oxidative stress. Oxidative stress inhibits expression of genes, such as Pax3, which control essential developmental processes. Pax3 protein is required during neural tube development to suppress p53-dependent cell death and consequent abortion of neural tube closure, but is not required to control expression of genes that direct neural tube closure. Impaired embryo gene expression resulting from oxidative stress, and consequent apoptosis or disturbed organogenesis, may be a general mechanism to explain diabetic embryopathy.


Use of L-asparaginase and cytosine arabinoside for refractory acute lymphocytic leukemia with particular reference to T-cell leukemia.
Ten patients with late-stage acute lymphocytic leukemia were treated with L-asparaginase and cytosine arabinoside. Complete remission was achieved in 8 patients including 5 of 5 patients with T-cell leukemia. Major toxicity included anaphylactic reactions in 3 of the 10 patients.


Tumor-derived extracellular vesicles: insights into bystander effects of exosomes after irradiation.
This review article aims to address the kinetic of TDEs in cancer cells pre- and post-radiotherapy. Radiotherapy is traditionally used for the treatment of multiple cancer types; however, there is growing evidence to show that radiotherapy exerts NTEs on cells near to the irradiated cells. In tumor mass, irradiated cells can affect non-irradiated cells in different ways. Of note, exosomes are nano-scaled cell particles releasing from tumor cells and play key roles in survival, metastasis, and immunosuppression of tumor cells. Recent evidence indicated that irradiation has the potential to affect the dynamic of different signaling pathways such as exosome biogenesis. Indeed, exosomes act as intercellular mediators in various cell communication through transmitting bio-molecules. Due to their critical roles in cancer biology, exosomes are at the center of attention. TDEs contain an exclusive molecular signature that they may serve as tumor biomarker in the diagnosis of different cancers. Interestingly, radiotherapy and IR could also contribute to altering the dynamic of exosome secretion. Most probably, the content of exosomes in irradiated cells is different compared to exosomes originated from the non-irradiated BCs. Irradiated cells release exosomes with exclusive content that mediate NTEs in BCs. Considering variation in cell type, IR doses, and radio-resistance or radio-sensitivity of different cancers, there is, however, contradictions in the feature and activity of irradiated exosomes on neighboring cells.


Release of vasoactive intestinal polypeptide (VIP) by electric stimulation of the vagal nerves.
The concentration of immunoreactive VIP was measured in portal venous and peripheral arterial plasma in anesthetized pigs. Following electric stimulation of the vagal nerves the median concentration of VIP in portal plasma rose from 21 to 58 pmol l-1 and a simultaneous increase was found in arterial plasma. Atropine did not abolish this effect of vagal stimulation. The response is interpreted as increased release of VIP.


A Comparative Study of Various Pretreatment Approaches for Bio-Ethanol Production from Willow Sawdust, Using Co-Cultures and Mono-Cultures of Different Yeast Strains.
The effect of different pretreatment approaches based on alkali (NaOH)/hydrogen peroxide (H2O2) on willow sawdust (WS) biomass, in terms of delignification efficiency, structural changes of lignocellulose and subsequent fermentation toward ethanol, was investigated. Bioethanol production was carried out using the conventional yeast Saccharomyces cerevisiae, as well as three non-conventional yeasts strains, i.e., Pichia stipitis, Pachysolen tannophilus, Wickerhamomyces anomalus X19, separately and in co-cultures. The experimental results showed that a two-stage pretreatment approach (NaOH (0.5% w/v) for 24 h and H2O2 (0.5% v/v) for 24 h) led to higher delignification (38.3 ± 0.1%) and saccharification efficiency (31.7 ± 0.3%) and higher ethanol concentration and yield. Monocultures of S. cerevisiae or W. anomalus X19 and co-cultures with P. stipitis exhibited ethanol yields in the range of 11.67 ± 0.21 to 13.81 ± 0.20 g/100 g total solids (TS). When WS was subjected to H2O2 (0.5% v/v) alone for 24 h, the lowest ethanol yields were observed for all yeast strains, due to the minor impact of this treatment on the main chemical and structural WS characteristics. In order to decide which is the best pretreatment approach, a detailed techno-economical assessment is needed, which will take into account the ethanol yields and the minimum processing cost.


Impact of device-guided slow breathing on symptoms of chronic heart failure: a randomized, controlled feasibility study.
In many patients with chronic heart failure (CHF) even normal daily life activities cause dyspnoea and fatigue, well-being might be considerably improved by even a modest decrease in such symptoms. The aim of this study was to investigate if lowering breathing rate with the help of a respiratory modulation (RM) device could improve symptoms in patients with CHF. Stable CHF patients with symptoms of dyspnoea were randomized to twice-daily 20 min sessions using an RM device or to music listening (ML) using a CD player, for a 4-week study period. Respiratory modulation guides the user to achieve a slow breathing rate (<10 breaths/min) while increasing exhalation time (Tex) relative to inhalation time (Tin). Lower breathing rate was accomplished by synchronizing respiratory movements with musical tones generated in response to breathing movements monitored with a belt-type sensor. Endpoints were reduced breathlessness and New York Heart Association (NYHA) class. Seventy-two patients (52 male, age 73 ± 11 years, NYHA 3.1 ± 0.9) were randomized and 65 completed the study (30 RM and 35 ML, respectively). There was no in-between group improvement in breathlessness and NYHA class. Patients in the RM group who displayed an average increase in Tex/Tin of >0.2 and a reduction in the average respiration rate during 30 sessions were considered responders. Responders reported reduced breathlessness (-0.86 ± 0.23 units, P < 0.005) and improved NYHA class (-0.64 ± 0.20, P < 0.01) compared with non-responders. Device-guided RM might have the potential to relieve symptoms of heart failure in outpatients by changing their breathing pattern.


An audit of lamotrigine, levetiracetam and topiramate usage for epilepsy in a district general hospital.
The aim of this audit was to ascertain outcomes for people who had taken or who were still taking three "new generation" broad-spectrum antiepileptic drugs (AEDs), namely lamotrigine, levetiracetam and topiramate. Thirteen percent of people became seizure free and approximately, one-third had a reduction of greater than 50% in their seizures. Two-thirds of people were still taking their audit AED. In addition, approximately one-third of people with a learning disability derived substantial benefit, although the rate of seizure freedom was lower. All three AEDs were most successful at treating primary generalised epilepsy and least successful with symptomatic generalised epilepsy. With some reservations the data suggests that levetiracetam and topiramate are the most efficacious AEDs, but topiramate is the least well tolerated. These results mean consideration of a "general prescribing policy" is important when using and choosing these AEDs. We conclude that lamotrigine, levetiracetam and topiramate are useful additions to the armamentarium of AEDs.


Guidelines for prevention of venous thromboembolism in immobile patients secondary to neurological impairment.
Venous thromboembolism (VTE) is a major cause of morbidity and mortality in hospitalized patients and 7% of these cases are due to immobility secondary to a neurological impairment. Many guidelines are available to guide clinicians dealing with medical or surgical patients. However, and with the exception of spinal injuries, no guidelines are available to deal with other neurologically impaired patients at risk of VTE. Our study aimed at gathering evidence from the literature to enable us to deal with the main controversial issues of VTE prevention. Guidelines will be formulated. A Clinical Standards Group is responsible for the development of clinical guidelines for the Greater Manchester Neurorehabilitation network with services covering a population of around 3 million. The development of VTE prevention guidelines started with the formulation of the main questions, then gathering evidence from the literature to address these questions. Wide consultation then took place. The guidelines were then put before the group for endorsement. Answers for the main questions such as duration of thromboprophylaxis, TEDS and antiplatelets drugs use were suggested. The resulting document was summarized as a flow chart for use. We feel that the proposed guidelines are a useful tool for clinicians as they reflect the evidence available from the literature at the moment.


Coping and depression in bulimia nervosa.
While theoretical models of bulimia have tended to emphasize single dimensions of the disorder, such as cognition or depression, factor analytic studies suggest that bulimia is best represented by a multifactorial model. In this study, we explore whether bulimia nervosa patients with different levels of depression display different types of coping. Bulimia nervosa clinic patients were divided into four subgroups based on level of depression and asked to respond to the Coping Strategies Inventory. The results suggest that avoidant or disengaged coping may be more related to affective symptoms than to bulimia, itself. While problem solving and cognitive restructuring did not appear to differ between the subgroups in this study, there were significant differences in social support seeking among the four groups. The findings suggest that bulimic patients who present with the affective and personality disordered dimension of bulimia need interventions that focus on the utilization of social support.


DOT-ELISA for detection of phenolic glycolipid PGL-Tb1 and diacyl-trehalose antigens of Mycobacterium tuberculosis.
A DOT-ELISA method for detection of 2,3-diacyl-trehalose (DAT, previously referred to as SL-IV antigen) and triglycosyl phenol phthiocerol di-mycocerosate (PGL-Tb1) antigens from Mycobacterium tuberculosis is described. The method enabled the detection of both antigens in 14 clinical isolates of M. tuberculosis from different geographic origins; the presence of the glycolipids was confirmed by chemical analysis. It was therefore concluded that the synthesis of both of these compounds is characteristic of the species.


Erysipelas in a stranded common bottlenose dolphin: first report in a South American odontocete.
Erysipelas is a zoonotic disease caused by Erysipelothrix rhusiopathiae. In cetaceans, this disease has two main clinical forms: a cutaneous one, grossly characterized by rhomboid lesions, and a septicemic and often fatal form. Erysipelas is considered an important cause of morbidity and mortality in captive cetaceans; however, information in free-ranging cetaceans is limited. An adult common bottlenose dolphin (Tursiops truncatus) was found dead and in advanced autolysis in Paraíba state, northeastern Brazil, on July 19th, 2020. Upon gross examination, 80% of the body surface presented disseminated rhomboid cutaneous lesions ranging from 4 to 6 cm-width, characterized by well-defined edges and occasional ulceration, consistent with erysipelas. Additionally, anthropic-made postmortem linear cuts and partial mechanical removal of the flank musculature were noted. Skin samples were collected for histopathologic and molecular analyses. Microscopically, it was possible to observe multifocal dermatitis with vasculitis. Erysipelothrix sp. was detected by PCR. Despite previous reports of human consumption of cetacean meat in northeastern Brazil, the observed marks and advanced carcass autolysis suggested that the animal was most likely used as bait for fishing instead of human intake. This case highlights the value of postmortem examination and PCR even in poorly preserved cadavers and contributes to the understanding of the epidemiology of cutaneous erysipelas in free-ranging cetaceans (first report in an odontocete from the Southern Hemisphere). Due to the zoonotic potential of certain Erysipelothrix species (i.e., E. rhusiopathiae), active public health policies are required to inform field professionals and the general public about the health threats associated with marine mammal manipulation and consumption.


The Multidisciplinary Management of Cutaneous Squamous Cell Carcinoma: A Comprehensive Review and Clinical Recommendations by a Panel of Experts.
Cutaneous squamous cell carcinomas (CSCC) account for about 20% of all keratinocyte carcinomas, which are the most common form of cancer. Heterogeneity of treatments and low mortality are a challenge in obtaining accurate incidence data and consistent registration in cancer registries. Indeed, CSCC mostly presents as an indolent, low-risk lesion, with five-year cure rates greater than 90% after surgical excision, and only few tumors are associated with a high-risk of local or distant relapse; therefore, it is particularly relevant to identify high-risk lesions among all other low-risk CSCCs for the proper diagnostic and therapeutic management. Chemotherapy achieves mostly short-lived responses that do not lead to a curative effect and are associated with severe toxicities. Due to an etiopathogenesis largely relying on chronic UV radiation exposure, CSCC is among the tumors with the highest rate of somatic mutations, which are associated with increased response rates to immunotherapy. Thanks to such strong pre-clinical rationale, clinical trials led to the approval of anti-PD-1 cemiplimab by the FDA (Food and Drug Administration) and EMA (European Medicines Agency), and anti-PD-1 pembrolizumab by the FDA only. Here, we provide a literature review and clinical recommendations by a panel of experts regarding the diagnosis, treatment, and follow-up of CSCC.


Does rapid maxillary expansion enlarge the nasal cavity and pharyngeal airway? A three-dimensional assessment based on validated analyses.
To evaluate the three-dimensional changes following rapid maxillary expansion (RME) of the nasal cavity (NC) and pharyngeal airway (PA) in growing patients, using innovative and validated evaluation methods and to investigate whether a correlation between skeletal expansion and increase in airway volume exists. Records of patients who had cone beam computed tomography taken before and after orthodontic treatment with or without RME were retrospectively collected and divided into two groups: (a) RME, 39 patients (mean age 10.40 ± 1.74 years); and (b) control, 29 patients, matched for age (mean age 11.07 ± 1.45 years) and follow-up period. Total and partial volumes of the NC and the PA were calculated. The PA centerline was determined to assess the minimal cross-sectional area and hydraulic diameter. Paired and unpaired t test were applied to compare the difference between time points and between groups. One-way ANOVA and post hoc Tukey's tests were used to compare subgroups with respect to changes in palatal width and lacrimal ducts distance. All of the NC, PA and skeletal parameters were significantly enlarged after RME. The NC volume and inter-molar distance in the RME were significantly larger compared to the control group. The initially lower mean values of minimal cross-sectional area and hydraulic diameter in the RME group when compared to the control group normalized after RME treatment. Based on validated analyses, the NC volume increase was evident after RME in the long term after controlling for growth.


Hypoxia-Induced Phenotypic Transformation of Corpus Cavernosum Smooth Muscle Cells After Cavernous Nerve Crush Injury by Down-Regulating P38 Mitogen-Activated Protein Kinase Expression.
Cavernosal nerve (CN) injury is commonly caused by radical prostatectomy surgery, and it might directly lead to erectile dysfunction (ED). Currently, the role of mitogen-activated protein kinase (MAPK) family proteins in phenotypic transformation of corpus cavernosum smooth muscle cell (CCSMC) after CNs injury is poorly understood. To investigate the role of p38 MAPK in hypoxia-induced phenotypic transformation of CCSMCs after CN injury. In total, 20 Sprague-Dawley rats (male and 8 weeks of age) were randomly divided into 2 groups, including a sham group and CNCI group. In the sham group, rats were sham-operated by identifying 2 CNs without causing direct damage to the CNs. In the CNCI group, rats were subjected to bilateral CN crush injury. CCSMCs were isolated from the normal corpus cavernosum tissues of the Sprague-Dawley rat and then cultured in 21% or 1% O2 concentration context for 48 hours. Intracavernous pressure/mean arterial pressure were analyzed to measure erectile response. The impact of hypoxia on penile pathology, as well as the expression of extracellular signal-regulated kinases, the c-Jun NH2-terminal kinase, and p38 MAPK, were analyzed. Compared with the sham group, the intracavernous pressure/mean arterial pressure rate and α-smooth muscle actin expression of CNCI group were decreased significantly (P = .0001; P = .016, respectively), but vimentin expression was significantly increased (P = .023). Phosphorylated p38 level in CNCI group was decreased significantly (P = .017; sham: 0.17 ± 0.005; CNCI: 0.14 ± 0.02). The CCSMCs in the normoxia group were long fusiform, whereas the morphology of CCSMCs in the hypoxia group became hypertrophic. After hypoxia for 48 hours, the expression of α-smooth muscle actin and phosphorylated p38 MAPK was decreased significantly (P = .01; P = .024, normoxia: 0.66 ± 0.18, hypoxia: 0.26 ± 0.08, respectively), and the expression of hypoxia-inducible factor-1α and collagen I was increased significantly in hypoxia group (P = .04; P = .012, respectively). Hypoxia induced the phenotypic transformation of CCSMCs after CNCI might be associated with the downregulation of phosphorylated p38 MAPK. Chen S, Huang X, Kong X, et al. Hypoxia-Induced Phenotypic Transformation of Corpus Cavernosum Smooth Muscle Cells After Cavernous Nerve Crush Injury by Down-Regulating p38 Mitogen-Activated Protein Kinase Expression. Sex Med 2019;7:433-440.


Ankle dorsiflexion deficit in the back leg is a risk factor for shoulder and elbow injuries in young baseball players.
The relationship between ankle joint function and throwing-related injuries has not been demonstrated. We hypothesized that limited ankle joint range of motion (ROM) was related to risk factors for shoulder and elbow injuries in young baseball players. This 12-month prospective cohort study evaluated the age, height, weight, playing position, shoulder, elbow, and ankle function of 228 enrolled baseball players. Shoulder and elbow injuries were tracked during the season. Univariate and multivariate analyses were performed to identify risk factors for shoulder and elbow injuries among participants divided into non-injured and injured groups. Univariate analysis showed that age, height, weight, ROM of elbow flexion in the dominant arm, muscle strength ratio of shoulder abduction, and the likelihood of being a pitcher or a catcher were significantly greater in the injured group than in the non-injured group. ROM of shoulder abduction-external/internal rotation, shoulder total arc on the dominant arm, ankle joint dorsiflexion, and plantar flexion on the back (non-lead) and front (lead) legs were significantly less in the injured group than in the non-injured group. In conclusion, ROM dorsiflexion deficits in the back leg, shoulder abduction-external rotation in the dominant arm, ROM increase in elbow flexion on the dominant side, older age, and being a pitcher were significant independent risk factors for injury.


Conservative versus tailored surgical treatment in patients with first time lateral patella dislocation: a randomized-controlled trial.
Patellar instability has a high incidence and occurs particularly in young and female patients. If the patella dislocates for the first time, treatment is usually conservative. However, this cautious approach carries the risk of recurrence and of secondary pathologies such as osteochondral fractures. Moreover, there is also risk of continuous symptoms apparent, as recurrent patella dislocation is related to patellofemoral osteoarthritis as well. An initial surgical treatment could possibly avoid these consequences of recurrent patella dislocation. A prospective, randomized-controlled trial design is applied. Patients with unilateral first-time patella dislocation will be considered for participation. Study participants will be randomized to either conservative treatment or to a tailored patella stabilizing treatment. In the conservative group, patients will use a knee brace and will be prescribed outpatient physical therapy. The surgical treatment will be performed in a tailored manner, addressing the pathologic anatomy that predisposes to patella dislocation. The Banff Patellofemoral Instability-Instrument 2.0, recurrence rate, apprehension test, joint degeneration, and the Patella Instability Severity Score will serve as outcome parameters. The main analysis will focus on the difference in change of the scores between the two groups within a 2-year follow-up. Statistical analysis will use linear mixed models. Power analysis was done for the comparison of the two study arms at 2-year follow-up with regard to the BPII Score. A sample size of N = 64 per study arm (128 overall) provides 80% power (alpha = 0.05, two-tailed) to detect a difference of 0.5 standard deviations in a t-test for independent samples. Although several studies have already dealt with this issue, there is still no consensus on the ideal treatment concept for primary patellar dislocation. Moreover, most of these studies show a unified surgical group, which means that all patients were treated with the same surgical procedure. This is regarded as a major limitation as surgical treatment of patella dislocation should depend on the patient's anatomic pathologies leading to patellar instability. To our knowledge, this is the first study investigating whether patients with primary patella dislocation are better treated conservatively or operatively with tailored surgery to stabilize the patella. The study will be prospectively registered in the publicly accessible database www.ClinicalTrials.gov .


High calcium, ATP, and poly(I:C) augment the immune response to β-glucan in normal human epidermal keratinocytes.
β-Glucans are pathogen-associated molecular patterns of fungi such as Candida albicans. Here, we studied their effects on normal human epidermal keratinocytes (NHEKs) from neonatal foreskin, and with high calcium to induce keratinocyte differentiation, danger signals, and pathogen-associated compounds such as adenosine 5'-triphosphate (ATP), poly(I:C), and lipopolysaccharide (LPS). β-Glucan stimulation significantly increased IL-8, IL-6, and IL-1α production by NHEKs. Well-differentiated NHEKs produced elevated IL-8 levels, whereas ATP, a danger signal, significantly increased IL-8 and IL-6 production, and the pathogen-associated compound, poly(I:C), augmented IL-1α production by β-glucan-stimulated NHEKs. No response to LPS from Escherichia coli was seen. Dectin-1 is known as the major receptor for β-glucans on phagocytes and dendritic cells. Dectin-1 mRNA was detected in NHEKs by reverse transcription-PCR. Flow-cytometric analyses confirmed the NHEK cell surface expression of dectin-1. Immunoblotting showed that β-glucan induced dual phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase (ERK)1/2), and p38 MAPK in NHEKs; these signaling pathways are known to be associated with dectin-1. Treatment with the ERK inhibitor PD98059 and with the p38 kinase inhibitor SB203580 effectively suppressed β-glucan-induced IL-8 production by NHEKs. Thus, high calcium, ATP, and poly(I:C) augment the cytokine and chemokine production by β-glucan-stimulated NHEKs. Dectin-1 is present on NHEKs and may have an important role in cell response to β-glucan.


Transient ischemic attacks: an update.
This is a review of extant concepts of transient ischemic attacks (TIAs), their definitions, prognostic significance, pathogenesis, physiology, and management. The natural history of TIAs depends upon the risk factors of the population group studied, so that therapeutic trials should be controlled and randomized and not dependent upon published natural history data. A strong association between TIAs and coronary artery disease has now been established. It may be difficult to establish the cause or pathogenesis of TIAs in any given patient in view of the relatively poor correlation between the patient's symptoms and location of arterial plaques. Recent studies have suggested mechanisms aside from impaired perfusion or embolization from carotid plaques or vertebral basilar disease. There are no proven indications for carotid endarterectomy, a procedure which has been excessively used in the United States, but presently ongoing prospective, randomized, controlled multi-center studies will likely resolve this important issue. Neither is there scientific validation for the use of long-term anticoagulants, but data support the efficacy of ASA in reducing the incidence of stroke and myocardial infarction in patients with TIAs.


Hematological characteristics, cytogenetic features, and post-induction measurable residual disease in thymic stromal lymphopoietin receptor (TSLPR) overexpressed B-cell acute lymphoblastic leukemia in an Indian cohort.
The overexpression of cytokine receptor-like factor-2 (CRLF2) identified by anti-thymic stromal lymphopoietin receptor/TSLPR flow cytometry (FCM) has been reported as a screening tool for the identification of BCR-ABL1-like B-cell acute lymphoblastic leukemia/B-ALL with CRLF2 re-arrangement. TSLPR expression was studied prospectively in consecutive 478 B-ALLs (≤ 12 years (n = 244); 13-25 years (n = 129); > 25 years (n = 105)) and correlated with various hematological parameters and end-of-induction measurable residual disease (day 29; MRD ≥ 0.01% by 10-color FCM). TSLPR positivity in ≥ 10% leukemic cells was detected in 14.6% (n = 70) of B-ALLs. CRLF2 re-arrangement was detected in eight cases (11.4%) including P2RY8-CRLF2 (n = 6), and IgH-CRLF2 (n = 2) with a median TSLPR positivity of 48.8% and 99% leukemic cells, respectively. Recurrent gene fusions/RGF (BCR-ABL1 (17.1%); ETV6-RUNX1 (4.2%), TCF3-PBX1 (1.4%)), other BCR-ABL1-like chimeric gene fusions/CGFs (PDGFRB-rearrangement (2.9%), IgH-EPOR (1.4%)), CRLF2 extra-copies/hyperdiploidy (17.1%), and IgH translocation without a known partner (10%) were also detected in TSLPR-positive patients. CD20 positivity (52.9% vs 38.5%; p = 0.02) as well as iAMP21 (4.3% vs 0.5%; p = 0.004) was significantly more frequent in TSLPR-positive cases. TSLPR-positive patients did not show a significantly higher MRD, compared to TSLPR-negative cases (37% vs 33%). Increasing the threshold cut-off (from ≥ 10 to > 50% or > 74%) increased the specificity to 88% and 100% respectively in identifying CRLF2 translocation. TSLPR expression is not exclusive for CRLF2 translocations and can be seen with various other RGFs, necessitating their testing before its application in diagnostic algorithms. In patients with high TSLPR positivity (> 50%), the testing may be restricted to CRLF2 aberrancies, while patients with 10-50% TSLPR positivity need to be tested for both CRLF2- and non-CRLF2 BCR-ABL1-like CGFs.


Evaluation of hand functions and distal radioulnar joint instability in elite wheelchair basketball athletes: a cross-sectional pilot study.
Wrist injury affects wheelchair basketball players' performance; however, the relationship between distal radioulnar joint (DRUJ) instability and hand functions is unclear. This cross-sectional pilot study investigated DRUJ instability in elite female wheelchair basketball athletes using force-monitor ultrasonography. Nine elite female wheelchair basketball athletes (18 wrists) were included in the study. A triangular fibrocartilage complex (TFCC) injury was confirmed using magnetic resonance imaging (MRI). Hand functions were evaluated based on the range of motion (ROM) of wrist palmar flexion, dorsiflexion, radial deviation, and ulnar deviation; grip strength; arm circumference; forearm circumference; and DRUJ instability or pain using the ballottement test. The Mann-Whitney U test was used to compare parameters between the TFCC-injured and intact wrists. Radioulnar displacement was measured using force-monitor ultrasonography and pressure data, and the displacement-to-force ratio was used as an indicator of DRUJ instability. The correlation between the DRUJ displacement-to-force ratio and each hand function assessment was evaluated using Pearson correlation coefficient for the TFCC-injured and intact wrists. A generalized linear mixed model (GLMM) was used to estimate the relationship between hand functions and DRUJ instability. TFCC injuries in seven wrists were confirmed using MRI findings (38.9%). The ulnar deviation ROM values of the TFCC-injured wrist (n = 7) and intact (n = 11) groups were 38.6 ± 8.0° and 48.6 ± 7.8°, respectively. The ulnar deviation ROM was significantly smaller in the TFCC-injured wrists (p = 0.02, r = - 0.54). In the TFCC-injured wrists, no correlation was observed between the displacement-to-force ratio and the hand function assessment. In contrast, the displacement-to-force ratio negatively correlated with grip strength, arm circumference, and forearm circumference in the intact wrists (Pearson correlation coefficient r = - 0.78, - 0.61, and - 0.74, respectively). The GLMM showed that the displacement-to-force ratio significantly affected grip strength, arm circumference, and forearm circumference in the intact group. In intact wrists, correlations were observed between hand functions such as upper arm/forearm strength and DRUJ stability evaluated using ultrasound. Maintaining and strengthening grip strength, forearm circumference, and arm circumference are associated with DRUJ stability and may be related to TFCC injury prevention in wheelchair basketball athletes. The protocol was registered with the UMIN Clinical Trials Registry (UMIN000043343) [Date of first registration: 16/02/2021].


The behavioral management of chronic pain: a response to critics.
Common criticisms of behavioral treatment programs for chronic pain are summarized. Some criticisms are based on conceptual misunderstandings; therefore, basic concepts and goals of behavioral programs are presented. Other criticisms question the effectiveness of these programs; therefore, the role of social reinforcers in maintaining or reducing pain behaviors is reviewed. The failure to isolate specific treatment variables is alleged; this is acknowledged, along with the practical and ethical questions making this virtually impossible. Finally we describe the need to change the thinking about 'pain' from the pathological or disease model, appropriate to acute pain, to a learning model when discussing the excess disability and suffering of chronic pain patients.


Neuroprotective repositioning and anti-tau effect of carvedilol on rotenone induced neurotoxicity in rats: Insights from an insilico& in vivo anti-Parkinson's disease study.
Current treatments for Parkinson's Disease (PD) only provide symptomatic relief; however, they don't delay the disease progression, hence new treatment options should be considered. Carvedilol is a nonselective β & α1 blocker with additional effects as an antioxidant, anti-inflammatory and neuro protective properties. In this research, an insilico study was conducted to primarily evaluate carvedilol as an anti-parkinsonian and anti-tau protein target. PASS prediction was performed followed by a docking study of carvedilol. Carvedilol yielded promising results and forward guided this study onto its in vivo evaluation. The in vivo study aimed to assess the neuro-protective effects of carvedilol in rotenone-induced rat model of PD and investigate the potential underlying mechanisms. The effects of carvedilol (2.5, 5, and 10 mg/kg) on the measured parameters of open field, catalepsy, Y-maze tests as well as brain histology, and tyrosine hydroxylase (TH) were evaluated. The effective doses (5 and 10 mg/kg) were further tested for their potential anti-tau protein effects. Carvedilol (5 and 10 mg/kg) prevented rotenone-induced motor deficits, spatial memory dysfunction, and histological damage. Additionally, carvedilol significantly inhibited rotenone-induced decrease in TH expression in the striata of the rats. These effects were associated with reduction of rotenone-induced neuro-inflammation, microglial activation and release of glial fibrillary acidic protein (GFAP), along with reduction in N-methyl-D-aspartate receptors activation, alpha-synculein and phospho-Tau (P-Tau) protein expression. Carvedilol also reduced tau protein hyper-phosphosrylation by Glycogen synthase 3β (GSK 3β) inhibition and Phosphoinositide 3-kinase (PI3K) stimulation. Collectively, these results suggest that carvedilol might be a possible candidate for management of PD.


Tandem indole C-H alkenylation/arylation for tetra-substituted alkene synthesis.
Alkynyl indoles undergo a novel sequence of Pd-catalysed indole C-H activation/alkyne carbopalladation/arylation, with diaryliodonium salts providing the aryl components. An array of functionalised indole alkenes have been prepared in good to excellent yield, with the reaction being selective for the Z-alkene.


Urethral stricture in children: treatment by urethroplasty with bladder mucosa graft.
Urethral strictures in children, which are not frequent, often require urethroplasty when dilations and/ or urethrotomies have failed. A bladder mucosa graft was used successfully for urethral reconstruction to treat posterior hypospadias. We describe our experience with a bladder mucosa graft during urethroplasty for acquired urethral strictures in 8 children. Urethral strictures secondary to the treatment of hypospadias were excluded. Bladder mucosa was used successfully as an onlay or patch graft urethroplasty in 7 patients. One patient had a tubularized graft with secondary stenosis treated successfully by dilation.


Production and characterisation of cell- and tissue-specific monoclonal antibodies for the flatworm Macrostomum sp.
Monoclonal antibodies (mABs) against various cell types of the basal free-living flatworm Macrostomum sp. were produced by immunising Balb/c mice with cell suspensions of disintegrated animals. We identified 360 positive supernatants with specific staining of various tissues, cell types, patterns or structures. Here we report immunocytochemical characterisation, histological stainings and isotyping of 11 mABs specific for muscle cells (MMu-1, MMu-2, MMu-3, MMu-4), digestive and prostate glands (MDr-1 and MDr-2, MPr-1), epidermal cells (MEp-1), the ventral nerve cord including neuron clusters (MNv-1), gastrodermal cells (MDa-1) and spermatids (MSp-1). Confocal microscopy, histological techniques, electron microscopy and immunoblotting were applied to demonstrate stainings in juveniles, adults, starved or well-fed animals. Considering the current lack of specific markers the obtained mABs will be particularly helpful studying embryonic and postembryonic development, pattern formation, cell differentiation, regeneration and reproductive allocation in Macrostomum sp., and possibly other basal flatworms. The small size, ease of culturing, short generation time, transparency and the basal phylogenetic position specify Macrostomum sp. as a suitable model organism for comparative analyses within Platyhelminthes and to Drosophila and C. elegans.


Non-Surgical Correction of Congenital Ear Anomalies: A Critical Assessment of Caretaker Burdens and Aesthetic Outcomes.
Congenital ear anomalies result from cartilage and skin compression in utero. They can be corrected in infancy before the cartilage hardens and loses its malleability. Caretaker burden of ear molding and its impact on esthetic outcomes has not been studied. Demographic and procedural variables were retrospectively collected for infants who underwent ear molding. Parents were surveyed regarding their experience, caretaker burden, and esthetic outcome. Outside physicians were provided with pre- and post-treatment photographs and asked to rate outcomes. A Likert scale was developed for responses and converted to a numeric score from 1 to 5 with 5 as the most desirable. Seventy-four patients comprising 121 ears were included. Mean age at treatment was 20.1 ± 21.4 days with treatment duration of 21.1 ± 7.7 days. Parental participation in the survey was 70.1%. Questions that queried parents' experiences revealed a "very positive" experience with minor burden related to bathing and cleaning (Mean Likert Score 4.1, Range 1-5). Favorable parent-reported outcomes were obtained regarding anticipated social distress (4.28, 1-5), satisfaction with results (4.27, 1-5), and perception of final appearance (4.18, 1-5). Physician assessments of esthetic outcomes were slightly lower, but favorable between "somewhat effective" and "very effective" (3.46, 1-5). Earlier treatment trended favorably, but did not reach significance. Ear malformations had higher parent-reported satisfaction than ear deformations (4.75 ± 0.46 vs 4.21 ± 1.25, p = 0.025). Despite the additional obligation for new parents, infant ear molding is rated low in terms of caretaker burden. Esthetic outcomes are excellent as assessed by parents and physicians. However, caretakers reported higher esthetic outcomes than physician evaluations. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.


Nonarteritic anterior ischemic optic neuropathy in a child with optic disk drusen.
Optic disk drusen are calcific deposits that form in the optic nerve head secondary to abnormalities in axonal metabolism and degeneration. The clinical course is variable, ranging from stable vision to acute or progressive visual loss. We evaluated a healthy 12-year-old boy with a history of asymptomatic bilateral disk drusen who presented with acute painless unilateral visual loss after hiking to an altitude of 11,000 feet. Findings were consistent with nonarteritic anterior ischemic optic neuropathy.


Methamphetamine facilitates pulmonary and splenic tissue injury and reduces T cell infiltration in C57BL/6 mice after antigenic challenge.
Methamphetamine (METH) is a strong addictive central nervous system stimulant. METH abuse can alter biological processes and immune functions necessary for host defense. The acquisition and transmission of HIV, hepatitis, and other communicable diseases are possible serious infectious consequences of METH use. METH also accumulates extensively in major organs. Despite METH being a major public health and safety problem globally, there are limited studies addressing the impact of this popular recreational psychostimulant on tissue adaptive immune responses after exposure to T cell dependent [ovalbumin (OVA)] and independent [lipopolysaccharide (LPS)] antigens. We hypothesized that METH administration causes pulmonary and splenic tissue alterations and reduces T cell responses to OVA and LPS in vivo, suggesting the increased susceptibility of users to infection. Using a murine model of METH administration, we showed that METH causes tissue injury, apoptosis, and alters helper and cytotoxic T cell recruitment in antigen challenged mice. METH also reduces the expression and distribution of CD3 and CD28 molecules on the surface of human Jurkat T cells. In addition, METH decreases the production of IL-2 in these T-like cells, suggesting a negative impact on T lymphocyte activation and proliferation. Our findings demonstrate the pleotropic effects of METH on cell-mediated immunity. These alterations have notable implications on tissue homeostasis and the capacity of the host to respond to infection.


Tumors after renal and cardiac transplantation.
Organ transplant recipients treated with immunosuppressive therapy are prone to develop malignancies particularly squamous cell carcinomas of the skin, non-Hodgkin's lymphomas, Kaposi's sarcomas, carcinomas of the vulva and perineum, in situ carcinomas of the uterine cervix, renal carcinomas, hepatomas, and various sarcomas. The earliest tumors to appear are the Kaposi's sarcoma at an average of 21 months after transplantation, and the latest are carcinomas of the vulva and perineum, at an average of 112 months after transplantation. The tumors that develop in cardiac allograft recipients compared with renal transplant recipients are predominantly non-Hodgkin's lymphomas and more rarely, skin, uterine cervical and vulvar tumors. Major factors accounting for these differences are the intensity of immunosuppressive therapy given to the cardiac patients and the much longer follow-up of the renal allograft recipients.


Electro-optical measurement of intense electric field on a high energy pulsed power accelerator.
We describe a direct electro-optical approach to measuring a strong 118 MV/m narrow pulse width (~ 33 ns) electric field in the magnetically insulated transmission line (MITL) of a pulsed power accelerator. To date, this is the highest direct external electric field measured electro-optically in a pulsed power accelerator, and it is between two to three orders of magnitude higher than values reported in comparable high energy scientific experiments. The MITL electric field is one of the most important operating parameters in an accelerator and is critical to understanding the properties of the radiation output. However, accurately measuring these high fields using conventional pulsed power diagnostics is difficult due to the strength of interfering particles and fields. Our approach uses a free-space laser beam with a dielectric crystal sensor that is highly immune to electromagnetic interference and does not require an external calibration. Here we focus on device theory, operating parameters, laboratory and pulsed power accelerator experiments as well as challenges that were overcome in the measurement environment.


Myosin light chain kinases and phosphatase in mitosis and cytokinesis.
At mitosis, cells undergo drastic alterations in morphology and cytoskeletal organization including cell rounding during prophase, mitotic spindle assembly during prometaphase and metaphase, chromatid segregation in anaphase, and cytokinesis during telophase. It is well established that myosin II is a motor responsible for cytokinesis. Recent reports have indicated that myosin II is also involved in spindle assembly and karyokinesis. In this review, we summarize current understanding of the functions of myosin II in mitosis and cytokinesis of higher eukaryotes, and discuss the roles of possible upstream molecules that control myosin II in these mitotic events.


Detection of Babesia canis rossi, B. canis vogeli, and Hepatozoon canis in dogs in a village of eastern Sudan by using a screening PCR and sequencing methodologies.
Babesia and Hepatozoon infections of dogs in a village of eastern Sudan were analyzed by using a single PCR and sequencing. Among 78 dogs, 5 were infected with Babesia canis rossi and 2 others were infected with B. canis vogeli. Thirty-three dogs were positive for Hepatozoon. Hepatozoon canis was detected by sequence analysis.


Effects of sublethal exposure to metofluthrin on the fitness of Aedes aegypti in a domestic setting in Cairns, Queensland.
Metofluthrin is highly effective at reducing biting activity in Aedes aegypti. Its efficacy lies in the rapid onset of confusion, knockdown, and subsequent kill of a mosquito. In the field, there are a variety of scenarios that might result in sublethal exposure to metofluthrin, including mosquitoes that are active at the margins of the chemical's lethal range, brief exposure as mosquitoes fly in and out of treated spaces or decreasing efficacy of the emanators with time. Sublethal effects are key elements of insecticide exposure and selection. The metofluthrin dose for each treatment group of male and female Ae. aegypti was controlled using exposure time intervals to a 10% active ingredient (AI) metofluthrin emanator. Room size and distance from the emanator for all groups was maintained at 3 m. In bioassay cages, male Ae. aegypti were exposed at 0, 5, 10, 20, 30 and 40-min intervals. Females were exposed in bioassay cages at 0, 10, 20, 30, 40 and 60-min intervals. Mortality rates and fecundity were observed between the exposure time groups for both sexes. Female Ae. aegypti exposed for 60 min had a significantly higher mortality rate (50%), after a 24-h recovery period, than other exposure times, 10, 20, 30 and 40 min (P < 0.001). An overall difference in fecundity was not observed in females between treatments. A significant effect on male mortality was only observed at 40 min exposure times, three meters from the 10% AI emanator [Formula: see text]. Males that survived metofluthrin exposure were as likely to produce viable eggs with an unexposed female as males that had not been exposed (P > 0.05). Regardless of sex, if a mosquito survived exposure, it would be as biologically successful as its unexposed counterpart. Portability of the metofluthrin emanator and delayed knockdown effects create opportunities for sublethal exposure and potential pyrethroid resistance development in Ae. aegypti, and should be taken into consideration in recommendations for field application of this product, including minimum exposure periods and a prescribed number of emanators per room based on volume.


Whole blood ionized magnesium in the healthy neonate.
We aimed to determine the normal range of ionized magnesium (IMg2+) concentration at birth and 24 hours of life in the healthy, term (37 to 41 weeks old) neonate. Cord blood was obtained from the umbilical vein of 30 patients. In addition, blood was obtained from 32 infants at 24 hours of life. Whole blood was analyzed to determine IMg2+ concentration, ionized calcium concentration, and pH. The normal range of IMg2+ concentration (mean +/- 2 SD) was found to be 0.40 to 0.56 mmol/L (0.97 to 1.36 mg/dL) at both birth and 24 hours of life. The normal range of IMg2+ concentration (mean +/- 2 SD) in the healthy neonate at birth and 24 hours of life is 0.40 to 0.56 mmol/L (0.97 to 1.36 mg/dL). This range can serve as a reference value for future studies regarding the clinical usefulness of IMg2+ concentration determination in neonatal disease states.


A Large Urinary Bladder Hemangioma Mimicking Urachal Cancer: A Case Report and Literature Review.
Urinary bladder hemangiomas are rare, especially in children and adolescents. We present a case of a 17-year-old young man with persistent gross hematuria for 1 month. Computed tomography revealed a 3.6 cm mass on the superior anterior wall of the urinary bladder, which was highly suspected as an urachal tumor. We carried out an en bloc resection of the urachus and bladder tumor. The pathologic report indicated a cavernous hemangioma of the urinary bladder. No tumor recurrence or bleeding was found during the 2-year follow-up. Urinary bladder hemangioma is an important differential diagnosis in young patients with hematuria.


Camera-Robot Calibration for the da Vinci® Robotic Surgery System.
The development of autonomous or semi-autonomous surgical robots stands to improve the performance of existing teleoperated equipment, but requires fine hand-eye calibration between the free-moving endoscopic camera and patient-side manipulator arms (PSMs). A novel method of solving this problem for the da Vinci® robotic surgical system and kinematically similar systems is presented. First, a series of image-processing and optical-tracking operations are performed to compute the coordinate transformation between the endoscopic camera view frame and an optical-tracking marker permanently affixed to the camera body. Then, the kinematic properties of the PSM are exploited to compute the coordinate transformation between the kinematic base frame of the PSM and an optical marker permanently affixed thereto. Using these transformations, it is then possible to compute the spatial relationship between the PSM and the endoscopic camera using only one tracker snapshot of the two markers. The effectiveness of this calibration is demonstrated by successfully guiding the PSM end effector to points of interest identified through the camera. Additional tests on a surgical task, namely grasping a surgical needle, are also performed to validate the proposed method. The resulting visually-guided robot positioning accuracy is better than the earlier hand-eye calibration results reported in the literature for the da Vinci® system, while supporting intraoperative update of the calibration and requiring only devices that are already commonly used in the surgical environment.


Computational exploration of polymorphisms in 5-hydoxytryptamine 5-HT₁A and 5-HT₂A receptors associated with psychiatric disease.
The huge polymorphic data have been prioritized towards a specific disease based on sequence and structure homology tools to a large extent. In this study, we have explored the potential non-synonymous Single Nucleotide Polymorphism (nsSNP) in serotonin (5-HT) receptors involved in psychotic syndromes and their response pathway. The most damaging point mutations were screened from 12 classes of serotonin receptors comprising 7743 variants. In 5HT(1A) receptor, two alleles were found to be highly deleterious located at ligand binding extracellular-2 and one at intracellular loop-3 domains. Similarly, we found two alleles predicted to be highly damaging in 5HT(2A) residing at N and C-Terminal domains. The above alleles were further confirmed based on their flexibility and stability difference using the molecular dynamic simulation analysis. Integrating these results appeared promising for being able to filter out potential non-synonymous Single Nucleotide Polymorphisms for neuropsychiatric disorders.


M.I.T./Canadian vestibular experiments on the Spacelab-1 mission: 4. Space motion sickness: symptoms, stimuli, and predictability.
Space sickness symptoms were observed by 4 specially trained observers on Spacelab-1. Three reported persistent symptoms, and vomited repeatedly during the first and/or second day of flight. Head movements on all axes were provocative, particularly in pitch and roll. Head acceleration data recorded from 2 symptomatic crewmen showed that after several hours of physical activity in orbit, symptoms appeared, and thereafter both crewmen were compelled to limit head movements. Firm body contact with motionless surfaces helped alleviate symptoms. When crewmembers floated into unfamiliar body orientations in the cabin, inherent ambiguities in static visual orientation cues sometimes produced spatial reorientation episodes which were also provocative. Symptoms largely resembled those of other forms of prolonged motion sickness, superimposed upon other symptoms attributable to fluid shift. All 4 eventually used anti-motion sickness drugs. When they did, vomiting frequency was reduced. By the 4th day, symptoms subsided, and head accelerations again increased in magnitude and variability. Sickness intensity in orbit was not predicted by statistically concordant results of 6 acute preflight susceptibility tests. However, results from a longer duration preflight prism goggles test showed an apparent correlation. All subjects were asymptomatic making head movements in parabolic flight 4 days after the mission, but not 1 year later. Overall, results support the view that space sickness is a motion sickness.


Application of Elastin-like Polypeptide in Tumor Therapy.
Elastin-like polypeptides (ELPs) are stimulus-responsive artificially designed proteins synthesized from the core amino acid sequence of human tropoelastin. ELPs have good biocompatibility and biodegradability and do not systemically induce adverse immune responses, making them a suitable module for drug delivery. Design strategies can equip ELPs with the ability to respond to changes in temperature and pH or the capacity to self-assemble into nanoparticles. These unique tunable biophysicochemical properties make ELPs among the most widely studied biopolymers employed in protein purification, drug delivery, tissue engineering and even in tumor therapy. As a module for drug delivery and as a carrier to target tumor cells, the combination of ELPs with therapeutic drugs, antibodies and photo-oxidation molecules has been shown to result in improved pharmacokinetic properties (prolonged half-life, drug targeting, cell penetration and controlled release) while restricting the cytotoxicity of the drug to a confined infected site. In this review, we summarize the latest developments in the application methods of ELP employed in tumor therapy, with a focus on its conjugation with peptide drugs, antibodies and photosensitizers.


Local inflammatory response to gastroesophageal reflux: Association of gene expression of inflammatory cytokines with esophageal multichannel intraluminal impedance-pH data.
Gene expression of inflammatory cytokines may take part in the pathophysiology of different forms of gastroesophageal reflux disease (GERD). To explore gene expression of inflammatory cytokines in esophageal mucosa in patients with erosive esophagitis (EE) and non-erosive forms of GERD (NERD) and its association with data of esophageal multichannel intraluminal impedance-pH (MII-pH) measurements. This was a single-center prospective study. Esophageal mucosa samples were taken from the lower part of the esophagus during endoscopy. Expression of interleukin (IL)-1β, IL-10, IL-18, tumor necrosis factor α (TNFA), toll-like receptor 4 (TLR4), GATA binding protein 3 (GATA3), differentiation cluster 68 (CD68) and β-2 microglobulin genes in esophageal mucosa was assessed with ImmunoQuantex assays. MII-pH measurements were performed on all the participants. Diagnosis of GERD was confirmed by the results of the MII-pH data. Based on the endoscopy, patients were allocated to the groups of EE and NERD. The control group consisted of non-symptomatic subjects with normal endoscopy and MII-pH results. We used nonparametric statistics to compare the differences between the groups. Association of expression of the mentioned genes with the results of the MII-pH data was assessed with Spearman's rank method. Data from 60 patients with GERD and 10 subjects of the control group were available for the analysis. Higher expression of IL-18 (5.89 ± 0.4 vs 5.28 ± 1.1, P = 0.04) and GATA3 (2.92 ± 0.86 vs 2.23 ± 0.96, P = 0.03) was found in the EE group compared to NERD. Expression of IL-1β, IL-18, TNFA, and TLR4 was lower (P < 0.05) in the control group compared to EE and NERD. Esophageal acid exposure correlated with the expression of IL-1β (Spearman's rank r = 0.29), IL-18 (r = 0.31), TNFA (r = 0.35), GATA3 (r = 0.34), TLR4 (r = 0.29), and CD68 (r = 0.37). Mean esophageal рН correlated inversely with the expression of IL-18, TNFA, GATA3, TLR4, and CD68. No association of gene expression with the number of gastroesophageal refluxes was found. In patients with EE, local expression of IL-18 and GATA3 was higher compared to subjects with NERD. Esophageal acid exposure correlated directly with expression of IL-1β, IL-18, TNFA, TLR4, CD68, and β-2 microglobulin genes. Inverse correlation was revealed between expression of IL-18, TNFA, GATA3, TLR4, and CD68 and mean esophageal pH.


Intravitreal silicone oil injection: complications and treatment of 415 consecutive patients.
Silicone oil injection in conjunction with pars plana vitrectomy was carried out by five surgeons in 415 consecutive patients using the same surgical equipment, the same surgical techniques and the same highly purified silicone oil (viscosity, 5000 mPa.s). Indications for silicone oil injection after vitrectomy included advanced stages of proliferative vitreoretinopathy following rhegmatogenous retinal detachment (49%), severe proliferative diabetic retinopathy (38%), and proliferative vitreoretinopathy following retinal detachment due to ocular trauma (13%). Postoperative complications were noted in a 6- to 30-month follow-up period. Cataractous changes of varying degree were seen in all phakic eyes. Silicone oil entered the anterior chamber in 6% of all phakic and pseudophakic eyes. Subretinal silicone oil was noted in 4%. Other complications associated with the use of intravitreal silicone oil included biomicroscopically visible silicone oil emulsification (0.7%), keratopathy (5.5%), glaucoma (6%), closure of the inferior iridectomy (6%), and reproliferation of epiretinal and subretinal fibrous membranes (40%). We anticipate that the physico-chemical characteristics of the highly purified silicone oil (viscosity, 5000 mPa.s) and the routine performance of an inferior iridectomy in all aphakic eyes had a positive impact on the low incidence of silicone-oil-related complications such as emulsification, keratopathy and secondary glaucoma.


Neonatal Epileptic Encephalopathies.
The majority of neonatal seizures are related to common diagnoses, including hypoxic-ischemic encephalopathy and intraventricular hemorrhage. While relatively uncommon, neonatal epileptic encephalopathies represent an important group of neonatal seizure disorders that require immediate diagnosis and intervention. In this review, we provide a summary of the benign and severe neonatal epilepsy syndromes. While benign epilepsy syndromes have favorable prognoses, rapid and accurate diagnosis may prevent an unnecessarily long course of antiseizure medications. The severe epilepsy syndromes may be related to a number of underlying genetic disorders and often carry a poor prognosis. Herein we review diagnostic and therapeutic strategies, and provide a set or algorithms for said purposes.


Flux balance analysis of cyanobacteria reveals selective use of photosynthetic electron transport components under different spectral light conditions.
Cyanobacteria acclimate and adapt to changing light conditions by controlling the energy transfer between photosystem I (PSI) and II (PSII) and pigment composition. Photosynthesis is driven by balancing the excitation between PSI and PSII. To predict the detailed electron transfer flux of cyanobacteria, we refined the photosynthesis-related reactions in our previously reconstructed genome-scale model. Two photosynthetic bacteria, Arthrospira and Synechocystis, were used as models. They were grown under various spectral light conditions and flux balance analysis (FBA) was performed using photon uptake fluxes into PSI and PSII, which were converted from each light spectrum by considering the photoacclimation of pigments and the distribution ratio of phycobilisome to PSI and PSII. In Arthrospira, the FBA was verified with experimental data using six types of light-emitting diodes (White, Blue, Green, Yellow, Red1, and Red2). FBA predicted the cell growth of Synechocystis for the LEDs, excepting Red2. In an FBA simulation, cells used respiratory terminal oxidases and two NADH dehydrogenases (NDH-1 and NDH-2) to balance the PSI and PSII excitations depending on the light conditions. FBA simulation with our refined model functionally implicated NDH-1 and NDH-2 as a component of cyclic electron transport in the varied light environments.


Radionuclide assessment of ventricular performance during propranolol withdrawal prior to aortocoronary bypass surgery.
The effects of oral propranolol upon left ventricular performance were assessed in 18 patients with angiographically documented coronary artery disease in whom propranolol was tapered prior to elective aortocoronary bypass surgery. Left ventricular ejection fraction, ejection rate, and regional wall motion were obtained on three occasions with first-pass radionuclide angiocardiographic techniques. Patients were studied at peak propranolol dose ( +/- SEM) 224 +/- 29 mg./day; serum propranolol level, 85 +/- 22 ng./ml.), intermediate dose (99 +/- 9 mg./day; serum propranolol, 30 +/- 6 ng./ml.), and 24 hours following discontinuation of propranolol therapy. Heart rate increased significantly (62 +/- 2.3 vs 67 +/- 3.0 vs 73 +/- 2.3 beats/minute, p less than 0.001) during propranolol withdrawal, while systolic blood pressure did not change significantly (114.7 +/- 4.3 vs 110.3 +/-3.0 vs 113 +/- 3.0 mm. Hg, p greater than 0.05). There was no significant change in ejection fraction (59.1 +/- 2.4 vs 60.4 +/- 2.0 vs 59.2 +/- 2.5 per cent) or ejection rate 2.80 +/- 0.18 vs 2.87 +/- 0.18 vs 2.92 +/- 0.20 sec.-1) as propranolol was tapered (p greater than 0.05). No patient demonstrated a change in regional wall motion in response to propranolol withdrawal. The results of this study suggest that oral propranolol in commonly used clinical dosages does not significantly affect radionuclide measures of left ventricular performance in the basal state.


Hydrogel spacer shrinkage during external-beam radiation therapy following low-dose-rate brachytherapy for high-risk prostate cancer: a case series.
Few studies have assessed hydrogel spacer shrinkage during external-beam radiation therapy following brachytherapy for localized high-risk prostate cancer. This case presentation evaluated the changes in hydrogel spacer appearance by magnetic resonance imaging during external-beam radiation therapy after brachytherapy for prostate cancer and analyzed the effect of this shrinkage on the dose distribution in four cases. In all cases, we implanted 125I sources using a modified peripheral loading pattern for seed placement. The prescribed dose for each implant was 110 Gy. After delivering the sources, a hydrogel spacer was injected. All cases underwent external-beam radiation therapy approximately 1-2 months after brachytherapy. The prescribed dose of external-beam radiation therapy was 45 Gy in 1.8-Gy fractions. Magnetic resonance imaging was performed for evaluation on the day following seed implantation (baseline), at external-beam radiation therapy planning, and during external-beam radiation therapy. The median hydrogel spacer volume was 16.2 (range 10.9-17.7) cc at baseline, 14.4 (range, 9.4-16.1) cc at external-beam radiation therapy planning, and 7.1 (range, 2.0-11.4) cc during external-beam radiation therapy. The hydrogel spacer volume during external-beam radiation therapy was significantly lower than that at external-beam radiation therapy planning. The rectum V60-80 (rectal volume receiving at least 60-80% of the prescribed dose of external-beam radiation therapy) during external-beam radiation therapy was significantly higher than that at external-beam radiation therapy planning. The potential reduction in hydrogel spacer size during external-beam radiation therapy following brachytherapy can lead to unexpected irradiation to the rectum. This case presentation would be helpful for similar cases.


Addictive disorders.
In conclusion, complex medical and psychiatric comorbidity is com-mon in individuals with substance use disorders. It is important to assess comorbidity because of the implications for prevention and treatment. Studies of the neurobiology of substance use and psychiatric disorders are accumulating rapidly and informing treatment development. Information about the prevention and treatment of infectious diseases and other medical conditions associated with substance use disorders also is growing, and it is important that patients are able to benefit from this. The articles in this issue provide state-of-the-art information about several issues related to comorbidity in substance use disorders.


Pathological application of carbocyanine dye-based multicolour imaging of vasculature and associated structures.
Simultaneous visualisation of vasculature and surrounding tissue structures is essential for a better understanding of vascular pathologies. In this work, we describe a histochemical strategy for three-dimensional, multicolour imaging of vasculature and associated structures, using a carbocyanine dye-based technique, vessel painting. We developed a series of applications to allow the combination of vessel painting with other histochemical methods, including immunostaining and tissue clearing for confocal and two-photon microscopies. We also introduced a two-photon microscopy setup that incorporates an aberration correction system to correct aberrations caused by the mismatch of refractive indices between samples and immersion mediums, for higher-quality images of intact tissue structures. Finally, we demonstrate the practical utility of our approach by visualising fine pathological alterations to the renal glomeruli of IgA nephropathy model mice in unprecedented detail. The technical advancements should enhance the versatility of vessel painting, offering rapid and cost-effective methods for vascular pathologies.


See (n)One, Do (n)One, Teach (n)One: Reality of Surgical Resident Training in Germany.
Due to technological changes, working time restrictions and the creation of specialized centers, surgical training has changed. A competence-based learning technique of surgical skills is the sub-step practice approach, which has been proven important in nationwide opinion surveys. The aim of this prospective multi-center trial was to determine the status quo of the sub-step concept in Germany. Over 6 months, the voluntarily participating centers evaluated the following index procedures: laparoscopic cholecystectomy (LCHE), laparoscopic and open sigmoid resection, minimally invasive inguinal hernia repair, thyroid resection and pylorus-preserving pancreaticoduodenectomy (PPPD). Patients with private insurance were excluded. The detailed sub-steps were documented as well as the reason why these were not performed. In addition, an online survey regarding the sub-step concept was performed before and after the study. In total, 21 centers included 2969 surgical procedures in 2018 for final analyses. While 24.4% of the procedures were performed by residents, sub-steps were performed in 22.2%. LCHE was most often performed completely by residents (43.3%), and PPPD revealed the highest rate of performed sub-steps (43.3%). Reasons for not assisting sub-steps to residents were often organizational and other reasons. After an initial increase, the number of performed sub-steps decreased significantly during the second half of the survey. The opinion survey revealed a high importance of the sub-step concept. The number of resident procedures was overestimated, and the number of performed sub-steps was underestimated. After the study, these estimations were more realistic. Even though the sub-step practice concept is considered highly important for surgical education, it needs to be put into practice more consequently. The current data suggest a low participation of surgical residents in the operating room, although the participating hospitals are most likely highly interested in surgical education, hence their voluntary participation. Conceptual changes and a control of surgical education are needed.


Do pretransplant C-peptide levels predict outcomes following simultaneous pancreas-kidney transplantation? A matched case-control study.
Following simultaneous pancreas-kidney transplantation (SPKT), survival outcomes are reported as equivalent in patients with detectable pretransplant C-peptide levels (Cp+) and a "type 2″ diabetes mellitus (DM) phenotype compared to type 1 (Cp negative [Cp-]) DM. We retrospectively compared 46 Cp+ patients pretransplant (≥2.0 ng/mL, mean 5.4 ng/mL) to 46 Cp- (level < 0.5 ng/mL) case controls matched for recipient age, gender, race, and transplant date. Early outcomes were comparable. Actual 5-year patient survival (91% versus 94%), kidney graft survival (69% versus 86%, p = .15), and pancreas graft survival (60% versus 86%, p = .03) rates were lower in Cp+ versus Cp- patients, respectively. The Cp+ group had more pancreas graft failures due to insulin resistance (13% Cp+ versus 0% Cp-, p = .026) or rejection (17% Cp+ versus 6.5% Cp-, p = .2). Post-transplant weight gain > 5 kg occurred in 72% of Cp+ versus 26% of Cp- patients (p = .0001). In patients with functioning grafts, mean one-year post-transplant HbA1c levels (5.0 Cp+ versus 5.2% Cp-) were comparable, whereas Cp levels were higher in Cp+ patients (5.0 Cp+ versus 2.6 ng/mL Cp-). In this matched case-control study, outcomes were inferior in Cp+ compared to Cp- patients following SPKT, with post-transplant weight gain, insulin resistance, and rejection as potential mitigating factors.


Phyto-fabrication, purification, characterisation, optimisation, and biological competence of nano-silver.
Published studies indicate that virtually any kind of botanical material can be exploited to make biocompatible, safe, and cost-effective silver nanoparticles. This hypothesis is supported by the fact that plants possess active bio-ingredients that function as powerful reducing and coating agents for Ag+. In this respect, a phytomediation method provides favourable monodisperse, crystalline, and spherical particles that can be easily purified by ultra-centrifugation. However, the characteristics of the particles depend on the reaction conditions. Optimal reaction conditions observed in different experiments were 70-95 °C and pH 5.5-8.0. Green silver nanoparticles (AgNPs) have remarkable physical, chemical, optical, and biological properties. Research findings revealed the versatility of silver particles, ranging from exploitation in topical antimicrobial ointments to in vivo prosthetic/organ implants. Advances in research on biogenic silver nanoparticles have led to the development of sophisticated optical and electronic materials with improved efficiency in a compact configuration. So far, eco-toxicity of these nanoparticles is a big challenge, and no reliable method to improve the toxicity has been reported. Therefore, there is a need for reliable models to evaluate the effect of these nanoparticles on living organisms.


A survey of wellness management strategies used by Canadian doctors of chiropractic.
The purpose of this study was to investigate if Canadian doctors of chiropractic consider using wellness strategies after functional recovery in acute and chronic conditions. This study also attempted to determine if there is a difference in the use of wellness management strategies between broad and narrow scope practitioners. Forty-one practicing, licensed chiropractors were recruited to complete an interview survey regarding 2 mock clinical case presentations. Interviews were recorded, and influential words or word pairings were identified. Investigators formulated criteria to divide practitioners into broad scope (mixers) and narrow scope (straights). Data were analyzed using Crawdad Analysis Software (version 1.2). All subjects indicated that they would provide information regarding public health and wellness strategies to a patient after functional resolution of the presenting chronic or acute complaints. The responses of broad scope (mixer) chiropractors appeared to be focused on the patient specifically, whereas narrow scope (straight) responses appeared to be more varied when analyzed for noun and noun-pair influence. This study of practicing, licensed Canadian chiropractors suggests that wellness strategies may be commonly considered in practice. All subjects in this study reported a number of strategies to educate patients regarding wellness after functional recovery of a complaint.


The role of FoxO1 in interleukin-1β-induced autostimulation in retina endothelial cells and retinas of diabetic rats.
Diabetic retinopathy is a chronic, low-grade inflammatory disease. The present study aimed to investigate the effect of forkhead transcription factor O1 (FoxO1) expression on interleukin-1β (IL-1β)-induced autostimulation, both in vitro in human retina microvascular endothelial cells (HRMECs), and in vivo in retinas isolated from streptozotocin-induced diabetic rats. High-glucose (HG) and recombinant IL-1β treatment were both shown to increase the expression of FoxO1 and IL-1β in HRMECs in a dose-dependent manner. IL-1 receptor antagonist (IL-1RA) and mitogen-activated protein kinase (MAPK) inhibitors reduced IL-1β-induced expression of FoxO1 in HRMECs. Moreover, the increased expressions of FoxO1 and IL-1β in the retinas of diabetic rats were significantly decreased by intravitreal injection of lentiviral vector-mediated FoxO1 small-interfering RNA. Together, these results suggest that HG triggers IL-1β synthesis in HRMECs. The produced IL-1β induces increased FoxO1 expression, as well as interacts with the IL-1 receptor to activate MAPK signaling and thereby induces IL-1β autostimulation. The IL-1β-induced autostimulation can be inhibited by downregulation of FoxO1, accompanied by a reduction of inflammation. Together, these findings identify novel functions for FoxO1 and IL-1β in diabetic retinopathy.


Activation of the complement system by polysaccharidic surfaces bearing carboxymethyl, carboxymethylbenzylamide and carboxymethylbenzylamide sulphonate groups.
Substituted Sephadex derivatives bearing carboxymethyl (CM), CM-benzylamide (CMB), CM-propylamide (CMP) and CMB-sulphonate (CMBS) groups are used as models of polysaccharidic surfaces to measure the effects of substituting OH groups on the complement activating capacity (CAC) of the modified surfaces in normal human serum. CM substitution decreases and can suppress the CAC of Sephadex. Low CMB substitution also decreases the CAC, whereas high CMB or CMP substitutions increase it again after a minimum. In addition to C3 cleavage occurring at high substitution with CMB or CMP groups, the presence of CMB induces consumption of a protein, limiting CH50 measurements. The CAC variations could be due to rearrangements of the polymer surfaces at the aqueous interface with proteins. Highly substituted CMB-bearing surfaces could activate complement-like polystyrene surfaces. The presence of CMBS groups does not reduce the CAC of the surface. Such polymer surfaces, which are heparin-like concerning coagulation, are not heparin-like concerning complement inhibition.