Recent onset neck pain with associated neurological deficit--Pott's disease remains an important differential diagnosis.
The incidence of spinal tuberculosis is increasing in developed nations. In Ireland, half of all cases seen in the most recent decade for which figures are available were diagnosed in 2005-2007, the three most recent years for which there is complete data. We discuss a patient who presented with neurological complications due to destructive spinal tuberculous disease affecting the sixth cervical vertebra.


Astrocytes stimulate interleukin-17 and interferon-gamma production in vitro.
Astrocytes play important roles in the complex and as yet not very well understood net of interactions among resident and infiltrating cells during central nervous system (CNS) inflammation. In such an intricate network, cytokines represent an essential means for intercellular communication, and astrocytes are able to affect their generation and/or release. Among various cytokines produced by infiltrating cells, interferon (IFN)-gamma and interleukin (IL)-17 are the focus of this research, because they are pivotal cytokines of helper T-cell type 1 (Th1) and helper T-cell type 17 (Th17), respectively. Importantly, both Th1 and Th17 cells, as well as their cytokines, have been shown to be of importance for the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of a prototypical CNS disease with inflammatory pathogenesis, multiple sclerosis. Therefore, the influence of astrocytes on the generation of IFN-gamma and IL-17 in concanavalin A- and myelin basic protein-stimulated lymph node cells of healthy rats and rats with developing EAE, respectively, was investigated in vitro. Astrocytes up-regulated IL-17 and IFN-gamma gene expression and protein synthesis in T cells, which coincided with astrocytes' ability to express IL-23 subunit p19 and common IL-12/IL-23 subunit p40 but not IL-12 subunit p35 in the co-cultivations. These results suggest one more way in which astrocytes could contribute to the complex interactions during CNS inflammation.


Predictive modeling of reliability engineering data using a new version of the flexible Weibull model.
The combined-unified hybrid sampling approach was introduced as a general model that combines the unified hybrid censoring sampling approach and the combined hybrid censoring approach into a unified approach. In this paper, we apply this censoring sampling approach to improve the estimation of the parameter via a novel five-parameter expansion distribution, which we call the generalized Weibull-modified Weibull model. The new distribution contains five parameters and is therefore very flexible in terms of accommodating different types of data. The new distribution provides graphs of the probability density function, e.g., symmetric or right skewed. The graph of the risk function can have a shape similar to a monomer of the increasing or decreasing model. Using the Monte Carlo method, the maximum likelihood approach is used in the estimation procedure. The Copula model was used to discuss the two marginal univariate distributions. The asymptotic confidence intervals of the parameters were developed. We present some simulation results to validate the theoretical results. Finally, a data set with failure times for 50 electronic components was analyzed to illustrate the applicability and potential of the proposed model.


It doesn't always pay to be fit: success landscapes.
Landscapes play an important role in many areas of biology, in which biological lives are deeply entangled. Here we discuss a form of landscape in evolutionary biology which takes into account (1) initial growth rates, (2) mutation rates, (3) resource consumption by organisms, and (4) cyclic changes in the resources with time. The long-term equilibrium number of surviving organisms as a function of these four parameters forms what we call a success landscape, a landscape we would claim is qualitatively different from fitness landscapes which commonly do not include mutations or resource consumption/changes in mapping genomes to the final number of survivors. Although our analysis is purely theoretical, we believe the results have possibly strong connections to how we might treat diseases such as cancer in the future with a deeper understanding of the interplay between resource degradation, mutation, and uncontrolled cell growth.


An evaluation of diphtheria--tetanus (adult) vaccine in unselected human volunteers.
One hundred unselected adult volunteers received an adult diphtheria (less than 2 Lf)-tetanus (greater than or equal to 40 IU) adsorbed vaccine without prior Schick testing. No volunteer had a moderate or severe reaction although 39% complained of a transient sore arm. Only 10% reported local erythema. Of the study group, 37/43 (86%) patients who were initially seronegative for diphtheria attained levels normally considered as seropositive. The results confirm the safety and efficacy of adult diphtheria-tetanus vaccine and allow its recommendation for use in 'at risk' individuals without the need for prior Schick testing.


[Contribution of immunoglobulin assays to the diagnosis of human African trypanosomiasis in patients immunologically suspect (immunofluorescence and ELISA). A preliminary report (author's transl)].
Can the diagnosis of sleeping sickness in patients immunologically suspect, without seeing the parasite, be obtained by dosing IgG and IgM? The authors demonstrate that two groups of people with positive immunodiagnosis, one parasitologically confirmed and the other not confirmed, do not show significant difference when dosing immunoglobulins. These two groups respectively show a significant difference when compared with a parasitologically and immunologicaly negative group. The simultaneous increase in IgG and IgM might confirm the immunodiagnosis.


Lopinavir-Ritonavir in the Treatment of COVID-19: A Dynamic Systematic Benefit-Risk Assessment.
COVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for the use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. Importantly, it allows additional data to be incorporated as they become available, and re-evaluation of the benefit-risk profile. A systematic benefit-risk assessment was conducted using the Benefit-Risk Action Team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in severe COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and Embase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance. We screened 143 papers from PubMed and 264 papers from Embase for lopinavir-ritonavir; seven papers were included in the final benefit-risk assessment. In comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (hazard ratio 1.31, 95% confidence interval 0.95-1.80). From one study, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared with standard of care (13% vs 27%). There also appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). Limited data were available for comparison of lopinavir-ritonavir to other treatments. Based on currently available data, there was no clear benefit for the use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events. There was a reduction in acute respiratory distress syndrome with lopinavir-ritonavir in one study. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.


Electromechanical-assisted gait training after stroke: a systematic review comparing end-effector and exoskeleton devices.
Although electromechanical-assisted gait training after stroke seems to be effective, in the absence of a direct comparison between electromechanical devices it is not clear which device may be the most effective for recovery of walking. The aim of this study was therefore to compare the effects of different devices used in gait training after stroke. We searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, EMBASE, CINAHL, AMED, SPORTDiscus, PEDro, COMPENDEX and INSPEC. In addition, we hand-searched relevant conference proceedings, trials and research registers, checked reference lists and contacted authors to identify further trials. Randomized studies were included. Authors independently selected trials for inclusion, assessed trial quality and extracted the data. Data were extracted with the help of a standardized data extraction form. Data were pooled for meta-analysis. The primary outcome was the proportion of patients walking independently. We included 18 trials involving 885 patients. We found significantly higher rates of independent walking in end-effector compared with exoskeleton-based training (p = 0.03). Complication rates in both groups were comparable. The results suggest that the type of electromechanical-assisted device might influence the outcome of gait rehabilitation after stroke.


Microtubule dynamics regulates Akt signaling via dynactin p150.
Following activation at the plasma membrane, Akt is subsequently deactivated in the cytoplasm. Although activation and deactivation of Akt must sometimes be separated in order to elicit and control cellular responses, the exact details of the spatiotemporal organization of Akt signaling are incompletely understood. Here we show that microtubule dynamics specifically modulate the deactivation phase of Akt signaling. Localization of Akt to microtubules sustains its activity, while disruption of microtubules attenuates Akt signaling independent of its initial activation. Conversely, stabilization of microtubules elevates Akt signaling both in vitro and in muscle tissues in vivo. Localization of Akt to microtubules is mediated by the microtubule binding protein dynactin p150, which is shown to be a direct target of Akt. Finally, microtubule disruption-induced Akt deactivation contributes to delayed cell cycle progression and accelerated cell death. Taken together, we revealed that, after initiation, the overall intensity and duration of oncogenic Akt signaling are determined by microtubule dynamics, a mechanism that could be exploited for therapeutic purposes.


Evaluating the Clinical and Immune Responses to Spotted Fever Rickettsioses in the Guinea Pig-Tick-Rickettsia System.
The guinea pig was the original animal model developed for investigating spotted fever rickettsiosis (SFR). This model system has persisted on account of the guinea pig's conduciveness to tick transmission of SFR agents and ability to recapitulate SFR in humans through clinical signs that include fever, unthriftiness, and in some cases the development of an eschar. The guinea pig is the smallest animal model for SFR that allows the collection of multiple blood and skin samples antemortem for longitudinal studies. This unit provides the basic protocols necessary to establish, maintain, and utilize a guinea pig-tick-Rickettsia model for monitoring the course of infection and immune response to an infection by spotted fever group Rickettsia (SFGR) that can be studied at biosafety level 2 (BSL-2) and arthropod containment level 2 (ACL-2); adaptations must be made for BSL-3 agents. The protocols cover methods for tick feeding and colony development, laboratory infection of ticks, tick transmission of Rickettsia to guinea pigs, and monitoring of the course of infection through clinical signs, rickettsial burden, and immune response. It should be feasible to adapt these methods to study other tick-borne pathogens. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Tick transmission of SFGR to guinea pigs Support Protocol 1: Laboratory infection of ticks by injection Alternate Protocol 1: Needle inoculation of SFGR to guinea pigs Basic Protocol 2: Monitoring the course of guinea pig rickettsial infection: clinical signs Basic Protocol 3: Monitoring the course of guinea pig rickettsial infection: collection of biological specimens Support Protocol 2: Guinea pig anesthesia Basic Protocol 4: Monitoring rickettsial burden in guinea pigs by multiplex qPCR Basic Protocol 5: Monitoring guinea pig immune response to infection: blood leukocytes by flow cytometry Basic Protocol 6: Monitoring immune response to guinea pig rickettsial infection: leukocyte infiltration of skin at the tick bite site by flow cytometry Basic Protocol 7: Monitoring the immune response to guinea pig rickettsial infection: antibody titer by ELISA Support Protocol 4: Coating ELISA Plates Alternate Protocol 2: Monitoring immune response to guinea pig rickettsial infection: antibody titer by immunofluorescence assay.


Pirfenidone inhibits stromal collagen deposition and improves intra-tumoral delivery and antitumor efficacy of Pegylated liposomal doxorubicin.
The effectiveness of cancer nanotherapeutics is greatly restricted by the dense collagen network in solid tumors. Pirfenidone (PFD) is a clinically approved oral antifibrotic agent widely used to treat idiopathic pulmonary fibrosis. To investigate whether PFD can enhance the penetration and tumor delivery efficiency of Pegylated liposomal doxorubicin (PLD), colorectal cancer xenograft mice were administered PFD, PLD, or combined regimens. As expected, high-dose PFD (H-PFD, 270 mg/kg/day) combined with PLD (H-PFD + PLD) exhibited a significantly higher tumor inhibition rate than PLD monotherapy (75.09% vs. 60.87%). Similarly, the intra-tumoral doxorubicin level was markedly elevated using H-PFD pretreatment, which induced over 34% elevation compared to PLD treatment alone (3.37 ± 0.41 vs. 2.51 ± 0.19 µg/mL). Additionally, Masson's trichrome staining and immunohistochemistry results of the H-PFD + PLD group revealed an attenuation of collagen deposition in vivo, and the in vitro TGF-β1, α-SMA, and collagen protein expression were inhibited using PFD treatment. In contrast, although low-dose PFD (60 mg/kg/day) did not present superior benefits in promoting PLD penetration into tumors, it did downregulate collagen expression in vivo. This study provides a new strategy for PFD combined with chemotherapeutic drugs to improve the antitumor efficacy of nanomedicines.


Rapid analysis of polycyclic aromatic hydrocarbons.
Polycyclic aromatic hydrocarbons are a continuing environmental and health concern. The analytical methods developed to analyze this class of compounds have relied on reversed phase liquid chromatography and are often on the order of tens of minutes. Reduction in analysis times through the application of sub-2 μm fully porous and superficially porous support materials can increase the throughput of these LC separations. Herein, we demonstrate similar selectivity between a fully porous 1.8 μm and a 2.7 μm superficially porous material. Separations were individually developed with in silico modeling for a given flow rate determined by the fully porous column's backpressure requirements. Since the 2.7 μm superficially porous materials inherently require less backpressure to achieve similar levels of efficiency as the 1.8 μm fully porous materials, a marked increase in throughput is possible with elevated flow rates. Good resolution for a standard 16-component sample mixture is demonstrated in a sub-minute separation.


Comparison of patients who were violent, victimized and violent-victimized during the first year after discharge from emergency psychiatry.
This prospective observational study included 345 (70%) of 489 patients discharged from an emergency psychiatric hospital during one year. Episodes of offending and victimization were recorded during first year after discharge. Forty-eight persons (14%) committed violent offenses only, 27 persons (8%) were violence victims only, and 42 persons (12%) were both offenders and victims. Significant differences in demographic and clinical variables were found between the three groups. The results pointed to two distinct groups of victims: one group with a robust offender-victim overlap and another group without offender-victim overlap. The latter group was difficult to distinguish from other discharged patients.


Cholecystokinin cholescintigraphy: methodology and normal values using a lactose-free fatty-meal food supplement.
The purpose of this investigation was to evaluate the use of a commercially available lactose-free fatty-meal food supplement, as an alternative to sincalide cholescintigraphy, to develop a standard methodology, and to determine normal gallbladder ejection fractions (GBEFs) for this supplement. Twenty healthy volunteers all had negative medical histories for hepatobiliary and gallbladder disease, had no personal or family history of hepatobiliary disease, and were not taking any medication known to affect gallbladder emptying. All were prescreened with a complete blood cell count, comprehensive metabolic profile, gallbladder and liver ultrasonography, and conventional cholescintigraphy. Three of the 20 subjects were eliminated from the final analysis because of an abnormality in one of the above studies. After gallbladder filling on conventional cholescintigraphy, the subjects ingested the supplement and an additional 60-min study was acquired. GBEFs were calculated and ranged from 33% to 95% (mean +/- SD, 62.6% +/- 21.3%). Statistical analysis determined the lower range of normal to be 32.6%. Maximal gallbladder emptying occurred between 55 and 60 min. A standard methodology and normal GBEFs (> or =33%) were established for supplement-stimulated cholescintigraphy.


Modified reposition of the JOTEC prosthesis in the frozen elephant trunk procedure.
We describe a procedure in which we inserted a modified JOTEC graft following a known complication in the case of a 78-year-old male patient who underwent surgery with the frozen elephant trunk technique for an acute Stanford type A aortic dissection.


3D multifrequency magnetic resonance elastography in distinguishing endometrial and cervical adenocarcinoma.
To prospectively evaluate the value of tomoelastography in determining the underlying origins of uterine adenocarcinoma. This prospective work was approved by our institutional review board, and all patients provided informed consent. 64 patients with histopathologically confirmed adenocarcinomas originated either from the cervix (CAC: cervical adenocarcinoma) or endometrium (EAC: endometrial adenocarcinoma) underwent MRI and tomoelastography examination on a 3.0 T MR scanner. To biomechanically characterize the adenocarcinoma, two MRE-derived parameters maps were provided in the tomoelastography, namely shear wave speed (c, m/s) and loss angle (φ, radian), which represented the stiffness and fluidity, respectively. The MRE-derived parameters were compared by using a two-tailed independent-sample t-test or Mann-Whitney U test. Five morphologic features were also analyzed by using the χ2 test. Logistic regression analysis was used to develop diagnosis models. Delong test was used to compare the receiver operating characteristic curves whith different diagnostic models and evaluate the diagnostic efficiency. CAC were significantly stiffer and behaved more fluid like than EAC (c: 2.58 ± 0.62 m/s vs.2.17 ± 0.72 m/s, p = 0.029, φ, 0.97 ± 0.19 rad vs.0.73 ± 0.26 rad, p < 0.0001). The diagnostic performance for distinguishing CAC from EAC was similar for c (AUC = 0.71) and for φ (AUC = 0.75). For distinguishing CAC from EAC, the AUC of tumor location was the higher than c and φ (AUC = 0.80). A cmobined model consisting of tumor location, c, and φ achieved the best diagnostic performance, with an AUC of 0.88 (77.27% sensitivity and 85.71% specificity). CAC and EAC displayed their unique biomechanical features. 3D multifrequency MRE provided added value to the conventional morphologic features in distinguishing the two types of diseases.


Adipogenic commitment induced by green tea polyphenols remodel adipocytes to a thermogenic phenotype.
The potential contribution of green tea (GT) to the development of thermogenic/beige cells have been scarcely investigated. Here we investigated if the beneficial effects of GT in the induction of thermogenic/beige adipocytes results from an initial cell commitment during adipogenesis. Male C57Bl/6 mice (3 months) were divided into 3 groups: Control (chow diet), Obese (cafeteria diet), and Obese + GT. Mice received GT gavage (500 mg/kg of BW) over 12 weeks (5 days/week), after 4 weeks of diet, totalizing 16 weeks of experimentation. GT treatment increased energy expenditure (EE) in mice fed with cafeteria-diet leading to reduced BW gain, decreased adiposity, reduced inflammation, and improving insulin sensitivity. Those phenotypes were associated with enhanced expression of oxidative, thermogenic and beige genes. GT induced a futile cycle through de novo lipogenesis activating the thermogenic pathway. Induction of beige phenotype occurs autonomously in adipocytes and involves the PPARγ/FGF21/AMPK/UCP1 pathway. Our study identified that metabolic changes caused by GT may involve the temporal expression of PPARγ promoting the induction of thermogenic cells by reprogramming initial steps of adipocyte commitment.


Quantitative polyacrylamide gel electrophoresis and specific activities of human somatotropin and its derivatives.
A preparation of human pituitary somatotropin examined in quantitative polyacrylamide gel electrophoresis is conformationally compact. The derived molecular weight by quantitative electrophoresis is consistant with the known mass of the hormone and value obtained by other methods. A plasmin-modified somatotropin is more compact and shows full activity in immunoassay, and in lymphocyte binding and somatotropic assays, with enhanced lactogenic activity. The N-terminal 134-amino acid fragment and a hendekakaihekaton fragment exist in non-monomeric forms. The N-terminal fragment has immunologic and biologic activity, with greatest activity in the in vivo somatotropic assay. The hendekakaihekaton fragment exhibited only marginal activity. All preparations showed heterogeneity of charge in quantitative electrophoresis with discreet charge isomerism recognizable for the native and plasmin-modified preparations.


Antifertility efficacy of the plant Aristolochia indica linn on mouse.
Two compounds isolated from the alcoholic extract of the roots of Aristolochia indica Linn were tested on day 6 pregnant mice. One of the compounds, p-coumaric acid showed 100% interceptive activity at the single oral dose of 50 mg/kg of body weight. The antifertility efficacy of these two compounds is discussed.


Absolute numbers of lymphocytes subsets migrating through the compartments of the normal and transplanted rat spleen.
Lymphocyte migration is one of the basic principles of the immune system. Up to now lymphocyte migration experiments have been performed either in a quantitative way, determining whole organ recoveries of radiolabeled lymphocytes without histologic localization, or based on autoradiography which does not provide absolute numbers of immigrant lymphocytes. In this study the traffic of lymphocyte subsets through the splenic compartments: red pulp (RP), marginal zone (MZ), periarteriolar lymphatic sheath (PALS) and follicle was evaluated in absolute numbers. In normal spleens and splenic transplants fluorescein isothiocyanate (FITC)-labeled immigrant lymphocytes were localized and characterized immunohistochemically in cryostat sections by light microscopy. In addition morphometry of the splenic compartments was performed and the recovery of 51Cr-labeled lymphocytes in the spleen was determined. The combination of these methods allowed total numbers of immigrant subset cells to be calculated in individual splenic compartments. At 15 min about 17% of the injected B lymphocytes were found in the MZ. This is the largest fraction of an injected lymphocyte subset found in a single splenic compartment. At 24 h immigrant B cells were not only found in the follicle, but they had reached comparable numbers in the three compartments: follicle, RP and MZ. Most immigrant T lymphocytes were found in the PALS, which from 6 h after injection onwards contained more T cell immigrants than any single organ of the body. CD4+ and CD8+ lymphocytes showed a similar distribution throughout the splenic compartments at early time points. At 24 h CD4+ lymphocytes homed preferentially to the PALS, whereas CD8+ cells seemed to prefer the RP and MZ. Both CD4+ and CD8+ cells also migrated into the follicles. In regenerated splenic tissue after autotransplantation lymphocyte immigration was reduced in all compartments and to the MZ in particular. An impaired lymphocyte migration to the MZ in splenic transplants may be one reason for the lack of protection provided against bacterial infections. Thus examining lymphocyte migration in absolute numbers provides additional information which cannot be gained by determining labeling indices or percentages of lymphocyte subsets alone.


Role of the endocannabinoid 2-arachidonoylglycerol in aversive responses mediated by the dorsolateral periaqueductal grey.
2-arachidonoylglycerol (2-AG) is an endogenous ligand of the cannabinoid CB1 receptor. This endocannabinoid and its hydrolyzing enzyme, monoacylglycerol lipase (MAGL), are present in encephalic regions related to psychiatric disorders, including the midbrain dorsolateral periaqueductal grey (dlPAG). The dlPAG is implicated in panic disorder and its stimulation results in defensive responses proposed as a model of panic attacks. The present work verified if facilitation of 2-AG signalling in the dlPAG counteracts panic-like responses induced by local chemical stimulation. Intra-dlPAG injection of 2-AG prevented panic-like response induced by the excitatory amino acid N-methyl-d-aspartate (NMDA). This effect was mimicked by the 2-AG hydrolysis inhibitor (MAGL preferring inhibitor) URB602. The anti-aversive effect of URB602 was reversed by the CB1 receptor antagonist, AM251. Additionally, a combination of sub-effective doses of 2-AG and URB602 also prevented NMDA-induced panic-like response. Finally, immunofluorescence assay showed a significant increase in c-Fos positive cells in the dlPAG after local administration of NMDA. This response was also prevented by URB602. These data support the hypothesis that 2-AG participates in anti-aversive mechanisms in the dlPAG and reinforce the proposal that facilitation of endocannabinoid signalling could be a putative target for developing additional treatments against panic and other anxiety-related disorders.


Cochlear implant imaging in the mouse and guinea pig using light-sheet microscopy.
Postmortem examination of the cochlea with a cochlear implant in the scala tympani presents several challenges. It is technologically difficult to section a cochlea with an implant due to the presence of its wires and metal components that are adjacent to the membranous and bony tissues of the cochlea. These metal components damage traditional steel blades of a microtome in celloidin, paraffin or frozen embedded tissues. However, plastic embedded implanted cochleas have been successfully sectioned using specialized methods (Irving et al., 2013). An alternative non-destructive method is to optically section a chemically cleared cochlea using light-sheet microscopy, which we will describe in this publication. However, since this method uses a light-sheet to section the cochlea the opaque and reflective metal components of the implant results in some artifacts in the 2D optical sections. The best image quality using light-sheet fluorescent microscopy is when the implant is removed prior to imaging.


Regional differences in tissue oxygenation during cardiopulmonary bypass for correction of congenital heart disease in neonates and small infants: relevance of near-infrared spectroscopy.
Cardiac surgery with cardiopulmonary bypass for correction of congenital heart disease in neonates and small infants is associated with considerable neurologic sequelae. We assessed the extent to which mixed venous oxygen saturation as a measure for adequacy of perfusion, reflects the oxygenation status of upper and lower body compartments. Moreover, we evaluated potential benefits of near-infrared spectroscopic monitoring of regional tissue oxygenation. Twenty patients (body weight < 10 kg) undergoing open cardiac procedures with cardiopulmonary bypass were enrolled. Blood samples were obtained in parallel from inferior and superior caval vein cannulas and mixed venous line and assessed for venous oxygen saturation and lactate levels. Data were compared to simultaneously measured tissue oxygenation indices obtained by near-infrared spectroscopy from brain and lower limb. Venous oxygen saturation was lower and lactate concentration higher in blood from superior relative to inferior venous line. Mixed venous oxygen saturation correlated with venous oxygen saturation from inferior venous line and tissue oxygenation index of lower limb. No correlation was found between mixed venous oxygen saturation and venous oxygen saturation from superior venous line or cerebral tissue oxygenation index. In neonates and small infants undergoing cardiac surgery with cardiopulmonary bypass, considerable regional differences exist in venous oxygen saturation. Mixed venous oxygen saturation primarily represents lower-torso oxygen status but poorly reflects and systematically overestimates upper-body oxygenation. Near-infrared spectroscopy yields additional information on regional oxygenation and may be valuable in early and sensitive detection of regional malperfusion in critical organs such as the brain.


Meningococcal purpura fulminans in children: I. Initial orthopedic management.
Purpura fulminans is a rare and extremely severe infection, mostly due to Neisseria meningitidis frequently causing early orthopedic lesions. Few studies have reported on the initial surgical management of acute purpura fulminans. The aim of this study is to look at the predictive factors in orthopedic outcome in light of the initial surgical management in children surviving initial resuscitation. Nineteen patients referred to our institution between 1987 and 2005 were taken care of at the very beginning of the purpura fulminans. All cases were retrospectively reviewed so as to collect information on the total skin necrosis, vascular insufficiency, gangrene, and total duration of vasopressive treatment. All patients had multiorgan failure; only one never developed any skin necrosis or ischemia. Eighteen patients lost tissue, leading to 22 skin grafts, including two total skin grafts. There was only one graft failure. Thirteen patients were concerned by an amputation, representing, in total, 54 fingers, 36 toes, two transmetatarsal, and ten transtibial below-knee amputations, with a mean delay of 4 weeks after onset of the disease. Necrosis seems to affect mainly the lower limbs, but there is no predictive factor that impacted on the orthopedic outcome. We did not perform any fasciotomy or compartment pressure measurement to avoid non-perfusion worsening; nonetheless, our outcome in this series is comparable to existing series in the literature. V.A.C.(®) therapy could be promising regarding the management of skin necrosis in this particular context. While suffering from general multiorgan failure, great care should be observed not to miss any additional osseous or articular infection, as some patients also develop local osteitis and osteomyelitis that are often not diagnosed. We do not advocate very early surgery during the acute phase of purpura fulminans, as it does not change the orthopedic outcome in these children. By performing amputations and skin coverage some time after the acute phase, we obtained similar results to those found in the literature.


Is dysfunction of the tissue plasminogen activator (tPA)-plasmin pathway a link between major depression and cardiovascular disease?
Epidemiological, genetic and clinical studies have demonstrated an association between major depressive disorder (MDD) and cardiovascular disease (CVD). For example, MDD is a risk factor for the development of CVD, while around one fifth of patients with CVD have MDD and a significantly larger percentage have subsyndromal symptoms of depression. Furthermore, patients with CVD and depression have an increased risk of future cardiac events compared to similar cohorts without depression, independent of baseline cardiac dysfunction. Despite evidence that CVD and MDD are epidemiologically linked, the cause of this correlation is still unknown. Several risk factors including physical and psychological stress, smoking, physical inactivity and inflammation have been proposed to mediate the interaction between MDD and CVD. The tissue-type plasminogen activator (tPA)-plasminogen proteolytic cascade is widely expressed in the brain. Accumulating evidence from preclinical and clinical studies suggests that tPA and its inhibitor, plasminogen activator inhibitor-1, are related to stress reaction and depression. In addition, brain-derived neurotrophic factor (BDNF) is important for the pathogenesis of MDD and the tPA-plasminogen proteolytic cascade has been implicated in the cleavage of proBDNF to BDNF in the brain, by which the direction of BDNF action is controlled. Thus, it is proposed that tPA-plasmin pathway dysfunction may play a role in the link between MDD and CVD. Future study of the components in the tPA-plasminogen system in CVD patients comorbid with MDD may lead to new, potentially important insights into the link between MDD and CVD, and might also contribute to novel strategies for the management of these two common and devastating diseases.


How drowsiness and distraction can interfere with take-over performance: A systematic and meta-analysis review.
Drowsiness and distraction are major factors of road crashes and responsible of>35% of road fatalities. Automated driving could solve or minimize their impact, yet it is also in itself a way to promote them. Previous literature reviews and meta-analysis regarding take-overs during automated driving primarily focused on distraction rather than drowsiness. We thus present a systematic and meta-analysis literature review focused on the effect of distraction and drowsiness on take-over performance. From an initial selection of 1896 articles from databases, we obtained by applying systematic review methodology a total of 58 articles with 42 articles dedicated to distraction and 17 articles related to drowsiness. According to our analysis, we demonstrated that distraction and drowsiness increased the take-over request reaction time (TOR-RT), which could also lead to a reduction of the quality of take-overs. In addition, this longer reaction time was even more important in the case of handheld non-driving related tasks, which is important to consider as phone use is among the most frequent tasks done during automated driving. On a more methodological aspect, we also demonstrated that take-over time budget had a significant effect on TOR-RT. However, it is difficult to estimate to what extend distraction and drowsiness could impact the take-over quality, even if several elements supported safety issues. We underpinned several limits of the current methodologies applied in the study of distraction and drowsiness such as (i) the lack of additional measures related to the take-over quality (e.g., accelerations, collision rate), (ii) the many different methodologies applied to the determination of the TOR-RT (e.g., deactivation by the steering wheel, pedals, button), (iii) the high frequency of take-over requests which can lead to habituation effects, (iv) the lack of control conditions, (v) the fact that the level of drowsiness was relatively low in most studies. We thus highlighted recommendations for a better estimation of the effect of distraction and drowsiness on take-over performance. Further studies should adopt more standardized measures of TOR-RT and additional take-over quality measures, try minimizing the number of take-over requests, and carefully consider the time budget available for the use case since it influences the TOR-RT. Regarding distraction, researchers should consider the impact of tasks requiring handholding items. Concerning drowsiness, further protocols should consider the non-linearity of drowsiness and presence of micro sleeps and favor take-over requests based on drowsiness level protocols rather than on fixed duration protocols.


Synergistic gangrene of the scrotum and penis secondary to colorectal disease.
We recently encountered 5 patients with synergistic gangrene of the genitalia secondary to colorectal disease. This number of cases suggests that there may be an increasing incidence of this entity that has been reported only several times in the past. Pseudomonas was one of the organisms cultured in all cases. Because of the high mortality rate we advocate aggressive therapy, consisting of early and repeated radical débridement into normal tissues and appropriate management of the colorectal source of contamination. Our experience indicates that the lower gastrointestinal tract should be considered as a possible cause of infection in all cases of synergistic gangrene of the scrotum and penis.


Multi-omics reveals that the host-microbiome metabolism crosstalk of differential rumen bacterial enterotypes can regulate the milk protein synthesis of dairy cows.
Dairy cows' lactation performance is the outcome of the crosstalk between ruminal microbial metabolism and host metabolism. However, it is still unclear to what extent the rumen microbiome and its metabolites, as well as the host metabolism, contribute to regulating the milk protein yield (MPY). The rumen fluid, serum and milk of 12 Holstein cows with the same diet (45% coarseness ratio), parity (2-3 fetuses) and lactation days (120-150 d) were used for the microbiome and metabolome analysis. Rumen metabolism (rumen metabolome) and host metabolism (blood and milk metabolome) were connected using a weighted gene co-expression network (WGCNA) and the structural equation model (SEM) analyses. Two different ruminal enterotypes, with abundant Prevotella and Ruminococcus, were identified as type1 and type2. Of these, a higher MPY was found in cows with ruminal type2. Interestingly, [Ruminococcus] gauvreauii group and norank_f_Ruminococcaceae (the differential bacteria) were the hub genera of the network. In addition, differential ruminal, serum and milk metabolome between enterotypes were identified, where the cows with type2 had higher L-tyrosine of rumen, ornithine and L-tryptophan of serum, and tetrahydroneopterin, palmitoyl-L-carnitine, S-lactoylglutathione of milk, which could provide more energy and substrate for MPY. Further, based on the identified modules of ruminal microbiome, as well as ruminal serum and milk metabolome using WGCNA, the SEM analysis indicated that the key ruminal microbial module1, which contains the hub genera of the network ([Ruminococcus] gauvreauii group and norank_f_Ruminococcaceae) and high abundance of bacteria (Prevotella and Ruminococcus), could regulate the MPY by module7 of rumen, module2 of blood, and module7 of milk, which contained L-tyrosine and L-tryptophan. Therefore, in order to more clearly reveal the process of rumen bacterial regulation of MPY, we established the path of SEM based on the L-tyrosine, L-tryptophan and related components. The SEM based on the metabolites suggested that [Ruminococcus] gauvreauii group could inhibit the energy supply of serum tryptophan to MPY by milk S-lactoylglutathione, which could enhance pyruvate metabolism. Norank_f_Ruminococcaceae could increase the ruminal L-tyrosine, which could provide the substrate for MPY. Our results indicated that the represented enterotype genera of Prevotella and Ruminococcus, and the hub genera of [Ruminococcus] gauvreauii group and norank_f_Ruminococcaceae could regulate milk protein synthesis by affecting the ruminal L-tyrosine and L-tryptophan. Moreover, the combined analysis of enterotype, WGCNA and SEM could be used to connect rumen microbial metabolism with host metabolism, which provides a fundamental understanding of the crosstalk between host and microorganisms in regulating the synthesis of milk composition.


Malignant lymphoma after liver transplantation for liver cirrhosis caused by human immunodeficiency virus and hepatitis C virus co-infection.
Here, we describe a rare case of malignant lymphoma after liver transplantation for liver cirrhosis caused by human immunodeficiency virus (HIV) and hepatitis C virus (HCV) co-infection. A male patient was diagnosed with hemophilia A at 8 months of age. Since then, he had been receiving blood products, which led to HIV and HCV co-infection. His HIV viral load was suppressed with antiretroviral therapy, and a sustained virologic response was achieved for HCV using direct-acting antivirals. However, his decompensated liver cirrhosis progressed, and deceased donor liver transplantation was performed. A post-transplant lymphoproliferative disorder (PTLD) developed 105 days after liver transplantation, with enlarged para-aortic and hilar lymph nodes, a right renal mass, and masses in the small and large intestines. Histopathological examination confirmed monomorphic PTLD (diffuse large B-cell lymphoma). Against the treatment (reduction of immunosuppression, rituximab, and chemotherapy), the response was poor, and the patient died 94 days after the outbreak of PTLD. Both transplantation and HIV infection are risk factors for lymphoproliferative diseases. To the best of our knowledge, this is one of the very few reports of PTLD in a patient with HIV/HCV co-infection.


Treatment induced seroconversion to HBsAb following HBV reactivation in the immunosuppressed haematology and oncology patient: a clinical survey of 5 cases in Catania, Italy.
In onco-haematological patients inactive or occult HBV infection may be reactivated as a result of disease-related immuno-suppression and/or chemotherapy with rituximab. This study reports the clinical features of five patients affected by onco-haematological disorders who experienced hepatitis B reactivation. From 2005 to 2010, five onco-haematological patients with hepatitis B reactivation were admitted to the department of Infectious Diseases, Ferrarotto Hospital, Catania, Italy. At the time of onco-haematological disease diagnosis, 3 patients were HBcAb positive; 1 HBsAb and HBcAb positive; and 1 HBsAg positive, HBV DNA negative. None of the patients received hepatitis B prophylaxis. Reactivation was observed following chemotherapy. One patient was treated with lamivudine, 2 with tenofovir and 2 with telbivudine. Following treatment all patients achieved undetectable HBV DNA and normalization of transaminases. Three patients, those treated with lamivudine and tenofovir, cleared HBsAg and developed protective titres of HBsAb. The remaining patients, who were treated with telbivudine, were HBV DNA negative and HBsAg positive one at 27 months and the other at 5 months of therapy. Treatment thus continued in these patients. HBV reactivation can be a severe complication in onco-haematological patients undergoing chemotherapy with rituximab. In our experience all nucleos(t)ide analogues were safe and effective. Three patients seroconverted to HBsAb. This may be as a result of the antivirals enhancing the immune response to HBV. A similar role may also be played by immune recovery following the withdrawal of immune-suppressive treatment. This report confirms the importance of anti-viral prophylaxis in patients with a high risk of HBV reactivation.


The aromatase active site: the C-6 "front" side of the androgen molecule is required for binding.
Solubilized microsomes from human placenta were partially purified by anion-exchange chromatography on a quaternary methylamino-silica column. The aromatase-active fractions were then used for measuring optical difference spectra with various androgens, substituted at positions C-1, 2, 6, 11, 16, 17, and 19. Of these, only androgens substituted at the C-6, or frontside of the steroid backbone induce a strong type I spectrum, as well as competitive inhibition with the natural substrate, 4-androstene-3,17-dione. An in-house made affinity support, synthesized by reacting 6 beta-bromo-androstenedione with aminohexyl-Sepharose at pH 10-11 via a SN2-mechanism, was unable to trap the aromatase cytochrome P-450 component of the enzyme. A 3-dimensional model of the active site accounting for these interactions is proposed.


"Not safe" is not enough: smokers have a right to know more than there is no safe tobacco product.
The right to health relevant information derives from the principles of autonomy and self direction and has been recognised in international declarations. Providing accurate health information is part of the basis for obtaining "informed consent" and is a recognised component of business ethics, safety communications, and case and product liability law. Remarkably, anti-tobacco and pro-tobacco sources alike have come to emphasise the message that there is "no safe cigarette" or "no safe tobacco product". We propose that the "no safe" message is so limited in its value that it represents a violation of the right to health relevant information. There is a need to go beyond saying, "there is no safe tobacco product" to indicate information on degree of risks. The "no safe tobacco" message does not contradict, for example, the mistaken belief that so called light or low tar cigarettes are safer choices than higher tar cigarettes. We encourage a kind of "rule utilitarian" ethical position in which the principle of truth telling is observed while trying to produce the greatest good for the greatest number of people. Although harm reduction approaches to easing the burden of tobacco related diseases are founded on science based comparative risk information, the right to health information is independently related to the need to promote health literacy. This right should be respected whether or not harm reduction policies are judged advisable.


Foreign medical graduates in rural primary care: the case of western New York State.
To determine whether foreign medical graduates (FMGs) provide a disproportionate and increasing share of primary care in some rural areas, changes in physician distribution in a rural section of upstate New York over a 20-year period (1953-1973) were evaluated by country of medical education and type of practice. A contiguous urban area was examined for comparison. In 1953, FMGs accounted for a higher proportion of primary care physicians in rural areas (11%) than in urban practice (6%) (p less than 0.01). By 1973, this distribution had increased to 26% rural and 14% urban (p less than 0.001). During the two decades, the number of U.S. medical graduates in primary care declined by 15% in the rural areas but increased by 13% in the urban center. The number of primary care FMGs in this same period increased 88% in the rural area. With a 10% decline in (rural) FMGs trained in developed countries, this net increase in FMGs was accounted for by physicians from developing countries. Primary care physicians trained in the U.S. or in developed countries increased more in the urban center, while physicians from developing countries increased more in rural (53%) than urban (47%) practices. Finally, by 1973, rural primary care physicians were more likely than urban primary care physicians to be from developing countries (p less than 0.001).


Sensitivity to values of the rate constants in a neurochemical metabolic model.
Equations were derived for the instantaneous relative sensitivities of reaction rates (controllability indices) and metabolite concentrations (response indices) to perturbations in the values of rate constants and were used to analyze the behavior of a model of in vivo glutamate metabolism in rat brain. Controllabilities of reversible reactions were found to increase as the values of the corresponding rate constants (i.e., the rate of approach to equilibrium) increased. Response indices generally declined with the metabolic distance between the metabolite and the rate constant, but they were unexpectedly high for reversible reactions with high controllabilities. The transient response of a given metabolite is most sensitive to reactions involving metabolites which are changing most rapidly relative to their respective pool sizes. Rapidly reversible reactions are most important for communication between metabolite pools.


Colonic delivery of docosahexaenoic acid improves impaired glucose tolerance via GLP-1 secretion and suppresses pancreatic islet hyperplasia in diabetic KK-A(y) mice.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates the insulin secretion depending on blood glucose level. Recent studies show that the unsaturated fatty acids can promote GLP-1 secretion from intestinal L-cells. We have shown previously that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) administered into a mouse closed intestinal loop, especially into the colonic segment, stimulate GLP-1 and insulin secretion and have a hypoglycemic effect, suggesting that DHA and EPA have potential as antidiabetic agents. The present study examined the antidiabetic effect of DHA following long-term in vivo delivery to the colon using normal ddY and diabetic KK-A(y) mice. The plasma GLP-1 concentration of KK-A(y) mice increased after long-term DHA administration, and this had a significant hypoglycemic effect. In contrast, although GLP-1 secretion in ddY mice tended to increase after DHA administration, blood glucose concentration did not differ between vehicle- and DHA-treated ddY mice. Immunostaining of the pancreas after long-term DHA administration showed that continuous DHA treatment stimulated β-cell apoptosis and accordingly suppressed islet cell growth in KK-A(y) mice. Colon targeting of DHA may provide a new strategy for improving impaired glucose tolerance in type 2 diabetes mellitus by stimulating GLP-1 secretion, which may subsequently suppress the compensatory hyperplasia of pancreatic islets.


Resource allocation of chilean herbs in response to climatic and microclimatic factors.
Resource allocation to aerial vegetative, underground vegetative, and reproductive biomass is studied in four Chilean herbs: the annuals Chaetanthera ciliata, Erodium cicutarium, Trisetobromus hirtus, and the perennial Solenomelus peduncularis. Absolute (weight), and relative (% vegetative/total, % root/shoot) changes in biomass were determined in relation to concomitant changes in a climatic (rain regime in two subsequent years) and a microclimatic factor (spatial distribution of herbs, whether underor between-shrubs). In regard to the climatic factor, taking as basis the normal rainfall year, our results can be summarized as: 1) All herbs studied exhibit greater production in the rainy year. This is accounted for by increases in the biomass of all herbs' fractions, i.e. in aerial vegetative, underground vegetative and reproductive. 2) All annuals exhibit greater vegetative fractions (i.e. smaller reproductive fractions) in the rainy year. The perennial does not change its vegetative: reproductive balance. 3) Herbs studied exhibit contrasting responses to rainy year concerning root/shoot ratio: C. ciliata increasing it, E. cicutarium decreasing it, T. hirtus and S. peduncularis not changing it. In regard to the microclimatic factor, taking as basis the patterns exhibited by T. hirtus and S. peduncularis under-shrubs, our results can be summarized as: 1) Both species exhibit smaller production in exposed areas between-shrubs, whether in the rainy or normal year. 2) T. hirtus does not change its vegetative fraction between-shrubs neither in the rainy nor in the normal year. S. peduncularis exhibits a smaller vegetative fraction (i. e. greater reproductive fraction) between-shrubs only in the normal year. 3) Neither species change its root/shoot ratio between-shrubs, neither in the rainy nor in the normal year. Results obtained are interpreted on basis of the theory of life-history strategies.


Somatosensory cortectomy induces motor cortical hyperexcitability and scoliosis: an experimental study in developing rats.
Dysfunctions in sensorimotor integration, reminiscent to those described in idiopathic dystonia, have been found in idiopathic scoliosis (IS) and might be involved in its pathogenesis. Studying the effects of experimental disruption of sensory cortex may shed further insight into the etiopathology of IS. To evaluate whether disruption of central sensorimotor integration through partial ablation of the somatosensory cortex leads to scoliosis in developing rats and to describe the effects of such an intervention on motor cortico-cortical inhibition and facilitation. Fifty Wistar rats aged 3 weeks were used in the study. Twenty-four rats underwent craniotomy and electrocoagulation of the sensory cortex (PAR1) in the right hemisphere. A second group of 16 rats underwent a sham operation with craniotomy but no electrocoagulation. A third group of 10 rats was used as intact controls. Four weeks after surgery, motor cortical excitability was assessed with paired-pulse electrical cortical stimulation. Neurologic and behavioral examinations were completed serially, and 10 weeks after surgery, X-ray examinations were performed in anesthetized rats to assess spinal curvature. Electromyographic recordings of paravertebral muscle activity were performed in waking rats. At the end of the study, rats were sacrificed, and histologic examinations of brain tissue were performed to confirm the extent of the lesion. A grant from a Government Health Research Fund without salaries assignment financed the study. Almost half of the animals with somatosensory cortectomy (46%) developed scoliosis, with an average Cobb angle of 23 ± 8°. None of the animals in the sham or control groups developed scoliosis. Despite cortical lesions, no motor or behavioral deficits were apparent in the experimental group, and cortectomized rats were neurologically indistinguishable from sham or control animals, except for the presence of scoliosis. Cortico-cortical inhibition was significantly reduced in the hemisphere of scoliotic concavity in the cortectomized group but was normal in the other groups. These findings indicate that altered sensorimotor integration may cause scoliosis without noticeable motor impairment. Reduced cortico-cortical inhibition was observed in cortectomized rats. This finding is consistent with results in adolescents with IS and suggests that alteration of cortical hemispheric balance of sensorimotor integration may play an important role in the pathogenesis of IS.


Young gastric cancer patient with high CA19-9 complicated by Trousseau syndrome.
A 47-year-old Japanese woman presented with epigastric discomfort and anorexia. Upper endoscopy showed type 4 advanced gastric cancer in the gastric antrum with stenosis of the pyloric portion. Abdominopelvic CT revealed peritoneal dissemination, and stage IV advanced gastric cancer was diagnosed. Laparoscopic gastrojejunostomy and enterostomy were performed. Trousseau syndrome occurred 7 days post-surgery. Despite appropriate treatment, the patient developed a pulmonary embolism 13 days later and died 18 days post-surgery. Even in young cancer patients without lifestyle disease complications, it is important to pay attention to Trousseau syndrome as part of cancer management.


[Possibilities of modern forms of antimicrobial peptides in the treatment of inflammatory pathology of the pharynx].
Inflammatory diseases of the pharynx occupy one of the leading places in the structure of otorhinolaryngological pathology. Acute and chronic inflammatory processes in the pharynx, as well as exacerbations of the latter, are faced by doctors of a wide range of specialties. Oropharyngeal swab laboratory testing is required to identify a specific pathogen, which takes time. In this regard, of particular interest are local drugs with the necessary spectrum of action, the use of which is possible, both as monotherapy and in combination with systemic therapy. The combination of tyrothricin (tyrothricin), benzalkonium chloride (benzalkonium chloride), and benzocaine (benzocaine) (dorithricin) is highly effective in the treatment of bacterial, viral and fungal infections of the pharynx, and microorganisms consistently demonstrate high sensitivity to the components of the drug.


[Synthesis of 3-hydroxybutyrate-CO-4-hydroxybutyrate copolymers by hydrogen-oxidizing bacteria].
Synthesis of 3- and 4-hydroxybutyrate copolymer (3HB-CO-4HB), the most promising member of the biodegradable polyhydroxyalcanoate (PHA) family, has been studied. Cultivation conditions of naturally occurring strains of hydrogen-oxidizing bacteria Ralstonia eutropha B5786 and Cupriavidus eutrophus B10646 have been optimized to ensure efficient synthesis of the 3HB-CO-4HB copolymer. A set of highly pure samples of the 3HB-CO-4HB copolymer with 4HB content varying from 8.7 to 24.3 mol % has been obtained. Incorporation of 4-HB into the copolymer was shown to cause a more pronounced decrease in polymer crystallinity than the incorporation of 3-hydroxyvalerate or 3-hydroxyhexanoate; samples with a degree of crystallinity below 30% have been obtained. The weight average molecular mass of the 3HB-CO-4HB copolymers was shown to be independent on the monomer ratio and to vary broadly (from 540 to 1110 kDa).


Multiscale simulations of protein and membrane systems.
Classical multiscale simulations are perfectly suited to investigate biological soft matter systems. Owing to the bridging between microscopically realistic and lower-resolution models or the integration of a hierarchy of subsystems, one gets access to biologically relevant system sizes and timescales. In recent years, increasingly complex systems and processes have come into focus such as multidomain proteins, phase separation processes in biopolymer solutions, multicomponent biomembranes, or multiprotein complexes up to entire viruses. The review shows factors that have contributed to this progress - from improved models to machine-learning-based analysis and scale-bridging methods.


Two-dimensional echocardiographic analysis of the dynamic geometry of the left ventricle: the basis for an improved model of wall motion.
To establish an appropriate echocardiographic model for wall motion analysis we first determined the precise dynamic geometry of the left ventricle during systole, as visualized by two-dimensional echocardiography. With the epicardial apex and the aortic-ventricular and mitral-ventricular junctions as anatomic landmarks, we quantitatively analyzed apical long-axis views in 61 normal subjects, 41 patients with anterior myocardial infarction, and nine patients with posterior myocardial infarction. Thoracic impedance registration allowed exclusion of extracardiac motion from the measurements. In normal subjects the epicardial apex moved outwardly only 0.6 +/- 0.3 mm (mean +/- standard error). Examination of 15 hearts fixed in formalin revealed apical myocardial thickness of 1.5 +/- 0.2 mm. These data suggest that the observed inward motion of the endocardial apex (4.1 +/- 0.7 mm) resulted from obliteration of the apical cavity as a result of inward motion of the adjacent walls. Translation of the base was considerable in normal subjects (14.1 +/- 0.4 mm) and decreased in myocardial infarction (9.1 +/- 0.5 mm, p less than 0.0001). Unequal shortening of the adjacent walls in anterior and posterior myocardial infarction caused basal rotation in the opposite direction (-9.1 +/- 0.8 degrees and 9.7 +/- 1.4 degrees, respectively, p less than 0.0001 versus that of normal subjects, -3.4 +/- 0.7 degrees). Long-axis rotation was not clinically significant (less than 1 degree). We conclude that during ventricular contraction the apex serves as a stable point, whereas the base translates toward the apex because of shortening of the adjacent walls. We then propose a model for analyzing regional wall motion from two-dimensional echocardiograms on the basis of these observations.


A randomized trial to compare the use of sublingual misoprostol with or without an additional 1 week course for the management of first trimester silent miscarriage.
This randomized controlled trial compared the use of sublingual misoprostol with or without an additional 1 week course of sublingual misoprostol for the medical management of silent miscarriage. A total of 180 women who had silent miscarriage (<13 weeks) was given 600 microg of misoprostol every 3 h for a maximum of three doses. These women were randomized into two groups: (i) no extended course of misoprostol or (ii) an extended course of sublingual misoprostol 400 microg daily for 1 week. The primary outcome measure was complete miscarriage rate. The success rates for complete miscarriage were similar in both groups (group 1: 92.2%; 95% CI: 86.1-97.5% and group 2: 93.2%; 95% CI: 84.6-96.8%). There were no serious complications. The incidence of diarrhoea was higher (P < 0.01) in the group with an extended course of sublingual misoprostol. Other side-effects were similar. Sublingual misoprostol is useful for the management of silent miscarriage. An additional 1 week course of sublingual misoprostol did not improve the success rate or shorten the duration of vaginal bleeding. Instead, it increased the incidence of diarrhoea.


Long-term healthcare use after postoperative complications: an analysis of linked primary and secondary care routine data.
Postoperative complications are associated with reduced long-term survival. We characterise healthcare use changes after sentinel postoperative complications. We linked primary and secondary care records of patients undergoing elective surgery at four East London hospitals (2012-7) with at least 90 days follow-up. Complication codes (wound infection, urinary tract infection, pneumonia, new stroke, and new myocardial infarction) recorded within 90 days of surgery were identified from primary or secondary care. Outcomes were change in healthcare contact days in the 2 yr before and after surgery, and 2 yr mortality. We report rate ratios (RaR) with 95% confidence intervals and adjusted for baseline healthcare use and confounders using negative binomial regression. We included 49 913 patients (median age 49 yr [inter-quartile range {IQR}: 34-64]), 27 958 (56.0%) were female. Amongst 3883 (7.8%) patients with complications (median age 58 [IQR: 43-72]), there were 18.4 days per year in contact with healthcare before surgery and 25.3 days after surgery (RaR: 1.38 [1.37-1.39]). Patients without complications (median age 48 [IQR: 33-63]) had 12.3 days per year in contact with healthcare before surgery and 14.0 days after surgery (RaR: 1.14 [1.14-1.15]). The adjusted incidence rate ratio of days in contact with healthcare associated with complications was 1.67 (1.49-1.87). More patients (391; 10.1%) with complications died within 2 yr than those without (1428; 3.1%). Patients with postoperative complications are older with greater healthcare use before surgery. However, their absolute and relative increases in healthcare use after surgery are greater than patients without complications.


Studies on the mechanism of metabolic stimulation in polymorphonuclear leucocytes during phagocytosis. I. Evidence for superoxide anion involvement in the oxidation of NADPH2.
1. The oxidation of NADPH2 by leucocyte granules, as measured at acid pH in the presence of Mn-2+, was found to be inhibited by superoxide dismutase. 2. Omission of Mn-2+ markedly lowered the oxidase activity at acid pH, which was still inhibited by superoxide dismutase. 3. At alkaline pH the oxidase activity was lower than at acid pH. 4. During oxidation of NADPH2 by leucocyte granules, reduction of cytochrome c occurred which was partially inhibited by superoxide dismutase. 5. It was concluded that NADPH2 oxidation occurs through an enzymatic reaction and a nonenzymatic chain reaction. Superoxide anion (O-minus-2 and NADPH- free radical would be involved in the chain reaction. The differential sensitivity of NADPH2 oxidation to superoxide dismutase in different experimental conditions (see above 1, 2 and 3) was explained on the basis of changes in the properties of the chain reaction.


o-Semiquinonic PCP-pincer nickel complexes with alkyl substituents: versatile coordination sphere dynamics.
o-Semiquinonic nickel pincer complexes (R2PCP)Ni(SQ) show a versatile coordination sphere dynamics via "swing" or "fan" oscillations depending on the steric properties of the phosphorus substituents.


Testicular biopsies in 101 cases of varicocele.
Testicular biopsies were done on 101 patients who underwent ligation of the internal spermatic vein as primary treatment for infertility. Retrospective analysis included evaluation of tubular thickening, Leydig cell hyperplasia, premature sloughing, maturation arrest and decreased spermatogenesis. A comparison was made of biopsy profiles, sperm counts and pregnancies in an attempt to determine further the value of testicular biopsy in the subfertile man. The pregnancy rate was 40 per cent over-all, with 32 per cent of the patients with tubular thickening reporting pregnancies. There was only 1 pregnancy in patients with Leydig cell hyperplasia. The controversial finding of premature sloughing had no consistent relationship to results.


Partitioning behavior of amino acids in aqueous two-phase systems formed by imidazolium ionic liquid and dipotassium hydrogen phosphate.
Partition coefficients of amino acids, including glycine, alanine, 2-aminobutyric acid, valine, leucine, threonine, methinoine, tryptophan and tyrosine, in [C(n)mim]Br (n=4, 6, 8)+K(2)HPO(4) aqueous two-phase systems (ATPSs) have been determined, and the relative hydrophobicity of the equilibrium phases in the ionic liquids-based aqueous two-phase systems has been characterized by the Gibbs energies of transfer for methylene group from the bottom salt-rich phase to the top ionic liquid-rich phase. Based on these results, factors affecting the partitioning behavior of the amino acids have been investigated. It is shown that partition coefficients of the amino acids increase with the increase of hydrophobicity of the amino acids and the ionic liquids, solution pH value, tie-line length of the ATPSs and temperature of the systems. The possible driving forces and the thermodynamic parameters for the partitioning of amino acids in the ionic liquids-based ATPSs have also been discussed.


Modelling of frequency-dependent effects of lignocaine homologues on the maximum upstroke velocity of action potentials in guinea-pig papillary muscles.
1. The effects of 14 lignocaine homologues on the maximum upstroke velocity (Vmax) of the action potentials (AP) were studied in guinea-pig papillary muscles. These drugs possess one, two or three methyl groups in different positions: an ortho-chloro, -carbomethoxy or -ethyl group instead of an ortho-methyl group; or an N-butyl group instead of an N-diethyl group in lignocaine molecules. 2. At 50-100 mumol/L, six drugs possessing two ortho substituents (but not the other eight) reduced Vmax more prominently at 2-4 Hz than at 1 Hz, and slowed the time courses of recovery of the premature responses. None of the drugs affected resting potential. 3. Besides the two-state piecewise exponential model (models I and II) frequently used, a time-dependent and time-independent, two-state model (model III) was formulated and applied to these experimental data. The above two groups were effectively distinguished by the difference of the estimated association and dissociation rate constants (model II) and equilibrium constants for phasic state (model III) and for resting (model II) or tonic (model III) states. 4. The equilibrium constants for resting or tonic state correlated well with log P (where P = the n-octanol: water partition coefficients), but correlated better with an indicator variable that denotes the existence of two ortho substituents, suggesting the importance of the contribution of steric factors to the activity.


Neurological injury markers in children with septic shock.
To determine whether known serum markers of neurologic injury are increased in children with septic shock. Prospective, observational study. Tertiary-care, pediatric intensive care unit. Two cohorts of children (n = 24) with septic shock were prospectively enrolled within 24 hrs of their diagnosis. In cohort 1, serum markers (S100beta, neuron-specific enolase [NSE], and glial fibrillary acidic protein [GFAP]) were determined (n = 18). In cohort 2, in addition to serum markers, urine S100beta and GFAP were determined, and continuous electroencephalography (cEEG) was performed. Children who presented to the emergency room with a fever served as controls (n = 32). Children with known neurologic conditions were excluded. None. Serum and urine were collected daily for up to 7 days or until pediatric intensive care unit discharge. Biomarker concentrations were determined by commercially available enzyme-linked immunosorbent assays. cEEG was performed on days 1, 2, 4, and 7 in a 16-channel montage for at least 6 hrs. Physical examinations did not reveal focal neurologic deficits. Children with septic shock demonstrated increased serum S100beta and NSE compared with controls (mean +/- SEM: 10.5 microg/L +/- 2.4 vs. .9 microg/L +/- .1, p < .001; 96.6 microg/L +/- 8.9 vs. 4.0 microg/L +/- 1.3, p < .001, respectively). Serum GFAP was detectable in five septic children and none of the controls. In cohort 2, urine of four patients demonstrated measurable S100beta levels, and GFAP was detected in one child (nonsurvivor). cEEG demonstrated moderate to severe encephalopathy in all children studied. Markers of neurologic injuries are increased in children with septic shock. This may indicate subclinical injuries that are either transient or permanent. Studies that correlate the long-term neurologic outcome of children with these markers are needed to identify children at risk for neurologic injuries from septic shock.


A comparison of depression screening instruments in hepatitis C and the impact of depression on somatic symptoms.
Treatment of hepatitis C (HCV) with pegylated interferon-alpha (IFNα) can cause depression in approximately 30% of patients and underscores the need for effective detection of depression prior to and during IFNα treatment. Elevated rates of depression in untreated HCV can be a barrier to initiating HCV therapy and can impact fatigue and physical symptoms. In this preliminary study, we examined the accuracy of the seven-item Hamilton Depression Rating Scale (HAM-7) and Patient Health Questionnairre-9 (PHQ-9) in detecting depression in HCV-infected patients and determined the effect of major depression on somatic symptoms. We conducted a preliminary comparison of operating characteristics of the PHQ-9 and HAM-7 to the MINI International Neuropsychiatric Interview for major depression in 116 individuals with chronic HCV assessed in an ambulatory office setting. We also examined the differences in fatigue and somatic symptoms in depressed HCV-infected patients. Currently depressed chronic hepatitis C patients had significantly higher scores on all the scales compared with nondepressed patients. HAM-7 and PHQ-9 scores were significantly correlated with somatic and physical symptoms scales. Both the PHQ-9 and HAM-7 demonstrated comparable accuracy in detecting depression in comparison to the MINI. Our results suggest that the HAM-7 and PHQ-9 both have good operating characteristics compared with a criterion standard measure. Given that depression was associated with fatigue and increased somatic complaints, improved detection and treatment of depression could reduce disability and facilitate treatment for depressed HCV-infected patients.


Introduction of early medical abortion in New Zealand: an audit of the first 67 cases.
In New Zealand, mifepristone became available in 2001, but because of uncertainty about the law, the first 67 cases were carried out under a very strict protocol. Once the prostaglandin had been administered it was necessary that the woman remain in the unit until the products of conception (POC) had been passed and, if this had not occurred within 8 h, she underwent suction curettage. To demonstrate that an early medical termination of pregnancy (EMTOP) service could be offered as a safe option for women, despite the constraints of the law. An audit of patient notes was carried out on the first 67 patients undergoing an EMTOP at the Level J Unit (LJU), Wellington Hospital. Data collected included age, ethnicity, parity, previous abortions, gestational age, length of time between the administration of mifepristone and misoprostol, length of time after administration of misoprostol to the completion of abortion, whether a fetal sac was seen, analgesia required, extent of heavy bleeding and any adverse effects. Patient characteristics were compared with those of the 3052 women who underwent surgical termination during the same time period. Data were analysed using EpiInfo 2000 (Centers for Disease Control and Prevention, Atlanta, GA) and Chi square tests for significance. Successful completion of EMTOP occurred in 63 of 67 cases (94%). Only four cases (6%) required completion by suction curettage and this was performed for legal and financial reasons, rather than for medical reasons. Clinical events requiring management, mainly bleeding problems, occurred in 11 patients (16%). EMTOP with mifepristone and misoprostol was successfully introduced and the experience provides useful data for others contemplating a similar service.


Imaging of Cardiac Support Devices.
Patients hospitalized in the intensive care unit (ICU) often have multiple support lines and devices that need routine imaging evaluation by radiologists. In patients with cardiogenic shock or depressed cardiac function, mechanical circulation support devices are used in combination with medical therapies to improve patient outcomes and sometimes can stabilize patients for surgical intervention. This article discusses some of the more commonly encountered mechanical circulation devices seen in ICU patients, including intra-aortic balloon pumps, Impella devices, extracorporeal membrane oxygenation cannulas, and ventricular assist devices. Normal appearance and commonly encountered device-related complications that can be diagnosed on imaging are reviewed.


A cytochrome P450 system initiates 4-nitroanisole degradation in Rhodococcus sp. strain JS3073.
Nitroanisoles are used widely as synthetic intermediates and explosives. Although bacteria have been reported to degrade 4-nitroanisole (4NA) under aerobic conditions, the key enzymes and the catalytic mechanism have remained elusive. Rhodococcus sp. strain JS3073 was isolated for its ability to grow on 4NA as the sole carbon and energy source. In this study, whole cell biotransformation experiments indicated that 4NA degradation is initiated by O-demethylation to form 4-nitrophenol (PNP), which undergoes subsequent degradation by a previously established pathway involving formation of 1,2,4-benzenetriol and release of nitrite. Based on comparative transcriptomics and heterologous expression, a novel three-component cytochrome P450 system encoded by pnaABC initiates the O-demethylation of 4NA to yield formaldehyde and PNP. The pnaABC genes encode a phthalate dioxygenase type reductase (PnaA), a cytochrome P450 monooxygenase (PnaB), and an EthD family protein (PnaC) with putative function similar to ferredoxins. This unusual P450 system also has a broad substrate specificity for nitroanisole derivatives. Sequence analysis of PnaAB revealed high identity with multiple self-sufficient P450s of the CYP116B subfamily. The findings revealed the molecular basis of the catabolic pathway for 4NA initiated by an unusual O-demethylase PnaABC and extends the understanding of the diversity among P450s and their electron transport chains.


Plant spinescence in arid southern Africa: does moisture mediate selection by mammals?
The prediction that spinescence in plants increases with aridity, soil fertility and mammalian herbivory was examined at regional and local scales in southern Africa. Spinescence tended to increase with aridity. Within arid areas, vegetation of moist, nutrient-rich habitats was more spinescent than that of the surrounding dry plains. Spinescence in plants of drainage lines and pans in arid southern Africa occurs in a wide range of genera and appears to have been selected by the effect of large mammals which concentrate on these moist patches. It is concluded that spinescence may be selected by breakage as well as herbivory, and that in arid areas moisture may be important in mediating mammalian selection of spinescence.


Unexpected AChE inhibitory activity of (2E)α,β-unsaturated fatty acids.
A small library of (E) α,β-unsaturated fatty acids was prepared, and 20 different saturated and mono-unsaturated fatty acids differing in chain length were subjected to Ellman's assays to determine their ability to act as inhibitors for AChE or BChE. While the compounds were only very weak inhibitors of BChE, seven molecules were inhibitors of AChE holding IC50 = 4.3-12.8 M with three of them as significant inhibitors of this enzyme. The results have shown trans 2-mono-unsaturated fatty acids are better inhibitors for AChE than their saturated analogs. Furthermore, the screening results indicate that the chain length is crucial for obtaining an inhibitory efficacy. The best results were obtained for (2E) eicosenoic acid (14) showing inhibition constants Ki = 1.51 ± 0.09 M and Ki' = 7.15 ± 0.55 M. All tested compounds were mixed-type inhibitors with a dominating competitive part. Molecular modelling calculations indicate a different binding mode of active/inactive compounds for the enzymes AChE and BChE.


Preoperative controlling nutritional status score predicts systemic disease recurrence in patients with resectable biliary tract cancer.
This study aimed to evaluate the association between the preoperative Controlling Nutritional Status (CONUT) score, survival outcomes, and recurrence pattern in patients with resectable biliary tract cancer (BTC). A total of 224 BTC patients (gallbladder, n = 69; intrahepatic bile ducts, n = 26; perihilar bile ducts, n = 72; distal bile duct, n = 57) who underwent surgery with curative intent were enrolled. The best cutoff point of the preoperative CONUT score in discriminating survival was determined using χ2 scores. The sites of recurrence were subclassified as locoregional or distant. Patients were subdivided into the CONUT-low (score ≤ 3, n = 156) and the CONUT-high (score > 3; n = 68) groups. In-hospital mortality occurred more frequently in the CONUT-high group than in the CONUT-low group (7.4% vs. 1.3%; p = 0.028). A high preoperative CONUT score was independently associated with worse overall survival (hazard ratio [HR] 1.906, p = 0.001), worse disease-specific survival (HR 1.840, p = 0.006), and worse recurrence-free survival (HR 1.680, p = 0.005). Recurrence developed in 110 (49.1%) patients. A high preoperative CONUT score was independently associated with a higher risk of distant recurrence (HR 2.245, p = 0.001), but not locoregional recurrence. The incidences of distant recurrence at 5 years were 55.4% and 34.2% in the CONUT-high and CONUT-low groups, respectively (p = 0.001). The preoperative CONUT score independently predicts survival outcomes and may serve as a surrogate marker of aggressive systemic disease recurrence in patients with resectable BTC.


Subacute sclerosing panencephalitis aggravated during the intraventricular interferon administration therapy.
Human lymphoblastoid interferon-alpha was given by intraventricular administration via an Ommaya reservoir to a woman who entered Jabbour stage III at the age of 25 years. The first dose was of 150,000 IU, and daily doses were gradually increased; the total dose over a 42-day period was 33,550,000 IU. The patient's neurological disability index score before this treatment was 56.3%, and 75% after interferon treatment ended. After other treatment for 6 months, the patient died. Results of the autopsy showed perivascular lymphocyte infiltration in the cerebrum and brain stem, with diffuse gliosis and demyelination. The virus was isolated from the frontal lobes, also. The interferon treatment may have been a factor in this patient's deterioration.


Synergy of phenobarbital and 3-methylcholanthrene in "superinduction" of cytochrome P-450c mRNA but not enzyme activity.
The combination of phenobarbital and 3-methylcholanthrene in the inductive process of the rat hepatic cytochrome P-450c gene was evaluated. Daily injections of phenobarbital (80 mg/kg, i.p.) had little or no effect on the amount of poly (A)+ RNA encoding cytochrome P-450c, whereas a single injection of 3-methylcholanthrene (25 mg/kg, i.p.) produced a significant accumulation at 15 hr in cytosolic mRNA coding for cytochrome P-450c. Four daily injections of phenobarbital followed by a single dose of 3-methylcholanthrene produced 5-24 times more poly (A)+ RNA coding for P-450c than 3-methylcholanthrene treatment alone. This superinduction of RNA transcripts was also observed for a species coding for cytochrome P-450d, which was increased 3-6 times over 3-methylcholanthrene treatment alone. However, the elevated concentration of transcripts for both the P-450d and P-450c RNA species did not result in an increase in the marker enzyme activity for cytochrome P-450c, 7-ethoxyresorufin O-deethylase. These data implicate a regulatory step in the induction of cytochrome P-450c enzyme activity which must occur at a level beyond transcription.


Single strand DNA catenane synthesis using the formation of G-quadruplex structure.
DNA is a good material for constructing nanostructures such as DNA origami. One of the challenges in this field is constructing a topologically complex structure. Here, we synthesized a DNA catenane through the formation of a G-quadruplex structure. The formation of the DNA catenane was investigated by gel electrophoresis. Interestingly, the synthesized DNA catenane was destroyed by heat treatment. Because conventional methods to construct DNA catenane include enzymatic ligation or chemical reactions, DNA is cyclized by covalent bond connection and never destroyed by heat treatment. To our knowledge, this is the first report of the synthesis of DNA catenane without using covalent bonds. Our novel way of synthesizing DNA catenane may be of use in easily recoverable DNA topological labeling.


iNKT17 cells play a pathogenic role in ethinylestradiol-induced cholestatic hepatotoxicity.
IL-17 is closely associated with inflammation in intrahepatic cholestasis (IHC). Targeting IL-17 ameliorates IHC in mice. Invariant natural killer T (iNKT) cells are predominantly enriched in the liver and they mediate drug-induced liver injury through their secreted cytokines. However, whether iNKT17 cells are involved in ethinylestradiol (EE)-induced IHC remains unclear. In the present study, the administration of EE (10 mg/kg in vivo and 6.25 μM in vitro) promoted the activation and expansion of iNKT17 cells, which contributed to a novel hepatic iNKT17/Treg imbalance. iNKT cell-deficient Jα18-/- mice and the RORγt inhibitor digoxin (20 μg) alleviated EE-induced cholestatic hepatotoxicity and downregulated the IL-17 signalling pathway. In contrast, the co-administration of EE with recombinant IL-17 (1 μg) to Jα18-/- mice induced cholestatic hepatotoxicity and increased the infiltration of hepatic neutrophils and monocytes. Importantly, the administration of IL-17-/- iNKT cells (3.5 × 105) to Jα18-/- mice resulted in the attenuation of hepatotoxicity and the recruitment of fewer hepatic neutrophils and monocytes than the adoptive transfer of wild-type iNKT cells. These results indicated that iNKT17 cells could exert pathogenic effects. The recruitment and activation of iNKT17 cells could be attributed to the high level of CXCR3 expression on their surface. CXCL10 deficiency ameliorated EE-induced cholestatic liver damage, reduced hepatic CXCR3+ iNKT cells and inhibited RORγt expression. These findings suggest that iNKT17 cells play a key role in EE-induced cholestatic liver injury via CXCR3-mediated recruitment and activation. Our study provides new insights and therapeutic targets for cholestatic diseases.


The 2009 pandemic H1N1 neuraminidase N1 lacks the 150-cavity in its active site.
Influenza A virus neuraminidase can be classified into groups 1 and 2 on the basis of its primary structure. The main structural feature of group 1 neuraminidase is an extra cavity in the active site, the 150-cavity. Here we present the crystal structure of neuraminidase from the 2009 pandemic H1N1 influenza strain. In contrast to other characterized N1 neuraminidases, which are all members of group 1, 2009 H1N1 neuraminidase does not have a 150-cavity.


The effect of dilution on plasma lidocaine levels with endotracheal administration.
In the many emergency situations in which it is difficult or impossible to obtain venous access rapidly endotracheal drug therapy can be effective and life saving. Yet relatively little is known about endotracheal drug therapy. Plasma lidocaine levels were measured in 23 dogs after the administration of endotracheal lidocaine at a dose of 2 or 4 mg/kg. Endotracheal lidocaine was given either as a dilution with normal saline (1:1 dilution) or undiluted (Group 1, no dilution; Group 2, dilution). Significantly higher plasma lidocaine levels occurred with the dilution group in all the time periods and with either dose of lidocaine (2 or 4 mg/kg) (P less than .001). Mean plasma lidocaine levels (microgram/mL) at five minutes were: (at 2 mg/kg dose) Group 1, 0.64; Group 2, 3.4; and (at 4 mg/kg dose) Group 1, 1.9, Group 2, 4.7 (P less than .001). Arterial blood gases were not significantly different before or after endotracheal drug administration. This study suggests that higher plasma lidocaine levels are achieved and maintained longer when diluted with normal saline than when given undiluted; and higher plasma lidocaine levels can be obtained by dilution without any detrimental effect on respiratory function as measured by arterial blood gases.


Synthesis and in vitro anti-hepatitis B virus activities of some ethyl 6-bromo-5-hydroxy-1H-indole-3-carboxylates.
A series of ethyl 6-bromo-5-hydroxy-1H-indole-3-carboxylates, 8a-11v, were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities in 2.2.15 cells. The selective indexes of inhibition on replication of HBV DNA of compounds 11s (>8.7) and 11t (10.8), which were introduced halogen on the phenyl ring at position 2, were greater than those of the other evaluated compounds including lamivudine (7.0). Compounds 9e, 9h, 9l, and 11v exhibited significant anti-HBV activities, and the IC(50) values on replication of HBV DNA of these compounds were 3.6, 6.37, 5.2, and 5.4 microg/ml, respectively, which were far more potent than the positive control lamivudine 228 microg/ml.


Advanced glaucoma at diagnosis: current perspectives.
Presentation with advanced glaucoma is a significant risk factor for lifetime blindness. The asymptomatic nature of glaucoma, particularly in early disease, means that substantial vision loss in one eye does not always translate into a perceptible loss of visual function. This, along with the lack of an effective screening strategy, contributes to late presentation. Those most at risk of presenting with advanced glaucoma have asymptomatic high intraocular pressure (IOP), no family history of glaucoma, are socially disadvantaged, and do not attend sight testing. Patients with glaucoma may have impaired functionality for daily activities, such as reading, walking and driving. Quality of life measures have shown this to be significantly worse in patients with more severe visual field loss, particularly if bilateral. In addition, quality of life decreases faster with further bilateral visual field loss when advanced visual field damage is present. Management of these patients requires disproportionally more resources than those with earlier disease. Both medical and surgical options are used as the initial approach to treat patients presenting with advanced glaucoma. The most recently published National Institute for Health and Care Excellence (NICE) guidelines suggest that patients presenting with advanced disease should be offered trabeculectomy as a primary intervention. However, more evidence is required to determine the best initial management. The Treatment of Advanced Glaucoma Study (TAGS) is being conducted, comparing primary medical management with primary mitomycin C-augmented trabeculectomy for people presenting with advanced open-angle glaucoma. The results of TAGS will provide robust evidence for the most appropriate initial intervention.


Endothelin-1 production via placental (pro)renin receptor in a mouse model of preeclampsia.
Preeclampsia (PE) pathogenesis is explained by the two-stage disorder theory. However, mechanisms underlying hypertension and proteinuria in PE remain unclear. The role of (pro)renin receptor (PRR) in PE pathology has received special attention. We examined endothelin-1 (ET-1) production via placental PRR in a PE mouse model. At 14.5 day-post-coitum (DPC), we performed a reduced uterine perfusion pressure (RUPP) operation, ligating the uterine arteriovenous vessels in female mice. We also infused these mice with a PRR inhibitor, decoy peptide in the handle region of prorenin (HRP) for mice (NH2-RIPLKKMPSV-COOH). At 18.5 DPC, blood, urine, and placenta were collected; fetus and placenta were weighed. We evaluated placental hypoxia using quantitative polymerase chain reaction (PCR), with hypoxia-inducible factor-1α (HIF-1α) as index. We also evaluated PRR, transforming growth factor-β1 (TGF-β1), and ET-1 expression in the placenta using quantitative PCR and western blotting. ET-1 concentration in blood plasma was assessed using enzyme-linked immunosorbent assay. Blood pressure and proteinuria significantly increased, and fetal and placental weights decreased in RUPP mice. HIF-1α, PRR, TGF-β1, and ET-1 expressions considerably increased in RUPP mice placentas. ET-1 concentration in RUPP mice blood plasma was markedly increased. PRR inhibitor suppressed these changes. In PE model mice that underwent RUPP treatment, placental hypoxia increased PRR and ET-1 expression suggesting a causative relationship between ET-1 and intracellular PRR signaling. RUPP treatment, when combined with HRP, reversed the effect of elevated ET-1 levels in the model. This study may help to elucidate the pathogenesis of PE considering PRR and ET-1.


Protein Hydrolysates and Biopeptides: Production, Biological Activities, and Applications in Foods and Health Benefits. A Review.
In recent years, a great deal of interest has been expressed regarding the production, characterization, and applications of protein hydrolysates and food-derived biopeptides due to their numerous beneficial health effects. In this regard, research is mainly focused on investigating the therapeutic potential of these natural compounds. Based on their amino acids composition, sequences, hydrophobicity, and length, peptides released from food proteins, beyond their nutritional properties, can exhibit various biological activities including antihypertensive, antioxidative, antithrombotic, hypoglycemic, hypocholesterolemic, and antibacterial activities among others. Protein hydrolysates are essentially produced by enzymatic hydrolysis of whole protein sources by appropriate proteolytic enzymes under controlled conditions, followed by posthydrolysis processing to isolate desired and potent bioactive peptides from a complex mixture of active and inactive peptides. Therefore, because of their human health potential and safety profiles, protein hydrolysates and biopeptides may be used as ingredients in functional foods and pharmaceuticals to improve human health and prevent diseases. In this review, we have focused on the major variables influencing the enzymatic process of protein hydrolysates production. The biological properties of protein hydrolysates will be described as well as their applications in foods and health benefits.


The effect of common imaging and hot water maceration on DNA recovery from skeletal remains.
Identifying human remains often begins with cleaning and imaging the material. Hot water maceration is used to remove adherent soft tissue from bone and radiographs are taken to better visualize osseous details. Heat and radiation are known to have harmful effects on DNA, but their ability to degrade DNA when used for cleaning and imaging has not been well studied. To better understand their individual and combined effects on the recoverability of DNA from bone, skeletal samples were subjected to (1) hot water maceration (62 °C for 45 min); (2) CT scanning (0.6mm slices, 120 kV, 10.4s); (3) X-ray (50 kVp, 150 mA, 0.03 s, 40 in); and (4) all 3 treatments combined. Forty-eight DNA samples were extracted, quantified and amplified with the AmpFLSTR(®) Identifiler(®) system. Nearly all of the processed samples had reduced RFU values relative to the unprocessed samples, indicating some amount of genetic loss. This loss did not always translate into loss of profile completeness, since only a few samples had a reduction in the number of loci detected after processing. DNA yields were not significantly reduced by any one of the processing methods, however the results indicate that the damaging effects are additive. It is possible that processing may reduce a bone's DNA reservoir and as more procedures are preformed, the pool of available genetic information might be diminished. Many intrinsic and extrinsic factors can affect the recoverability of DNA from bone. Collecting a DNA sample prior to processing avoids the negative effects from hot water maceration and radiological imaging.


The Relevance of State Laws Regulating Opioid Prescribing for People Living With Serious Illness.
Opioids are commonly used to relieve symptoms such as pain and dyspnea in people living with serious illness. In recent years, 36 states enacted limitations for opioid prescriptions to mitigate the impact of the opioid overdose crisis. Palliative care clinicians have been vocal about the unintended consequences of opioid policies, yet little is known about how state policies apply to opioid prescribing in non-cancer-related serious illness. To summarize current state-level limitations to opioid prescribing and exemptions relevant to people living with non-cancer-related serious illness. Investigators searched publicly available laws ("[state] + opioid legislation") to extract information on opioid prescribing and exemptions. Laws were examined for application to palliative care, hospice, non-cancer-related serious illness, and language about specific symptoms was documented when applicable (e.g., pain, dyspnea). Most state laws focused on acute pain and/or initial opioid prescriptions. Thirty-three of the thirty-six states with opioid-limiting legislation exempt situations applicable to people living with non-cancer-related serious illness. Three states did not have any exemptions relevant to people living with non-cancer-related serious illness. The results indicate that while most states recognize the importance of timely opioid access for palliation of pain, clinically relevant exemptions for people living with non-cancer-related serious illness may be lacking. When present, language describing palliative care, hospice, and terminal illness exemptions is often broad and may generate confusion between primary and specialty palliative care.


Differences in smooth pursuit eye movement between posttraumatic stress disorder with secondary psychotic symptoms and schizophrenia.
Studies show high comorbidity between post-traumatic stress disorder and psychotic symptoms. Despite this fact, there has been only one published study of the neurobiology of this enigmatic disorder. This preliminary study examines the relationship between psychotic symptoms in post-traumatic stress disorder (PTSD) and schizophrenia by measuring smooth pursuit eye movement (SPEM) in subjects with PTSD and secondary psychotic symptoms, schizophrenia, and healthy controls. The results show that PTSD with secondary psychotic symptoms is associated with a SPEM deficit that is different from the SPEM deficit associated with schizophrenia.


Insights into Nanotherapeutic Strategies as an Impending Approach to Liver Cancer Treatment.
Liver cancer, being the utmost prevalent fatal malignancy worldwide, is ranked as the fifth leading cause of deaths associated with cancer. Patients with liver cancer are diagnosed often at an advanced stage, contributing to poor prognosis. Of all forms of liver cancer, hepatocellular carcinoma (HCC) contributes to 90% of cases, with chemotherapy being the treatment of choice. However, unfavorable toxicity of chemotherapy drugs and the vulnerability of nucleic acid-based drugs to degradation, have limited their application in clinical settings. So, in order to improvise their therapeutic efficacy in HCC treatment, various nanocarrier drug delivery systems have been explored. Furthermore, nanoparticle based imaging provides valuable means of accurately diagnosing HCC. Thus, in recent years, the advent of nanomedicine has shown great potential and progress in dramatically altering the approach to the diagnosis as well as treatment of liver cancer. Nanoparticles (NPs) are being explored as potential drug carriers for small molecules, miRNAs, and therapeutic genes used for liver cancer treatment. This review emphasizes on the current developments and applications of nanomedicine based therapeutic and diagnostic approaches in HCC.