Simian Immunodeficiency Virus Infection Increases Blood Ethanol Concentration Duration After Both Acute and Chronic Administration.
Alcohol use disorder (AUD) is a frequent comorbidity among people living with HIV/AIDS (PLWHA). Alcohol consumption is a significant predictor of nonadherence to antiretroviral therapy (ART), as well as worsening immunological and virological indicators among PLWHA. Clinical studies indicate that higher viral loads increase sensitivity to alcohol in PLWHA. The factors that influence alcohol kinetics after HIV infection and initiation of ART are not well understood, limiting the information upon which interventions can be designed to ameliorate the impact of alcohol misuse on this vulnerable patient population. To better understand the relationship between viral load and alcohol kinetics, we measured changes in doses of intragastric ethanol administration to achieve target blood ethanol concentration (BEC) in a rhesus macaque model of chronic binge alcohol (CBA) administration and acute changes following a single acute binge dose of alcohol (ABA) pre- and post-simian immunodeficiency virus (SIV) infection, and following ART initiation. Our results from CBA (14 months)-administered SIV-infected male macaques showed that, following ART initiation, macaques required higher doses of alcohol to achieve a target peak BEC compared with non-ART-treated SIV-infected macaques. In animals given ABA, we found prolonged duration of elevated BEC and decreased elimination rate of alcohol that was not corrected following 7 weeks of ART. These findings suggest that binge drinking associated with AUD could negatively interact with HIV infection and enhance disease progression. These findings further support the need for implementation of behavioral or therapeutic interventions to decrease alcohol consumption to improve the quality of life in PLWHA.


[Role of biometric analysis in the retrospective assessment of exposure to asbestos].
Despite intrinsic limitations due to differences in the bio-persistence of the various asbestos types, in the definition of control populations and in analytical techniques used by the laboratories, mineralogical analysis of biological samples is useful in the assessment of past exposure to asbestos. It provides additional information to occupational and environmental questionnaires, particularly when exposure to asbestos is doubtful, unknown or forgotten by a subject. Results should be interpreted taking into account clinical information. A positive result does not mean existence of asbestos-related disease. A negative result does not exclude previous significant asbestos exposure, clearly identified by an occupational questionnaire (particularly for exposure to chrysotile). Threshold values indicative of a high probability of previous asbestos exposure have been established for bronchoalveolar lavage fluid (BALF) samples and lung tissue samples. Quantification of asbestos bodies by light microscopy is easy to perform. Sensitivity and specificity of this analysis towards the total pulmonary asbestos fiber burden is good. Therefore this analysis should be performed first. Mineralogical analysis in BALF or lung tissue should be considered only when sampling is supported by diagnostic or therapeutic implications.


Diverse Underlying Mechanisms and Sex Differences Found in Translational Models of Cannabinoids Use: Towards Validation in Human Studies.
This Special Issue represents a continuation of our previous Special Issue entitled "Endocannabinoids, Cannabinoids and Psychiatry: Biological Mechanisms" [...].


[A case of right B2 hillar lung cancer treated by sleeve segmentectomy].
A 47-year-old male, a heavy smoker, was referred to our hospital after Class IV was detected by screening of sputum cytology. His chest X-ray film showed no abnormalities, but bronchoscopy revealed a small nodular lesion at the orifice of right B2. Squamous cell carcinoma was diagnosed by transbronchial biopsy. The clinical stage was I (T1N0M0), and S2 sleeve segmentectomy with lymph node dissection (R 2 b) was performed. The pathological stage was I (T1N0M0), and it was confirmed as early hilar lung cancer. There were no post operative complications and he is well without any evidence of recurrence 5 months after surgery. It may well be considered that this segmental bronchoplastic procedure is useful for cases with early stage squamous cell carcinoma of the segmental bronchus to preserve pulmonary function.


Role of Fe(III) in preventing humic interference during As(III) detection on gold electrode: spectroscopic and voltammetric evidence.
A drawback of As(III) detection using square wave anodic stripping voltammetry (SWASV) is that it is susceptible to interferences from various metals or organic compounds, especially in real sample water. This study attempts to understand the interference of co-existing of Fe(III) and humic acid (HA) molecules to the electrochemical detection of As(III) using Fourier transform infrared (FTIR) spectrum and X-ray photoelectron spectroscopy (XPS). The electrochemical experiments include stripping of As(III) in the solutions containing HA with different concentrations, cyclic voltammetry in 0.5M H2SO4 in the presence of HA or Fe(III) with/without addition of Fe(III) or HA, and stripping of As(III) in the presence of HA or Fe(III) with/without addition of Fe(III) or HA. FTIR and XPS are employed to confirm the affinity of HA to Fe(III) or As(III) in acidic condition.


[Effects of the combination of angiotensin receptor blockers and thiazide diuretics on laboratory values (levels of serum potassium, sodium, and uric acid)].
The combination of angiotensin receptor blockers (ARB) and a thiazide diuretic (hereafter, ARB/diuretic) is expected to improve patient adherence and increase the therapeutic effects because of the lower number of pills that require to be administered. In addition, an ARB/diuretic combination alleviates hypokalemia that frequently develops in patients receiving thiazide diuretics. In this study, we used electronic medical records to investigate the laboratory values (serum levels of potassium, sodium, and uric acid) of 194 ambulatory and hospitalized patients at the Gifu Municipal Hospital who received ARB/diuretic combination therapy for the first time between February 2010 and September 2012. According to the grade of classification of low serum potassium and sodium levels, the serum potassium level in one patient was grade 3 and the serum sodium level in two patients was grade 3 after the initiation of ARB/diuretic combination therapy. After administration of ARB/diuretic combination therapy, two patients received potassium supplements because their serum potassium levels decreased below the reference value. Similarly, one patient received a sodium supplement because of a decrease in the sodium level below the reference value. Uric acid level increased above the reference value after administration of the ARB/diuretic combination therapy in one patient; thus, this patient received antihyperuricemic agents. Therefore, pharmacists must carefully monitor the serum levels of potassium, sodium, and uric acid, particularly in the first six months after the initiation of ARB/diuretic combination therapy.


Biomimetic Macrophage Membrane-Camouflaged Nanoparticles Induce Ferroptosis by Promoting Mitochondrial Damage in Glioblastoma.
The increasing understanding of ferroptosis has indicated its role and therapeutic potential in cancer; however, this knowledge has yet to be translated into effective therapies. Glioblastoma (GBM) patients face a bleak prognosis and encounter challenges due to the limited treatment options available. In this study, we conducted a genome-wide CRISPR-Cas9 screening in the presence of a ferroptosis inducer (RSL3) to identify the key driver genes involved in ferroptosis. We identified ALOX15, a key lipoxygenase (LOX), as an essential driver of ferroptosis. Small activating RNA (saRNA) was used to mediate the expression of ALOX15 promoted ferroptosis in GBM cells. We then coated saALOX15-loaded mesoporous polydopamine (MPDA) with Angiopep-2-modified macrophage membranes (MMs) to reduce the clearance by the mononuclear phagocyte system (MPS) and increase the ability of the complex to cross the blood-brain barrier (BBB) during specific targeted therapy of orthotopic GBM. These generated hybrid nanoparticles (NPs) induced ferroptosis by mediating mitochondrial dysfunction and rendering mitochondrial morphology abnormal. In vivo, the modified MM enabled the NPs to target GBM cells, exert a marked inhibitory effect on GBM progression, and promote GBM radiosensitivity. Our results reveal ALOX15 to be a promising therapeutic target in GBM and suggest a biomimetic strategy that depends on the biological properties of MMs to enhance the in vivo performance of NPs for treating GBM.


AAPM task group report 273: Recommendations on best practices for AI and machine learning for computer-aided diagnosis in medical imaging.
Rapid advances in artificial intelligence (AI) and machine learning, and specifically in deep learning (DL) techniques, have enabled broad application of these methods in health care. The promise of the DL approach has spurred further interest in computer-aided diagnosis (CAD) development and applications using both "traditional" machine learning methods and newer DL-based methods. We use the term CAD-AI to refer to this expanded clinical decision support environment that uses traditional and DL-based AI methods. Numerous studies have been published to date on the development of machine learning tools for computer-aided, or AI-assisted, clinical tasks. However, most of these machine learning models are not ready for clinical deployment. It is of paramount importance to ensure that a clinical decision support tool undergoes proper training and rigorous validation of its generalizability and robustness before adoption for patient care in the clinic. To address these important issues, the American Association of Physicists in Medicine (AAPM) Computer-Aided Image Analysis Subcommittee (CADSC) is charged, in part, to develop recommendations on practices and standards for the development and performance assessment of computer-aided decision support systems. The committee has previously published two opinion papers on the evaluation of CAD systems and issues associated with user training and quality assurance of these systems in the clinic. With machine learning techniques continuing to evolve and CAD applications expanding to new stages of the patient care process, the current task group report considers the broader issues common to the development of most, if not all, CAD-AI applications and their translation from the bench to the clinic. The goal is to bring attention to the proper training and validation of machine learning algorithms that may improve their generalizability and reliability and accelerate the adoption of CAD-AI systems for clinical decision support.


[Synchronous or metachronous extragastric neoplasms associated with gastric neoplasia. Common pathogenesis of gastric intestinal and colonic carcinoma?].
Coexistence of syncronous or metacronous extragastric carcinomas, particularly of the colon and small bowel may favour the hypothesis of a common origin with gastric carcinoma. Three cases of colonic carcinoma coexisting with early gastric cancer, are presented. The etiopathogenesis of intestinal-type gastric cancer and colonic cancer are discussed in the light of a possible common mechanism.


Octreotide in the control of post-sclerotherapy bleeding from oesophageal varices, ulcers and oesophagitis.
Bleeding from oesophageal varices, oesophageal ulcers or oesophagitis is occasionally massive and difficult to control. Octreotide, a synthetic analogue of somatostin lowers portal pressure and collateral blood flow including that through varices, increases lower oesophageal sphincter pressure, and inhibits the gastric secretion of acid as well as pepsin. Our current experience suggests it is effective in controlling acute variceal haemorrhage. Therefore we have examined the efficacy of octreotide in the control of post-sclerotherapy bleeding from oesophageal varices, oesophageal ulcers and oesophagitis. During the study period 77 patients experienced a significant gastrointestinal bleed (blood pressure < 100 mm Hg, pulse > 100 beats per min or the need to transfuse 2 or more units of blood to restore the hemoglobin level) following injection sclerotherapy of oesophageal varices. The source of bleeding was varices in 42 patients, oesophageal ulcers in 31 and oesophagitis in 4. All patients received a continuous intravenous infusion of octreotide (50 micrograms/h) for between 40-140h. If bleeding was not controlled in the first 12h after commencing octreotide hourly bolus doses (50 micrograms) for 24h were superimposed on the continuous infusion. Haemorrhage was successfully controlled by an infusion of octreotide in 38 of the 42 patients with bleeding from varices, in 30 of 31 patients with oesophageal ulceration, and all patients with oesophagitis. In the 1 patient with persistent bleeding from oesophageal ulceration and in 2 of the 4 with continued haemorrhage from varices, haemostasis was achieved by hourly boluses of 50 micrograms octreotide for 24h in addition to the continuous infusion. No major complications were associated with octreotide administration. The results of this study clearly indicate that octreotide is a safe and effective treatment for the control of severe haemorrhage after technically successful injection of sclerotherapy.


Discovery of senolytics using machine learning.
Cellular senescence is a stress response involved in ageing and diverse disease processes including cancer, type-2 diabetes, osteoarthritis and viral infection. Despite growing interest in targeted elimination of senescent cells, only few senolytics are known due to the lack of well-characterised molecular targets. Here, we report the discovery of three senolytics using cost-effective machine learning algorithms trained solely on published data. We computationally screened various chemical libraries and validated the senolytic action of ginkgetin, periplocin and oleandrin in human cell lines under various modalities of senescence. The compounds have potency comparable to known senolytics, and we show that oleandrin has improved potency over its target as compared to best-in-class alternatives. Our approach led to several hundred-fold reduction in drug screening costs and demonstrates that artificial intelligence can take maximum advantage of small and heterogeneous drug screening data, paving the way for new open science approaches to early-stage drug discovery.


Investigation of the diffusion abnormality index as a new imaging biomarker for early assessment of brain tumor response to radiation therapy.
Diffusion MRI, although having the potential to be a biomarker for early assessment of tumor response to therapy, could be confounded by edema and necrosis in or near the brain tumors. This study aimed to develop and investigate the ability of the diffusion abnormality index (DAI) to be a new imaging biomarker for early assessment of brain metastasis response to radiation therapy (RT). Patients with either radiosensitive or radioresistant brain metastases that were treated by whole brain RT alone or combined with bortezomib as a radiation sensitizer had diffusion-weighted (DW) MRI pre-RT and 2 weeks (2W) after starting RT. A patient-specific diffusion abnormality probability function (DAProF) was created to account for abnormal low and high apparent diffusion coefficients differently, reflecting respective high cellularity and edema/necrosis. The DAI of a lesion was then calculated by the integral of DAProF-weighted tumor apparent diffusion coefficient histogram. The changes in DAI from pre-RT to 2W were evaluated for differentiating the responsive, stable, and progressive tumors and compared with the changes in gross tumor volume and conventional diffusion metrics during the same time interval. In lesions treated with whole brain RT, the DAI performed the best among all metrics in predicting the posttreatment response of brain metastases to RT. In lesions treated with whole brain RT + bortezomib, although DAI was the best predictor, the performance of all metrics worsened compared with the first group. The ability of DAI for early assessment of brain metastasis response to RT depends upon treatment regimes.


An LcMYB111-LcHY5 Module Differentially Activates an LcFLS Promoter in Different Litchi Cultivars.
Flavonol synthase (FLS) is the crucial enzyme of the flavonol biosynthetic pathways, and its expression is tightly regulated in plants. In our previous study, two alleles of LcFLS,LcFLS-A and LcFLS-B, have been identified in litchi, with extremely early-maturing (EEM) cultivars only harboring LcFLS-A, while middle-to-late-maturing (MLM) cultivars only harbor LcFLS-B. Here, we overexpressed both LcFLS alleles in tobacco, and transgenic tobacco produced lighter-pink flowers and showed increased flavonol levels while it decreased anthocyanin levels compared to WT. Two allelic promoters of LcFLS were identified, with EEM cultivars only harboring proLcFLS-A, while MLM cultivars only harbor proLcFLS-B. One positive and three negative R2R3-MYB transcription regulators of LcFLS expression were identified, among which only positive regulator LcMYB111 showed a consistent expression pattern with LcFLS, which both have higher expression in EEM than that of MLM cultivars. LcMYB111 were further confirmed to specifically activate proLcFLS-A with MYB-binding element (MBE) while being unable to activate proLcFLS-B with mutated MBE (MBEm). LcHY5 were also identified and can interact with LcMYB111 to promote LcFLS expression. Our study elucidates the function of LcFLS and its differential regulation in different litchi cultivars for the first time.


Evaluation of patients with phenylalanine metabolism disorder: a single center experience.
The aim is to evaluate the clinical, demographic and laboratory data of the patients we followed up with phenylalanine metabolism disorder. In this study, patients with phenylalanine metabolism disorder who applied to Bursa Uludag University Faculty of Medicine, Department of Pediatrics, Pediatric Metabolism Department between 2011 and 2021 were retrospectively examined. The files of 397 patients who were followed up in our pediatric metabolism outpatient clinic and were found to have phenylalanine metabolism disorder by plasma phenylalanine level and molecular genetic analysis were evaluated. According to the highest plasma phenylalanine levels at admission, mild hyperphenylalaninemia phenotype constituted the largest group of 397 patients with 282 cases (71.1%), while the least common phenotype was malignant phenylketonuria (BH4 metabolism disorder) with four patients (1.0%). The number of patients with classical phenylketonuria was 90 (22.6%). 61 (62.8%) of 97 phenylalanine metabolism disorder cases who underwent BH4 loading test had a response. The mean phenylalanine level of the patients was 3.62 ± 1.31 mg/dL in mild hyperphenylalaninemia, 7.98 ± 3.99 mg/dL in mild phenylketonuria and 11.71 ± 4.39 mg/dL in classical phenylketonuria. While 241 (76%) of 317 patients younger than 8 years old were in the well-controlled group, 76 (24%) were in the poorly-controlled group. While 41 (53.9%) of 76 patients older than 8 years of age were in the well-controlled group, 35 (46.1%) were in the poorly-controlled group. In our study, the largest patient group consisted of patients with mild hyperphenylalaninemia, and the least common phenotype was mild phenylketonuria.


Short-term intermittent energy restriction interventions for weight management: a systematic review and meta-analysis.
This systematic review synthesized the available evidence on the effect of short-term periods of intermittent energy restriction (weekly intermittent energy restriction; ≥7-d energy restriction) in comparison with usual care (daily continuous energy restriction), in the treatment of overweight and obesity in adults. Six electronic databases were searched from inception to October 2016. Only randomized controlled trials of interventions (≥12 weeks) in adults with overweight and obesity were included. Five studies were included in this review. Weekly intermittent energy restriction periods ranged from an energy intake between 1757 and 6276 kJ/d-1 . The mean duration of the interventions was 26 (range 14 to 48) weeks. Meta-analysis demonstrated no significant difference in weight loss between weekly intermittent energy restriction and continuous energy restriction post-intervention (weighted mean difference: -1.36 [-3.23, 0.51], p = 0.15) and at follow-up (weighted mean difference: -0.82 [-3.76, 2.11], p = 0.58). Both interventions achieved comparable weight loss of >5 kg and therefore were associated with clinical benefits to health. The findings support the use of weekly intermittent energy restriction as an alternative option for the treatment of obesity. Currently, there is insufficient evidence to support the long-term sustainable effects of weekly intermittent energy restriction on weight management.


Strategies for Recruiting Women Living with Human Immunodeficiency Virus in Community-Based Research: Lessons from Canada.
This study sought to describe the recruitment of women living with HIV (WLWH) into the community-based Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS), because women are under-represented in HIV research. There were 1,424 WLWH were enrolled from British Columbia, Ontario, and Québec, who completed detailed questionnaires administered by peer research associates (PRAs; WLWH with research training). During screening, participants were asked: "How did you hear about the study?" We describe recruitment strategies by subpopulation and offer reflections on challenges and successes. Of 1,131 participants with complete data, 40% identified as White, 33% African/Caribbean/Black, and 19% Indigenous. The median age was 45 years (interquartile range, 37-51) and 4% identified as trans women. Overall, 35% were recruited through PRAs/peers, 34% clinics, and 19% AIDS service organizations (ASOs). PRAs/peers were the predominant recruitment method in Ontario (49%), compared with clinics in British Columbia (40%), and Québec (43%). Nationally, PRAs/peers were more successful in recruiting WLWH commonly considered to be "harder to reach" (e.g., women identifying as trans, using drugs, not receiving HIV care). Clinics were more effective in recruiting younger women (16-29 years) and women not using ASOs. Recruitment challenges centered on engaging these harder to reach women. Successes included hiring PRAs who built participant trust, linking with clinics to reach women isolated from HIV communities, involving outreach workers to engage street-involved women, and disseminating study information to diverse stakeholders. Having multiple approaches, engaging a diverse team of PRAs, ensuring flexibility, and cultivating reciprocal relationships with community stakeholders were key to recruiting a diverse and representative sample of WLWH.


Effect of acute hypoxia on inspiratory muscle oxygenation during incremental inspiratory loading in healthy adults.
To non-invasively examine the effect of acute hypoxia and inspiratory threshold loading (ITL) on inspiratory muscles [sternocleidomastoid (SCM), scalene (SA) and parasternal (PS)] oxygenation in healthy adults using near-infrared spectroscopy (NIRS). Twenty healthy adults (12 M/8 F) were randomly assigned to perform two ITL tests while breathing a normoxic or hypoxic (FIO2 = 15 %) gas mixture. NIRS devices were placed over the SCM, PS, SA, and a control muscle, tibialis anterior (TA), to monitor oxygenated (O2Hb), deoxygenated (HHb), total hemoglobin (tHb) and tissue saturation index (TSI). With the nose occluded, subjects breathed normally for 4 min through a mouthpiece that was connected to a weighted threshold loading device. ITL began by adding a 100-g weight to the ITL device. Then, every 2 min 50-g was added until task failure. Vital signs, ECG and ventilatory measures were monitored throughout the protocol. Participants were 31 ± 12 year and had normal spirometry. At task failure, the maximum load and ventilatory parameters did not differ between the hypoxic and normoxic ITL. At hypoxic ITL task failure, SpO2 was significantly lower, and ∆HHb increased more so in SA, SCM and PS than normoxic values. SCM ∆TSI decreased more so during hypoxic compared to normoxic ITL. ∆tHb in the inspiratory muscles (SCM, PS and SA) increased significantly compared to the decrease in TA during both hypoxic and normoxic ITL. The SCM, an accessory inspiratory muscle was the most vulnerable to deoxygenation during incremental loading and this response was accentuated by acute hypoxia.


[Evaluation of complex therapy efficiency for urogenital tuberculosis].
It is most expedient to develop effective modes of improving the etiotropic therapy of urogenital tuberculosis, by applying the multipronged approach which includes chemoenzyme therapy with native and immobilized terrilytine, enhanced activity of basic tuberculostatic agents through their combination with nonspecific antibiotics and the use of helium-neon laser, and delivery of drugs just to the focus of tuberculous inflammation by endolymphatic injection.


Effect of aorto-coronary grafts and native vessel patency on the occurrence of angina pectoris after coronary bypass surgery.
Exercise testing of 52 patients on average 11 months after coronary bypass surgery for the relief of angina pectoris disclosed improvement in total work (P is less than 0.001), maximal tolerated load (P is smaller than 0.001), maximal heart rate (P is smaller than 0.01), and reduction of maximal ST segment depression (P is smaller than 0.001) in a group of 36 patients with all grafts patent. In another group of 16 patients with one or more grafts occluded the only significant change was a reduction in the maximal ST segment depression (P is smaller than 0.01). Early and late postoperative angiograms showed that 75 per cent of the grafts that became occluded were already closed a few weeks after operation. Occluded grafts were accompanied by persistence of collaterals, which disappeared or dimished in the majority of patients with patent grafts. Progression in native vessel lesions occurred in 40 per cent of patients. It was related to the grafting procedure (P is smaller than 0.01) but not to the state of grafts. The change in native vessels and other variables studied was equal in the patent and occluded graft groups, justifying the conclusion that graft patency was the major factor alleviating angina after operation.


Deep Sketch-Guided Cartoon Video Inbetweening.
We propose a novel framework to produce cartoon videos by fetching the color information from two input keyframes while following the animated motion guided by a user sketch. The key idea of the proposed approach is to estimate the dense cross-domain correspondence between the sketch and cartoon video frames, and employ a blending module with occlusion estimation to synthesize the middle frame guided by the sketch. After that, the input frames and the synthetic frame equipped with established correspondence are fed into an arbitrary-time frame interpolation pipeline to generate and refine additional inbetween frames. Finally, a module to preserve temporal consistency is employed. Compared to common frame interpolation methods, our approach can address frames with relatively large motion and also has the flexibility to enable users to control the generated video sequences by editing the sketch guidance. By explicitly considering the correspondence between frames and the sketch, we can achieve higher quality results than other image synthesis methods. Our results show that our system generalizes well to different movie frames, achieving better results than existing solutions.


Amphiphilized poly(ethyleneimine) nanoparticles: a versatile multi-cargo carrier with enhanced tumor-homing efficiency and biocompatibility.
Current theranostic approaches in cancer therapy demand delivery systems that can carry multiple drugs or imaging agents in a single nanoplatform with uniform biodistribution and improved target specificity. In this study, we have developed amphiphilized poly(ethyleneimine) nanoparticles (aPEI NPs) as a versatile multi-cargo delivery platform. The aPEI NPs were engineered to have the loading capacity for both hydrophobic molecules and negatively charged hydrophilic colloidal cargos through amphiphilic modification, i.e., octadecylation and subsequent PEGylation of poly(ethyleneimine). In the aqueous phase, the resulting aPEIs underwent amphiphilic self-assembly into spherical nanoparticles whose structure is constituted of the hydrophobic core with the positively charged surface and the hydrophilic neutral corona. The high degree of PEGylation resulted in the tiny colloidal size (<15 nm in diameter) and rendered the outmost surface coated with an antifouling corona which minimizes general shortcomings of poly(ethyleneimine)-based nanocarriers (e.g., cytotoxicity and liver filtration) while keeping its advantage (loading capability for negatively charged drugs). The unique nanostructure of aPEI NPs allowed for facile loading of hydrophobic model drugs (rubrene and IR780) in the core as well as negatively charged colloids (Pdots, proteins and DNA) on the inner surface via the hydrophobic and electrostatic interactions, respectively. Fluorescence imaging experiments demonstrated that the highly PEGylated aPEI-25 NPs showed prolonged blood circulation with minimal liver filtration and efficient delivery of the loaded cargos to the tumor. These combined merits, along with negligible toxicity profiles both in vitro and in vivo, validate the potential of aPEI-25 NPs as versatile nanocarriers for multi-cargo delivery.


Immunoassays in monitoring biotechnological drugs.
For the evaluation and interpretation of pharmacokinetic data reliable quantitative determinations are a requirement that can only be met by well-characterized and fully validated analytical methods. To cope with these requirements a method is being established that is based on an integrated and automated fiber-optic biospecific interaction analysis system (FOBIA) for immunoassays. Performance characteristics of this system used in monitoring of recombinant hirudin (CGP 39 393) are presented. Recombinant hirudin is a highly potent and selective inhibitor of human thrombin. Owing to its size and charge, recombinant hirudin is mainly eliminated by glomerular filtration. But only a fraction of the hirudin dose seems to be reabsorbed at the proximal tubule by luminal endocytosis and hydrolyzed by lysosomal enzymes, leaving approximately 50% of the dose to be extracted in the urine. Thus, renal clearance of recombinant hirudin in the absence of renal insufficiency appears to depend primarily on the glomerular filtration rate. During a 3-month i.v. tolerability study in dogs, some of the dogs developed antibodies against recombinant hirudin. The hirudin-antibody complex accumulated in plasma and apparent hirudin plasma concentrations were therefore much higher than expected from single-dose kinetics. Hirudin captured by antibodies showed an extended half-life and the hirudin-antibody complex is still pharmacologically active, as demonstrated by the observed increase in thrombin time. In conclusion, only appropriate analytical methods allow adequate monitoring and pharmacokinetic characterization of biotechnology drugs in biological materials.


Interactome Mapping Reveals the Evolutionary History of the Nuclear Pore Complex.
The nuclear pore complex (NPC) is responsible for nucleocytoplasmic transport and constitutes a hub for control of gene expression. The components of NPCs from several eukaryotic lineages have been determined, but only the yeast and vertebrate NPCs have been extensively characterized at the quaternary level. Significantly, recent evidence indicates that compositional similarity does not necessarily correspond to homologous architecture between NPCs from different taxa. To address this, we describe the interactome of the trypanosome NPC, a representative, highly divergent eukaryote. We identify numerous new NPC components and report an exhaustive interactome, allowing assignment of trypanosome nucleoporins to discrete NPC substructures. Remarkably, despite retaining similar protein composition, there are exceptional architectural dissimilarities between opisthokont (yeast and vertebrates) and excavate (trypanosomes) NPCs. Whilst elements of the inner core are conserved, numerous peripheral structures are highly divergent, perhaps reflecting requirements to interface with divergent nuclear and cytoplasmic functions. Moreover, the trypanosome NPC has almost complete nucleocytoplasmic symmetry, in contrast to the opisthokont NPC; this may reflect divergence in RNA export processes at the NPC cytoplasmic face, as we find evidence supporting Ran-dependent mRNA export in trypanosomes, similar to protein transport. We propose a model of stepwise acquisition of nucleocytoplasmic mechanistic complexity and demonstrate that detailed dissection of macromolecular complexes provides fuller understanding of evolutionary processes.


Functional polymorphisms in matrix metalloproteinases-1, -3, -9 are associated with arteriovenous fistula patency in hemodialysis patients.
Matrix metalloproteinases (MMPs) are risk factors for cardiovascular diseases. This study evaluated the association of genotype polymorphisms of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in hemodialysis (HD) patients with arteriovenous fistula (AVF) failure. Genotype polymorphism of MMP-1, MMP-2, MMP-3, and MMP-9 and TIMP-1 and TIMP-2 and clinical and laboratory parameters were compared between Chinese HD patients with (n = 170) and without (n = 426) AVF failure. Significant associations were found between AVF failure and the following factors (hazard ratio): longer HD duration (1.007 per month), lower pump flow (0.991 per ml/min), higher dynamic venous pressure (1.016 per mmHg), location of AVF on right side (1.630 versus left side) and upper arm (2.385 versus forearm), history of cardiovascular disease (1.656 versus absence of history), 1G/1G genotype of MMP-1 -1607 1G >2G SNP (2.315 versus 1G/2G + 2G/2G genotypes), 6A/6A genotype of MMP-3 -1612 5A >6A SNP (1.712 versus 5A/6A + 5A/5A), and C/C genotype of MMP-9 -1562 C>T SNP (1.650 versus C/T+T/T). The positive predictive rates for AVF failure were 63.0% and 6.7% for patients with the highest-risk (1G1G/6A6A/CC) and lowest-risk (2G2G or 2G1G/5A5A or 6A6A/TT or TC) composite MMP-1/MMP-3/MMP-9 genotype, respectively. The unassisted patency of AVF at 5 years decreased significantly from 93.3% to 38.4% for the composite MMP-1/MMP-3/MMP-9 genotypes (lowest versus highest risk, P < 0.001). Specific genotypes of MMP-1, MMP-3 and MMP-9 with lower transcriptional activity are associated with higher frequencies of AVF failure, which may result from more accumulation of extracellular matrix, leading to AVF stenosis.


Effects of protein-calorie restriction on the immune response to skin allografts in the rat.
The effect of protein depletion on immune responsiveness was examined using a skin allograft model. Protein depletion was induced in adult Fischer (F344) male rats by the ad libitum provision of a 5% protein diet. Total serum protein, total body weight, total body nitrogen, and total body lipid were all markedly decreased in these rats. Skin from control-fed Brown Norway (BN) male rats was grafted to the middorsal region of control and protein-depleted F344 rats. BN skin allografts survived significantly longer on protein-depleted recipients (13.3 days) than on controls (8.5 days). Splenic lymphoid cells from skin grafted F344 rats were assayed for cytotoxicity against BN and F344 lymphoid cells in a 51Cr release assay. At effector to target ratios of 50:, 100:, and 200:1, spleen cells from control rats exhibited greater than 35% allospecific cytotoxicity 8 days after grafting. Spleen cells from protein-depleted rats exhibited no greater than 10% cytotoxicity from 6 to 15 days after grafting. A depression of cytotoxicity by protein depletion was also observed in rats immunized by i.p. injection of BN spleen cells. Heat-inactivated sera from skin grafted F344 rats were assayed against BN and F344 lymphoid cells in a complement-dependent trypan blue exclusion assay. Cytotoxic alloantibodies were measurable in both control and protein-depleted rats 9 days after grafting, but were of significantly lower titer in the protein-depleted group. The results indicate that both humoral and cell-mediated immune responses to alloantigens are impaired by protein-calorie malnutrition.


Thioredoxin-Mediated ROS Homeostasis Explains Natural Variation in Plant Regeneration.
Plant regeneration is fundamental to basic research and agricultural applications. The regeneration capacity of plants varies largely in different genotypes, but the reason for this variation remains elusive. Here, we identified a novel thioredoxin DCC1 in determining the capacity of shoot regeneration among Arabidopsis (Arabidopsis thaliana) natural variation. Loss of function of DCC1 resulted in inhibited shoot regeneration. DCC1 was expressed mainly in the inner tissues of the callus and encoded a functional thioredoxin that was localized in the mitochondria. DCC1 protein interacted directly with CARBONIC ANHYDRASE2 (CA2), which is an essential subunit of the respiratory chain NADH dehydrogenase complex (Complex I). DCC1 regulated Complex I activity via redox modification of CA2 protein. Mutation of DCC1 or CA2 led to reduced Complex I activity and triggered mitochondrial reactive oxygen species (ROS) production. The increased ROS level regulated shoot regeneration by repressing expression of the genes involved in multiple pathways. Furthermore, linkage disequilibrium analysis indicated that DCC1 was a major determinant of the natural variation in shoot regeneration among Arabidopsis ecotypes. Thus, our study uncovers a novel regulatory mechanism by which thioredoxin-dependent redox modification regulates de novo shoot initiation via the modulation of ROS homeostasis and provides new insights into improving the capacity of plant regeneration.


Study of arachidonoyl specificity in two enzymes of the PI cycle.
We identified a conserved pattern of residues L-X((3-4))-R-X((2))-L-X((4))-G, in which -X((n))- is n residues of any amino acid, in two enzymes acting on the polyunsaturated fatty acids, diacylglycerol kinase epsilon (DGKɛ) and phosphatidylinositol-4-phosphate-5-kinase Iα (PIP5K Iα). DGKɛ is the only one of the 10 mammalian isoforms of DGK that exhibits arachidonoyl specificity and is the only isoform with the motif mentioned above. Mutations of the essential residues in this motif result in the loss of arachidonoyl specificity. Furthermore, DGKα can be converted to an enzyme having this motif by substituting only one residue. When DGKα was mutated so that it gained the motif, the enzyme also gained some specificity for arachidonoyl-containing diacylglycerol. This motif is present also in an isoform of phosphatidylinositol-4-phosphate-5-kinase that we demonstrated had arachidonoyl specificity for its substrate. Single residue mutations within the identified motif of this isoform result in the loss of activity against an arachidonoyl substrate. The importance of acyl chain specificity for the phosphatidic acid activation of phosphatidylinositol-4-phosphate-5-kinase is also shown. We demonstrate that the acyl chain dependence of this phosphatidic acid activation is dependent on the substrate. This is the first demonstration of a motif that endows specificity for an acyl chain in enzymes DGKε and PIP5K Iα.


Analysis and impact of a multidisciplinary lymphoma virtual tumor board.
The aim is to prospectively evaluate the impact of a multidisciplinary lymphoma virtual tumor board. The utility of multi-site interactive lymphoma-specific tumor boards has not been reported. The Mayo Clinic Lymphoma Tumor Board is a component of the International Mayo Clinic Care Network (MCCN). The format includes the clinical case presentation, presentation of radiology and hematopathology findings by the appropriate subspecialist, proposed treatment options, review of the literature pertinent to the case, pharmacy contributions, and discussion followed by recommendations. Three hundred and nine consecutive highly selected real-time cases with a diagnosis of lymphoma were presented at the Mayo Clinic Lymphoma Tumor Board from January 2014 to June 2018 and decisions were prospectively tracked to assess its impact on the treatment decisions. A total of 309 cases were prospectively evaluated. One hundred and forty (45.3%) cases had some changes made or recommended. The total changes suggested were 179, as some cases had more than one recommendation. There were 93 (30%) clinical management recommendations, 45 (14.6%) additional testing recommendations, 29 (9.4%) pathology changes, and 6 (1.9%) radiology changes. In an electronic evaluation process, 93% of the responders reported an improvement in knowledge and competence, and 100% recommended no change in format of the board. A multidisciplinary lymphoma tumor board approach was found to have a meaningful impact on lymphoma patients while enhancing interdisciplinary interactions and education for multiple levels of the clinical care team.


Seropositivity for dengue and Leptospira IgM among patients with acute febrile illness: an indicator of co-infection?
Presentation of febrile illness with nonspecific features, overlapping manifestations of dengue and leptospirosis, limited laboratory diagnostic tests, make the clinical diagnosis of pyrexia a challenge. The present study aimed to determine the prevalence of Leptospira and dengue IgM co-infection among acute febrile illness patients. This is a retrospective hospital-based study which included patient data collected from June 2016 to May 2017. Inpatients' samples (n=2139) were tested for dengue and/or Leptospira IgM at the Microbiology Laboratory. Data like duration of fever, platelet count, hemoglobin, white blood cell count, erythrocyte sedimentation rate, results of liver and renal function tests, mode of treatment, were collected from medical records of laboratory-confirmed co-infection cases. Among 1612 serum samples tested for dengue IgM by ELISA, 382 (23.7%) were positive, 17 equivocal and 1213 were negative. Of the 811 Leptospira IgM ELISA done, 119 (14.7%) were positive, 17 equivocal and 675 negative. Two hundred eighty-four samples were tested for both infections and nine (3.2%) were positive for both and 275 were negative. These nine patients positive for dual infections showed elevated transaminases, alkaline phosphatase, serum bilirubin, creatinine, and blood urea, thrombocytopenia and leukocytosis. They received effective antibiotics along with supportive treatment and were cured of the infection. The study emphasizes the possibility of leptospirosis and dengue co-infection (3.2%) and need for confirmation by a highly specific test like PCR. If co-infection is suspected, treatment with specific antibiotics for leptospirosis and supportive treatment for dengue is mandatory, with due attention to complexity of organ involvement.


[Pain beliefs of cancer patients and associated factors].
The aim is to determine the pain beliefs and related factors of cancer patients. The study was designed as a descriptive and analytical type. It was completed between January and June 2019 with 100 individuals who were 18 years of age or older, who were receiving chemotherapy, and who agreed to participate in the study. Data were collected using a patient information form, a pain assessment form, and the Pain Beliefs Scale. In the results of the regression analysis, the psychological belief scores of those who acted nervously were statistically 0.408 points higher than those who acted calmly. Organic beliefs scores were statistically 0.814 points and 0.599 points higher in basically literate and primary school graduates, respectively, compared to university graduates. They were 0.372 points higher for those whose income was less than their expenditure compared to those whose income was balanced with their expenditure, 0.414 points higher in those who had experienced pain in the last 6 months compared to those who had not, and 0.561 points higher in those who did not use non-pharmacological methods in pain control compared to those who did. Those who expressed pain verbally were found to have points that were 0.447 higher than those who did not say they had pain. Based on the results obtained, it is recommended that cancer patients be given training that will improve self-management and self-efficacy with cognitive-behavioral methods, taking into account their pain beliefs and affecting factors, in order for them to be successful in pain management.


Altered growth of transgenic tobacco lacking leaf cytosolic pyruvate kinase.
Previously, we reported that transformation of tobacco (Nicotiana tabacum L.) with a vector containing a potato cytosolic pyruvate kinase (PKc) cDNA generated two plant lines specifically lacking leaf PKc (PKc-) as a result of co-suppression. PKc deficiency in these primary transformants did not appear to alter plant development, although root growth was not examined. Here we report a striking reduction in root growth of homozygous progeny of both PKc- lines throughout development under moderate (600 microE m-2 s-1) or low (100 microE m-2 s-1) light intensities. When both PKc- lines were cultivated under low light, shoot and flower development were also delayed and leaf indentations were apparent. Leaf PK activity in the transformants was significantly decreased at all time points examined, whereas root activities were unaffected. Polypeptides corresponding to PKc were undetectable on immunoblots of PKc- leaf extracts, except in 6-week-old low-light-grown PKc- plants, in which leaf PKc expression appeared to be greatly reduced. The metabolic implications of the kinetic characteristics of partially purified PKc from wild-type tobacco leaves are discussed. Overall, the results suggest that leaf PKc deficiency leads to a perturbation in source-sink relationships.


Histopathological characteristics of BRCA1- and BRCA2-associated intraperitoneal cancer: a clinic-based study.
The aim of the research was to assess possible histopathological differences between BRCA1- and BRCA2-associated malignant intraperitoneal (ovarian/fallopian tube/peritoneal) tumors and their sporadic counterparts. Dutch families harboring pathogenic BRCA1 or BRCA2 mutations were selected. Included were patients who had had malignant primary ovarian, fallopian tube or peritoneal tumors. Histopathological data was compared with data obtained from the Dutch cancer registry between 1989 and 1993 (reference group). A total of 63 with primary intraperitoneal malignant tumors were identified in 41 families. Non-epithelial malignant tumors were not observed in the study group versus 6% (n = 404) in the reference group (n = 6789, P = 0.04). These tumors were excluded from further analysis, as were ovarian adenocarcinomas not otherwise specified, since these were detected in 22% of the study group, and in 19% of the reference group (P = 0.76). Serous carcinomas were detected in 94% (47/50) of the women in the study group in contrast to 62% (3145/5088) of the reference group (P < 0.01). In the study group, mucinous and endometrioid ovarian adenocarcinomas and serous ovarian borderline tumors each comprised 2.0% of the tumors. Clear cell ovarian carcinomas were not detected. In contrast, these percentages were 16% (P < 0.01), 10% (P = 0.07), 7% (P = 0.16) and 5% (P = 0.12), respectively, in the reference group. In the study group, 6.0% of the carcinomas arose in the fallopian tube versus 1.9% in the reference group (P = 0.03). Four percent of the study group developed primary serous peritoneal carcinomas, versus six percent in the reference group (P = 0.57). Serous carcinoma is the predominant type of intraperitoneal malignancy occurring in women harboring BRCA1 or BRCA2 mutations. Non-epithelial cancer does not seem to be part of the tumor spectrum of BRCA mutation carriers. This suggests, therefore, that serous tumors may be the only subtype related to a BRCA1 or BRCA2 mutation. Furthermore, fallopian tube carcinoma occurred more often in BRCA mutation carriers than in the reference population.


Alignment sensing for optical cavities using radio-frequency jitter modulation.
Alignment sensing is often required in precision interferometry applications such as Advanced LIGO in order to achieve the optimum performance. Currently favored sensing schemes rely on the use of two separate radio-frequency (RF) quadrant photodetectors and Gouy phase telescopes to determine the alignment of a beam relative to an optical cavity axis. In this paper, we demonstrate an alternative sensing scheme that has potential advantages over the current standard schemes. We show that by using electro-optic beam deflectors to impose RF jitter sidebands on a beam, it is possible to extract full alignment signals for two in-line optical cavities from just one single-element photodetector in reflection of each cavity.


[Chronic thromboembolic pulmonary hypertension with and without antiphospholipid syndrome].
Chronic thromboembolic pulmonary hypertension (CTE-PH) is defined as the chronic obstruction by organized thrombi in pulmonary artery and their branches causing pulmonary hypertension. The objective is to evaluate features and outcome of CTE-PH in patients with and without coexisting antiphospholipid syndrome (APS). All patients studied at our Institution with CTE-PH between June 1993 and June 2005 were analyzed retrospectively. Sixteen out of 38 patients were APS positive (group A), and 22/38 patients (group B) disclosed normal results (n = 10) or other thrombophilic abnormalities (n =12). both groups were similar in age (mean 41 vs. 50 years), NYHA class at diagnosis (81 vs. 100% in III-IV) and the presence of previous or coexistent thrombosis in other territories (31 vs. 27%). Sixty three percent of patients in group A and 55% of patients in group B underwent thromboendarterectomy. The patients were followed during an average of 45 months (0.5-144). At the end of follow up all the APS patients and all the chirurgical patients were in I-II functional class (p=0.053). The median survival from diagnosis was 59 months for group A and 27 months for group B (p=0.199). The mean survival of patients who underwent thromboendarterectomy was 56 months for group A vs. 33 months for group B (p=0.08). We conclude that patients with CTE-PH and APS disclosed a trend to a better survival than patients with CTE-PH without APS. Those patients with CTE-PH and APS who underwent thromboendarterectomy tended to achieve a better functional class and survival than those who received medical treatment.


[Significance of the antibiotic resistance of the causative agents of salmonellosis in its epidemiology and the procedure for controlling the infection].
Antibiotic resistance of a wide set of strains (1501) of different serovars (69) was studied and the nature of the resistance was determined. Virulent bacteriophages designed with regard to the biological properties of the isolates were considered as possible agents for the control of antibiotic-resistant microorganisms. It was shown that multiple resistance to antibacterial drugs was mainly characteristic of the serovar of S. typhimurium. In Gorky and its region, strains carrying R plasmids determining the resistance to tetracycline and chloramphenicol with a molecular weight of 58-64 Md predominated. The antibiotic-resistant strains were dangerous from the epidemiological point of view. The use of the bacteriophages is advisable for the treatment of patients, sanation of bacterial carriers or decontamination of disease sources and prophylactic phaging with regard to the epidemiological indications for preventing group diseases.


Vitamin D deficiency and adult asthma exacerbations.
There is growing evidence indicating a connection between vitamin D deficiency and the severity of asthma exacerbations. This study seeks to assess the relationship between vitamin D deficiency and the number and severity of asthma exacerbation in adults. A retrospective analysis was conducted in 92 patients being treated for asthma at the University of New Mexico Adult Asthma Clinic. Serum 25-hydroxyvitamin D3 levels were analyzed in adults with mild to severe persistent asthma. Using multi-variant modeling, the relationship was examined between serum vitamin D levels and the odds of asthma exacerbations ranging in severity from moderate to severe over the span of five years. This study demonstrates that vitamin D sufficiency was significantly associated with a decreased total number of asthma exacerbations (incidence rate ratio [IRR]: 0.61, 95% confidence interval [CI]: 0.44-0.84, p = 0.002), decreased total severe asthma exacerbations (IRR: 0.41, 95% CI: 0.24-0.72, p = 0.002) and decreased emergency room visits (IRR: 0.42, 95% CI: 0.20-0.88, p = 0.023). Vitamin D deficiency may be linked to the risk of severe asthma exacerbations in adults.


Therapeutic ultrasound. Light and electron microscopic findings in an eye treated for glaucoma.
Focused high-intensity (FHI) ultrasound has recently been used to treat advanced glaucoma. This report describes the pathologic findings in the eye of a 30-year-old woman treated with FHI ultrasound for glaucoma. Major findings consisted of highly localized destruction of the pigmented and nonpigmented ciliary epithelium, profound atrophy of the ciliary muscle, and loss of scleral collagen. While the mechanism by which FHI ultrasound reduces intraocular pressure is not completely understood, the histologic effects of ultrasonic radiation are localized to the site of treatment.


Using a 29-mRNA Host Response Classifier To Detect Bacterial Coinfections and Predict Outcomes in COVID-19 Patients Presenting to the Emergency Department.
Clinicians in the emergency department (ED) face challenges in concurrently assessing patients with suspected COVID-19 infection, detecting bacterial coinfection, and determining illness severity since current practices require separate workflows. Here, we explore the accuracy of the IMX-BVN-3/IMX-SEV-3 29 mRNA host response classifiers in simultaneously detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and bacterial coinfections and predicting clinical severity of COVID-19. A total of 161 patients with PCR-confirmed COVID-19 (52.2% female; median age, 50.0 years; 51% hospitalized; 5.6% deaths) were enrolled at the Stanford Hospital ED. RNA was extracted (2.5 mL whole blood in PAXgene blood RNA), and 29 host mRNAs in response to the infection were quantified using Nanostring nCounter. The IMX-BVN-3 classifier identified SARS-CoV-2 infection in 151 patients with a sensitivity of 93.8%. Six of 10 patients undetected by the classifier had positive COVID tests more than 9 days prior to enrollment, and the remaining patients oscillated between positive and negative results in subsequent tests. The classifier also predicted that 6 (3.7%) patients had a bacterial coinfection. Clinical adjudication confirmed that 5/6 (83.3%) of the patients had bacterial infections, i.e., Clostridioides difficile colitis (n = 1), urinary tract infection (n = 1), and clinically diagnosed bacterial infections (n = 3), for a specificity of 99.4%. Two of 101 (2.8%) patients in the IMX-SEV-3 "Low" severity classification and 7/60 (11.7%) in the "Moderate" severity classification died within 30 days of enrollment. IMX-BVN-3/IMX-SEV-3 classifiers accurately identified patients with COVID-19 and bacterial coinfections and predicted patients' risk of death. A point-of-care version of these classifiers, under development, could improve ED patient management, including more accurate treatment decisions and optimized resource utilization. IMPORTANCE We assay the utility of the single-test IMX-BVN-3/IMX-SEV-3 classifiers that require just 2.5 mL of patient blood in concurrently detecting viral and bacterial infections as well as predicting the severity and 30-day outcome from the infection. A point-of-care device, in development, will circumvent the need for blood culturing and drastically reduce the time needed to detect an infection. This will negate the need for empirical use of broad-spectrum antibiotics and allow for antibiotic use stewardship. Additionally, accurate classification of the severity of infection and the prediction of 30-day severe outcomes will allow for appropriate allocation of hospital resources.


Extracorporeal Acoustic Wave Therapy and Multiple Symmetric Lipomatosis.
Acoustic waves are mechanical waves recently used to activate tissue metabolism by exploiting the cell permeabilization caused by their passage. We report a case of a retroauricular lipoma in a 44-year-old woman affected by multiple symmetric lipomatosis and treated with extracorporeal acoustic wave therapy. The adipose thickness of the lipoma was reduced from 35.8 to 21 mm, with increased softness at palpatory examination.


Human thalamus regulates cortical activity via spatially specific and structurally constrained phase-amplitude coupling.
Although the thalamus is believed to regulate and coordinate cortical activity both within and across functional regions, such as motor and visual cortices, direct evidence for such regulation and the mechanism of regulation remains poorly described. Using simultaneous invasive recordings of cortical and thalamic electrophysiological activity in 2 awake and spontaneously behaving human subjects, we provide direct evidence of thalamic regulation of cortical activity through a mechanism of phase-amplitude coupling (PAC), in which the phase of low frequency oscillations regulates the amplitude of higher frequency oscillations. Specifically, we show that cortical PAC between the theta phase and beta amplitude is spatially dependent on and time variant with the magnitude of thalamocortical theta coherence. Moreover, using causality analysis and MR diffusion tractography, we provide evidence that thalamic theta activity drives cortical theta oscillations and PAC across structures and that these thalamocortical relationships are structurally constrained by anatomic pathways. This relationship allows for new evidence of thalamocortical PAC. Given the diffuse connectivity of the thalamus with the cerebral cortex, thalamocortical PAC may play an important role in addressing the binding problem, including both integration and segregation of information within and across cortical areas.


Random-walk-based stochastic modeling of three-dimensional fiber systems.
For the simulation of fiber systems, there exist several stochastic models: systems of straight nonoverlapping fibers, systems of overlapping bending fibers, or fiber systems created by sedimentation. However, there is a lack of models providing dense, nonoverlapping fiber systems with a given random orientation distribution and a controllable level of bending. We introduce a new stochastic model in this paper that generalizes the force-biased packing approach to fibers represented as chains of balls. The starting configuration is modeled using random walks, where two parameters in the multivariate von Mises-Fisher orientation distribution control the bending. The points of the random walk are associated with a radius and the current orientation. The resulting chains of balls are interpreted as fibers. The final fiber configuration is obtained as an equilibrium between repulsion forces avoiding crossing fibers and recover forces ensuring the fiber structure. This approach provides high volume fractions up to 72.0075%.


Camouflage, detection and identification of moving targets.
Nearly all research on camouflage has investigated its effectiveness for concealing stationary objects. However, animals have to move, and patterns that only work when the subject is static will heavily constrain behaviour. We investigated the effects of different camouflages on the three stages of predation-detection, identification and capture-in a computer-based task with humans. An initial experiment tested seven camouflage strategies on static stimuli. In line with previous literature, background-matching and disruptive patterns were found to be most successful. Experiment 2 showed that if stimuli move, an isolated moving object on a stationary background cannot avoid detection or capture regardless of the type of camouflage. Experiment 3 used an identification task and showed that while camouflage is unable to slow detection or capture, camouflaged targets are harder to identify than uncamouflaged targets when similar background objects are present. The specific details of the camouflage patterns have little impact on this effect. If one has to move, camouflage cannot impede detection; but if one is surrounded by similar targets (e.g. other animals in a herd, or moving background distractors), then camouflage can slow identification. Despite previous assumptions, motion does not entirely 'break' camouflage.


Neural representation of spectral and temporal information in speech.
Speech is the most interesting and one of the most complex sounds dealt with by the auditory system. The neural representation of speech needs to capture those features of the signal on which the brain depends in language communication. Here we describe the representation of speech in the auditory nerve and in a few sites in the central nervous system from the perspective of the neural coding of important aspects of the signal. The representation is tonotopic, meaning that the speech signal is decomposed by frequency and different frequency components are represented in different populations of neurons. Essential to the representation are the properties of frequency tuning and nonlinear suppression. Tuning creates the decomposition of the signal by frequency, and nonlinear suppression is essential for maintaining the representation across sound levels. The representation changes in central auditory neurons by becoming more robust against changes in stimulus intensity and more transient. However, it is probable that the form of the representation at the auditory cortex is fundamentally different from that at lower levels, in that stimulus features other than the distribution of energy across frequency are analysed.


Influence of Chronic Coenzyme Q10 Supplementation on Cognitive Function, Learning, and Memory in Healthy and Diabetic Middle-Aged Rats.
Diabetes mellitus can induce impairment in learning and memory. Cognitive and memory deficits are common in older adults and especially in those with diabetes. This is mainly because of hyperglycemia, oxidative stress, and vascular abnormalities. Coenzyme Q10 (CoQ10) can decrease oxidative stress, hyperglycemia, and inflammatory markers, and improve vascular function. Therefore, the aim of the present study was to investigate the possible effects of CoQ10 on cognitive function, learning, and memory in middle-aged healthy and diabetic rats. Adult middle-aged male Wistar rats (390-460 g, 12-13 months old) were divided into 6 experimental groups. Diabetes was induced by a single i.p. injection of streptozotocin (60 mg/kg). CoQ10 (20 or 120 mg/kg, orally by gavage) was administered for 45 days. The cognitive function and learning memory of rats were evaluated using novel object recognition (NOR) and passive avoidance tests. The discrimination index of the NOR test in the diabetic groups receiving CoQ10 (20 or 120 mg/kg) and the healthy group receiving CoQ10 (120 mg/kg) was significantly higher than that in the control group. In addition, the step through latency was significantly longer and the time spent in the dark compartment was significantly shorter in the diabetic groups receiving CoQ10 than in the control group. CoQ10 supplementation can improve learning and memory deficits induced by diabetes in older subjects. In addition, CoQ10 at higher doses can improve cognitive performance in older healthy subjects.


[A 33 year old woman with a six-year history of slight thoracic-abdominal pain].
We present a case of a benign hybrid nerve sheath tumor showing features of both cellular schwannoma and perineurioma.The patient was a 33 year-old female who presented with a 6 month history of pain in the thorax-lumbar region.Axial CT and MIR images showed and homogeneously enhancing solid oval mass involving the left paravertebra region in contact with the vertebral foramina T9-T11. Morphologically the tumor presented a well formed capsule and showed a uniform highly spindle cell proliferation. The spindle cells were arranged in whorls and intersecting fascicles with focal intervening sclerosis and relatively uniform cellularity with a prominent perivascular lymphocytic infiltrate. No cytological atypia, necrosis or mitoses were present. A second cell component was present composed of spindle-shaped cells with inconspicuous bipolar, pale, eosinophilic cytoplasm with oval nuclei. By immunohistochemistry there was a diffuse staining for S-100, and the elongated bipolar cells were EMA, Glut-1 and Claudin-1. To our knowledge this is the first reported case of a hybrid cellular schwannoma/perineurioma.


Mechanism of parturition and preterm labor.
Preterm birth occurs in 5 to 10 percent of all pregnancies and accounts for 75 percent of neonatal mortality and morbidity, including long-term handicap. Thirty percent of preterm birth may be associated with an underlying infective process, and approximately 50 percent are idiopathic. Preterm birth corresponds to a syndrome with a variety of causes. The factors contributing to preterm birth may vary at different "windows" of gestation. Glucocorticoids seem to have a central role in processes of birth at term and preterm, and alter synthesis and/or activity of key enzymes in prostaglandin synthesis and metabolism as well as increasing corticotropin-releasing hormone output by intrauterine tissues. This new information should facilitate development of improved methods of diagnosis and therapy for patients at risk of preterm labor. Gynecologists and Family Physicians After completion of this article, the reader will be able to describe potential mechanisms of partition and preterm labor and to list the various substances that can inhibit and promote myometrial contractions.


Structural correlations in the generation of polaron pairs in low-bandgap polymers for photovoltaics.
Polymeric semiconductors are materials where unique optical and electronic properties often originate from a tailored chemical structure. This allows for synthesizing conjugated macromolecules with ad hoc functionalities for organic electronics. In photovoltaics, donor-acceptor co-polymers, with moieties of different electron affinity alternating on the chain, have attracted considerable interest. The low bandgap offers optimal light-harvesting characteristics and has inspired work towards record power conversion efficiencies. Here we show for the first time how the chemical structure of donor and acceptor moieties controls the photogeneration of polaron pairs. We show that co-polymers with strong acceptors show large yields of polaron pair formation up to 24% of the initial photoexcitations as compared with a homopolymer (η=8%). π-conjugated spacers, separating the donor and acceptor centre of masses, have the beneficial role of increasing the recombination time. The results provide useful input into the understanding of polaron pair photogeneration in low-bandgap co-polymers for photovoltaics.


Test-retest reliability of the Women's Health Initiative physical activity questionnaire.
Few physical activity (PA) questionnaires were designed to measure the lifestyles and activities of women. We sought to examine the test-retest reliability of a PA questionnaire used in the Women's Health Initiative (WHI) study. Differences in reliability were also explored by important covariates. Participants (n = 1092) were postmenopausal women aged 50-79 yr, randomly selected from the baseline sample of participants in the WHI Observational Study. The WHI PA questionnaire collects usual frequency, duration, and pace of recreational walking, frequency, and duration of other recreational activities or exercises (mild, moderate, and strenuous), household, and yard activities. Approximately half of the women (n = 569) repeated questions on recreational PA, the other half (n = 523) repeated questions related to household and yard activities (mean 3 months apart). Test-retest reliability was assessed with kappa and intraclass correlation coefficients (ICC 1,1). Overall, questions on recreational walking, moderate recreational PA, and strenuous recreational PA had higher test-retest reliability (weighted kappa range = 0.50-0.60) than questions on mild recreational PA (weighted kappa range = 0.35-0.50). The ICC 1,1 for moderate to strenuous recreational PA was 0.77 (95% confidence interval [CI] = 0.73-0.80), and the total recreational PA was 0.76 (95% CI = 0.71-0.79). Substantial reliability was observed for the summary measures of yard activities (ICC 1,1 = 0.71; 95% CI = 0.66-0.75) and household activities (ICC 1,1 = 0.60, 95% CI = 0.55-0.66). No meaningful differences were observed by race/ethnicity, age, time between test and retest, and amount of reported PA. The WHI PA questionnaire demonstrated moderate to substantial test-retest reliability in a diverse sample of postmenopausal women.


Genetic alterations of WWOX in Wilms' tumor are involved in its carcinogenesis.
Loss of heterozygosity (LOH) in 16q appears in ~20-30% cases of Wilms' tumor. Within this region, known as common fragile site FRA16D, the WWOX tumor suppressor gene is located. Abnormalities of WWOX gene expression levels were observed in many tumor types and were associated with worse prognosis. The purpose of this study was to investigate the role of the WWOX tumor suppressor gene in Wilms' tumor samples. We evaluated the correlation between expression of WWOX and genes involved in proliferation (Ki67), apoptosis (BCL2, BAX), signal transduction (ERBB4, ERBB2, EGFR), cell cycle (CCNE1, CCND1), cell adhesion (CDH1) and transcription (TP73) using real-time RT-PCR in 23 tumor samples. We also analyzed the potential causes of WWOX gene expression reduction i.e., promoter methylation status (MethylScreen method) and loss of heterozygosity (LOH) status. We revealed a positive correlation between WWOX expression and BCL2, BCL2/BAX ratio, EGFR, ERBB4 isoform JM-a, TP73 and negative correlation with both cyclins. Loss of heterozygosity of the WWOX gene was observed only at intron 8, however, it had no influence on the reduction of its expression levels. Contrary to LOH, methylation of the region covering the 3' end of the promoter and part of exon 1 was associated with statistically significant reduction of WWOX gene expression levels. In the present study we reveal that in Wilms' tumors the WWOX expression levels are positively associated with the process of apoptosis, signal transduction through the ErbB4 pathway and EGFR and negatively with the regulation of the cell cycle (by cyclin E1 and D1). Moreover, our analysis indicates that in this type of tumor the expression of the WWOX gene can be regulated by an epigenetic mechanism--its promoter methylation.


Achieving optimal welfare for the Nile hippopotamus (Hippopotamus amphibius) in North American zoos and aquariums.
Compared to other megafauna managed in zoos and aquariums, the current state of welfare for the Nile hippopotamus (Hippopotamus amphibius) is poorly understood. Complex behavior and physiological characteristics make hippos a difficult species to manage. Thus, hippos in managed care are currently at risk for a decreased state of welfare. In an effort to assess and improve conditions for this species, a survey was administered to North American institutions housing Nile hippos. This assessment utilized a multiple-choice format and consisted of questions relating to group structure, behavior, and exhibit design, allowing for the creation of cross-institutional, welfare-based analysis. Responses were gathered from 85.29% of the institutions to which the survey was distributed. Despite recommendations for maintaining groups of at least five individuals (Forthman, 1998), only 34.25% of hippos in North America were housed in groups of three or more. The survey also highlighted that 39.29% of institutions secure their hippos in holding areas overnight, despite their highly active nocturnal propensities. A better understanding of hippo behavior and environmental preferences can be used to inform wellness-oriented management practices to achieve a state of "optimal welfare".


Measuring functional connectivity in stroke: Approaches and considerations.
Recent research has demonstrated the importance of global changes to the functional organization of brain network following stroke. Resting functional magnetic resonance imaging (R-fMRI) is a non-invasive tool that enables the measurement of functional connectivity (FC) across the entire brain while placing minimal demands on the subject. For these reasons, it is a uniquely appealing tool for studying the distant effects of stroke. However, R-fMRI studies rely on a number of premises that cannot be assumed without careful validation in the context of stroke. Here, we describe strategies to identify and mitigate confounds specific to R-fMRI research in cerebrovascular disease. Five main topics are discussed: (a) achieving adequate co-registration of lesioned brains, (b) identifying and removing hemodynamic lags in resting BOLD, (c) identifying other vascular disruptions that affect the resting BOLD signal, (d) selecting an appropriate control cohort, and (e) acquiring sufficient fMRI data to reliably identify FC changes. For each topic, we provide guidelines for steps to improve the interpretability and reproducibility of FC-stroke research. We include a table of confounds and approaches to identify and mitigate each. Our recommendations extend to any research using R-fMRI to study diseases that might alter cerebrovascular flow and dynamics or brain anatomy.


[Diagnostic and prognostic significance of the antibodies to the myelin basic protein in acute neuroinfections in children].
The development of severe CNS damages including encephalitis is highly probable in some respiratory and exanthemata viral infections (measles, rubella, parotitis). A high level of IgG antibodies to the myelin basic protein was found in patients with parotitis meningitis and rubella encephalitis but it was not high in 80% of patients with encephalitis of the unclear etiology and in 25% of cases with rubella encephalitis. More accurate analysis of clinical, neurovisual and immunologic data revealed a link of appearance of such complications with both the presence of more pronounced demyelinization and prolongation of the disease.


Long circulating PEGylated poly(D,L-lactide-co-glycolide) nanoparticulate delivery of Docetaxel to solid tumors.
The aim of this study was to investigate the ability of PEGylated poly(D,L-lactide-co-glycolide) nanoparticles (NPs) to deliver Docetaxel (DTX) (an anticancer agent) to solid tumors. PLGA-mPEG diblock copolymers were synthesized by ring opening polymerization reaction and characterized by (1)H NMR, FT-IR and gel permeation chromatography. NPs, with a smooth spherical shape and near 100 nm size were prepared using the emulsion solvent evaporation technique and characterized. The drug release rate was investigated in acidic and physiological media (phosphate buffer saline, pH 5.0 and 7.4). The therapeutic efficacy and biocompatibility of NP formulations were evaluated for in vitro cytotoxicity by MTT assay using MCF-7 and C26 cell lines. The pharmacokinetic and biodistribution studies were performed on C26 tumor bearing mice. The antitumor efficacy of DTX NP formulations on C26 tumor bearing mice was investigated. DTX-loaded PEGylated NPs increased the drug's biological half-life while providing substantial accumulation at the solid tumors. PEGylated NPs appear to be a promising alternate carrier for DTX having greater efficacy in inhibiting tumor growth.


Modeling the Fluorescence Quantum Yields of Aromatic Compounds: Benchmarking the Machinery to Compute Intersystem Crossing Rates.
The from-first-principles calculation of fluorescence quantum yields (FQYs) and lifetimes of organic dyes remains very challenging. In this article, we extensively test the machinery to calculate FQYs. Specifically, we perform an extensive analysis on the parameters influencing the intersystem crossing (ISC), internal conversion (IC), and fluorescence rate constants calculations. The impact of (i) the electronic structure (chosen exchange-correlation functional and spin-orbit Hamiltonian), (ii) the vibronic parameters (coordinate system, broadening function, and dipole expansion), and (iii) the excited-state kinetic models are systematically assessed for a series of seven rigid aromatic molecules. Our studies provide more insights into the choice of parameters and the expected accuracy for the computational protocols aiming to deliver FQY values. Some challenges are highlighted, such as, on the one hand, the difficulty to benchmark against the experimental nonradiative rate constants, for which the separation between the IC and ISC contributions is often not provided in the literature and, on the other hand, the need to go beyond the harmonic approximation for the calculation of the IC rates.


The role of sphingomyelin cycle metabolites in transduction of signals of cell proliferation, differentiation and death.
Sphingomyelin cycle metabolites ceramide, sphingosine and sphingosine 1-phosphate play an important role in cell proliferation, differentiation, reception, oncogenesis and apoptosis. Ceramide is an intracellular second messenger for apoptosis activating proteases and specific phosphatases. Sphingosine is an endogenous inhibitor of protein kinase C and has an inhibitory effect on many cell functions depending on the activity of this enzyme. On the other hand, sphingosine can activate other kinases depending on the concentration, cell type and nature of a stimulus and release Ca2+ from intracellular stores thereby regulating cell proliferation. Sphingosine induces apoptosis and its level is increased in cells as a result of action of apoptotic inducers. A phosphorylated product of sphingosine, sphingosine 1-phosphate, mediates the mitogenic signal, induces Ca2+ mobilization and protects cells from apoptosis resulting from elevation of ceramide. The quantitative levels of sphingomyelin metabolites in the cell determine the dynamic balance between the apoptotic and mitogenic signals.


Acceleration of nitrogen ions to 7.4 gev in the princeton particle accelerator.
Nitrogen ions in charge states N(5+) and N(6+) have been accelerated in the Princeton Particle Accelerator to 4 and 7.4 billion electron volts (Gev), respectively. An external N(5+) beam of 1 x 10(6) particles per second has been obtained and focused to a 6-millimeter-diameter spot. The N(6+) beam was about 2 x 10(5) particles per second. The total charge-changing collision cross section of N(5+) in water vapor was determined as a function of ion energy. The improvement in vacuum necessary to increase the N(5+) beam at least tenfold was calculated. The N(6+) total cross section is probably smaller than that of N(5+) at the higher energies.


Getting the basics right: delays in phlebotomy and intravenous cannulation: a survey of foundation year 1 doctors.
Junior doctors frequently experience delays in routine ward-based procedures. There is little published data on this subject, but it is clear that such delays can have implications in terms of costs, efficiency, length of patient stay, team working and patient safety and experience. We formulated an anonymous online survey to quantify the experiences of foundation year 1 (FY1) doctors with respect to phlebotomy services and intravenous (IV) cannulation. We gathered data on equipment availability, time taken to carry out these tasks and the factors thought to contribute to delays. The results were compared to clinically relevant standards. Between April and August 2012, 199 responses were received. For IV cannulation, 21% of doctors reported equipment availability as 'very good', but only 3% said that they were able to find all of the pieces of equipment they needed close to each other ('essentially in the same place'). Similar results were obtained for phlebotomy. Nevertheless, there appears to be significant room for improvement and we offer recommendations to address delays.


Assessment of sequence-based p53 gene analysis in human breast cancer: messenger RNA in comparison with genomic DNA targets.
The high prevalence of p53 mutations in human cancers and the suggestion from several groups that the presence or absence of p53 mutations might have both prognostic and therapeutic consequences point to the importance of optimal methods for p53 determination. Several strategies exploring this have been described, based either on mRNA or genomic DNA as a template. However, no comparative study on the reliability of the two templates has been performed. The principal aim of this study was to study the concordance of RNA- and DNA-based direct sequencing methods in detecting p53 mutations in breast tumors. In 100 tumors, 22 mutations were detected by both methods. Furthermore, one stop mutation, two splice-site mutations, and one intron alteration were found only by genomic sequencing. In addition, the comparative study suggests that cells with missense mutations have increased steady-state concentrations of p53-specific mRNA, in contrast to cells with a gene encoding a truncated protein.


Is parasite pressure a driver of chemical cue diversity in ants?
Parasites and pathogens are possibly key evolutionary forces driving recognition systems. However, empirical evidence remains sparse. The ubiquitous pioneering ant Formica fusca is exploited by numerous socially parasitic ant species. We compared the chemical cue diversity, egg and nest mate recognition abilities in two Finnish and two UK populations where parasite pressure is high or absent, respectively. Finnish populations had excellent egg and nest mate discrimination abilities, which were lost in the UK populations. The loss of discrimination behaviour correlates with a loss in key recognition compounds (C(25)-dimethylalkanes). This was not owing to genetic drift or different ecotypes since neutral gene diversity was the same in both countries. Furthermore, it is known that the cuticular hydrocarbon profiles of non-host ant species remain stable between Finland and the UK. The most parsimonious explanation for the striking difference in the cue diversity (number of C(25)-dimethylalkanes isomers) between the UK and Finland populations is the large differences in parasite pressure experienced by F. fusca in the two countries. These results have strong parallels with bird (cuckoo) studies and support the hypothesis that parasites are driving recognition cue diversity.


Effects of pupil discretization and Littrow illumination in the simulation of bright-field defect detection.
The simulation of optical defect detection on wafers by microscopy requires several approximations. For the simulation with Fourier modal methods, the number of modes is limited by memory and time consumption. Furthermore, the illumination pupil has to be divided into discrete incidence angles for plane waves. We present a way to save the computation of most of these incidence angles. It works only for certain configurations of grating period and illumination wavelength but is an accurate and robust approximation in these cases. We present sample calculations for one- and two-dimensional periodic structures with defects.


Crystal Modifications of a Cyclic Guanosine Phosphorothioate Analogue, a Drug Candidate for Retinal Neurodegenerations.
In contribution to the pharmaceutical development of cyclic guanosine monophosphorothioate analogue cGMPSA as a potential active pharmaceutical ingredient (API) for the treatment of inherited retinal degenerations (IRDs), its neutral form (cGMPSA-H) and salts of sodium (-Na), calcium (-Ca), ammonium (-NH4 ), triethylammonium (-TEA), tris(hydroxymethyl)aminomethane (-Tris), benethamine (-Bnet), and benzathine (-BZ) were prepared. Their solid-state properties were studied with differential scanning calorimetry, thermogravimetric analysis, hot-stage microscopy, and dynamic vapor sorption, and their solubilities were measured in deionized H2 O as well as aqueous HCl and NaOH buffers. A total of 21 crystal modifications of cGMPSA were found and characterized by X-ray powder diffraction. Despite their crystalline character, no API forms featured any observable melting points during thermal analyses and instead underwent exothermic decomposition at ≥163 °C. Both the vapor sorption behavior and solubility were found to differ significantly across the API forms. cGMPSA-BZ featured the lowest aqueous solubility and hygroscopicity, with 50 μg/mL and 5 % mass gain at maximum relative humidity. The synthesis and crystallization of some crystal modifications were upscaled to >10 g. Single crystal X-ray diffraction was performed which resulted in the first crystal structure determination and absolute configuration of a cyclic guanosine monophosphorothioate, confirming the RP - conformation at the phosphorus atom.


Investigation by electron paramagnetic resonance spectroscopy of the molybdenum centre of respiratory nitrate reductase from Paracoccus denitrificans.
The molybdenum centre of respiratory nitrate reductase from Paracoccus denitrificans has been investigated by e.p.r. spectroscopy of Mo(V). In common with the centres of the analogous enzymes from Escherichia coli and Pseudomonas aeruginosa, it undergoes a pH- and anion-dependent transition between two different e.p.r. signal-giving species. Comparison of the relevant e.p.r. parameters extracted with the help of computer simulations reveals ligation of the metal in the active centres of the three enzymes to be identical.


Relationship between staphylococcal antiserum titer and zone development on immune serum plates.
A workable relationship was established between the standard serum titers of staphylococcal immune antisera and the development of precipitin zones on serum agar around colonies of staphylococcal strains producing homologous antigens (enterotoxins). The standard titer of a serum is defined as the reciprocal of that serum dilution which, with 10 mug of pure enterotoxin per ml, will give a precipitin zone 10 mm in length in single gel-diffusion tubes after 7 days of incubation at 25 C. A numerical scale was set up for determining the intensity of precipitin zones on serum agar. A reading of 3 was considered optimum. This correlated well with a standard serum titer of 25, when 1 ml of such a serum was used per 20 ml of medium per serum plate. From this relationship, the minimum volume of serum required to give optimum precipitin zone development can be calculated.


Advancements in magnetic resonance-guided robotic interventions in the prostate.
Magnetic resonance imaging (MRI) provides more detailed anatomical images of the prostate compared with the transrectal ultrasound imaging. Therefore, for the purpose of intervention in the prostate gland, diagnostic or therapeutic, MRI guidance offers a possibility of more precise targeting that may be crucial to the success of prostate interventions. However, access within the scanner is limited for manual instrument handling and the MR environment is most demanding among all imaging equipment with respect to the instrumentation used. A solution to this problem is the use of MR-compatible robots purposely designed to operate in the space and environmental restrictions inside the MR scanner allowing real-time interventions. Building an MRI-compatible robot is a very challenging engineering task because, in addition to the material restrictions that MRI instruments have, the robot requires actuators and sensors that limit the type of energies that can be used. Several important design problems have to be overcome before a successful MR-compatible robot application can be built. A number of MR-compatible robots, ranging from a simple manipulator to a fully automated system, have been developed, proposing ingenious solutions to the design challenge. Several systems have been already tested clinically for prostate biopsy and brachytherapy. As technology matures, precise image guidance for prostate interventions performed or assisted by specialized MR-compatible robotic devices may provide a uniquely accurate solution for guiding the intervention directly based on MR findings and feedback. Such an instrument would become a valuable clinical tool for biopsies directly targeting imaged tumor foci and delivering tumor-centered focal therapy.


Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism.
Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/intermediate levels of SERT occupancy, vortioxetine affected rapid eye movement (REM) sleep differently than paroxetine. Here we investigated clinically meaningful doses (80-90% SERT occupancy) of vortioxetine and paroxetine on sleep-EEG in rats to further elucidate the serotoninergic receptor mechanisms mediating this difference. Cortical EEG, electromyography (EMG), and locomotion were recorded telemetrically for 10 days, following an acute dose, from rats receiving vortioxetine-infused chow or paroxetine-infused water and respective controls. Sleep stages were manually scored into active wake, quiet wake, and non-REM or REM sleep. Acute paroxetine or vortioxetine delayed REM onset latency (ROL) and decreased REM episodes. After repeated administration, vortioxetine yielded normal sleep-wake rhythms while paroxetine continued to suppress REM. Paroxetine, unlike vortioxetine, increased transitions from non-REM to wake, suggesting fragmented sleep. Next, we investigated the role of 5-HT3 receptors in eliciting these differences. The 5-HT3 receptor antagonist ondansetron significantly reduced paroxetine's acute effects on ROL, while the 5-HT3 receptor agonist SR57227A significantly increased vortioxetine's acute effect on ROL. Overall, our data are consistent with the clinical findings that vortioxetine impacts REM sleep differently than paroxetine, and suggests a role for 5-HT3 receptor antagonism in mitigating these differences.


Impact of comorbidity in adults with attention-deficit/hyperactivity disorder.
Persistence of attention-deficit/hyperactivity disorder (ADHD) into adulthood and male-to-female ratios of this disorder in childhood and adulthood have been controversial issues in the ADHD diagnosis in adults. Research has resolved these controversies and in turn provided support for the validity of the diagnosis in adults. Support for the diagnosis can also be found in data that show the lifetime prevalence rate for comorbid conditions such as antisocial disorders, mood and anxiety disorders, and substance abuse disorders to be consistent across pediatric and adult populations with ADHD. These coexisting conditions add not only to the impairment associated with ADHD in adults but also to the disorder's economic burden, the extent of which is currently unknown. However, adults with the disorder, like children, probably have higher health care use and costs than people without the disorder. Little, too, is known about the social cost of ADHD, but if left untreated, the impact may be substantial. Research to determine the occupational costs associated with ADHD is ongoing, but until that and other cost-of-illness data are available, studies on the economic costs of the comorbid conditions depression, anxiety, and substance abuse and dependence may be used to make suppositions about the economic impact of ADHD in adults. More studies are needed on the outcomes of adults with this disorder, especially cost-of-illness studies.


Sugammadex for the reversal of muscle relaxation in general anaesthesia: a systematic review and economic assessment.
Sugammadex (Bridion) is a newly developed agent for the reversal of neuromuscular blockade (NMB) induced by rocuronium or vecuronium. Sugammadex can reverse profound blockade and can be given for immediate reversal and its use would avoid the potentially serious adverse effects of the currently used agent, succinylcholine. Also, sugammadex can reverse NMB more quickly and predictably than existing agents. To determine the clinical effectiveness and cost-effectiveness of sugammadex for the reversal of muscle relaxation after general anaesthesia in UK practice following routine or rapid induction of NMB. Medical databases [including MEDLINE, EMBASE, CINAHL, Science Citation Index, BIOSIS and Cochrane Central Register of Controlled Trials (CENTRAL), conference proceedings, internet sites and clinical trials registers] were searched to identify published and unpublished studies. The main searches were carried out in May 2008 and supplemented by current awareness updates up until November 2008. For the clinical effectiveness review, randomised controlled trials of sugammadex against placebo or an active comparator (neostigmine + glycopyrrolate) for the reversal of moderate or profound NMB and for immediate reversal (spontaneous recovery from succinylcholine-induced blockade) were included. The primary effectiveness outcome was speed of recovery from NMB, as measured by objective monitoring of neuromuscular function. For the cost-effectiveness review, a de novo economic assessment considered the routine induction of NMB and the rapid induction and/or reversal of NMB, and threshold analyses were carried out on a series of pairwise comparisons to establish how effective sugammadex needs to be to justify its cost. The review of clinical effectiveness included four randomised active-control trials of sugammadex, nine randomised placebo-controlled trials and five studies in special populations. A total of 2132 titles and abstracts and 265 full-text publications were screened. The included trials indicated that sugammadex produces more rapid recovery from moderate or profound NMB than placebo or neostigmine. Median time to recovery from moderate blockade was 1.3-1.7 minutes for rocuronium + sugammadex, 21-86 minutes for rocuronium + placebo and 17.6 minutes for rocuronium + neostigmine. In profound blockade, median time to recovery was 2.7 minutes for rocuronium + sugammadex, 30 to > 90 minutes for rocuronium + placebo, and 49 minutes for rocuronium + neostigmine. Results for vecuronium were similar. In addition, recovery from NMB was faster with rocuronium reversed by sugammadex 16 mg/kg after 3 minutes (immediate reversal) than with succinylcholine followed by spontaneous recovery (median time to primary outcome 4.2 versus 7.1 minutes). The evidence base for modelling cost-effectiveness is very limited. However, assuming that the reductions in recovery times seen in the trials can be achieved in routine practice and can be used productively, sugammadex [2 mg/kg (4 mg/kg)] is potentially cost-effective at its current list price for the routine reversal of rocuronium-induced moderate (profound) blockade, if each minute of recovery time saved can be valued at approximately 2.40 pounds (1.75 pounds) or more. This is more likely to be achieved if any reductions in recovery time are in the operating room (estimated value of 4.44 pounds per minute saved) rather than the recovery room (estimated value of 0.33 pounds per minute saved). The results were broadly similar for rocuronium- and vecuronium-induced blockade. For rapid reversal of NMB it appeared that any reduction in morbidity from adopting sugammadex is unlikely to result in significant cost savings. The evidence base was not large and many of the published trials were dose-finding and safety studies with very small sample sizes. Also, some relevant outcomes, in particular patient experience/quality of life and resources/costs used, were either not investigated or not reported. In addition, it is likely that the patients included in the efficacy trials were relatively young and in good general health compared with the overall surgical population. Regarding the economic evaluation, there appears to be no evidence linking measures of clinical efficacy to patients' health-related quality of life and mortality risks. Sugammadex may be a cost-effective option compared with neostigmine + glycopyrrolate for reversal of moderate NMB and also provides the facility to recover patients from profound blockade. Rocuronium + sugammadex could be considered as a replacement for succinylcholine for rapid induction (and reversal) of NMB, although this may not be a cost-effective option in some types of patient at current list prices for sugammadex. Considerable uncertainties remain about whether the full benefits of sugammadex can be realised in clinical practice.