Free radical formation induced by ultrasound and its biological implications.
The chemical effects of ultrasound in aqueous solutions are due to acoustic cavitation, which refers to the formation, growth, and collapse of small gas bubbles in liquids. The very high temperatures (several thousand K) and pressures (several hundred atmospheres) of collapsing gas bubbles lead to the thermal dissociation of water vapor into .OH radicals and .H atoms. Their formation has been confirmed by electron spin resonance (ESR) and spin trapping. The sonochemistry of aqueous solutions of gases and of volatile and nonvolatile solutes is reviewed. The similarities and differences between sonochemistry and radiation chemistry of aqueous solutions are explained. Some unusual characteristics of aqueous sonochemistry can be understood by considering the properties of supercritical water. By the use of rare gases with different thermal conductivities, it is possible to distinguish between temperature-dependent processes such as redox reactions initiated by .OH radicals and .H atoms and pressure-dependent processes which lead to polymer degradation and cell lysis. The evidence for free radical formation in aqueous solutions by pulsed ultrasound is discussed. This subject is of interest because it is related to the possible deleterious effects of ultrasonic diagnostic devices. The role of free radicals and of mechanical effects induced by ultrasound in DNA degradation, inactivation of enzymes, lipid peroxidation, and cell killing is reviewed.


The COVID-19 Pandemic Increased the Use of Virtual Fellowship Interviews, Reduced Case Volume, and Limited Sideline Coverage Opportunities During Sports Medicine Surgeon Training.
As one-year orthopaedic sports medicine fellowships rely heavily on elective cases and sports coverage, the COVID-19 pandemic necessitated fellowship programs to temporarily transition to virtual mediums for fellow education. Early in the pandemic, there was uncertainty as to how programs would address concerns of trainee readiness, adequate education, and accompanying psychological impact. However, with a return to prepandemic elective procedure volumes and sideline sports coverage responsibilities, sports medicine fellowships have regained some of their traditional education opportunities. Moreover, the implementation of novel training resources, including virtual didactics, augmented reality surgical skills labs, and telehealth medicine training are poised to outlast the current public health crisis and further supplement fellowship education. This article seeks to report on current evidence-based strategies and developments across several critical aspects of sports medicine training during the COVID-19 pandemic.


The antinociceptive effect of iontophoretic direct application of diclofenac to arthritic knee-joints of rats.
This study compared the antinociceptive effect produced by cathodic iontophoresis of sodium diclofenac close to an arthritic knee-joint in rats with that of systemic application. Arthritic nocifensive incapacitation was induced by LPS (1 microg) injection into a knee-joint previously (72 h) primed with carrageenan (300 microg). Diclofenac (0.1, 0.25 and 0.5 mg/kg) given intraperitoneally 1 h after LPS injection caused dose-dependent inhibition of incapacitation. Diclofenac iontophoresis was performed by varying either the current density (0.1, 0.2, and 0.3 mA/cm2) or the duration of application (4, 10, 20 and 30 min) of a polyvinylpirrolydone-hydroxymethylcellulose gel containing 1% sodium diclofenac. A clear, current density-dependent effect was observed for 0.1, 0.2 and 0.3 mA/cm2 (10 min period), which was similar to the effect observed for the intraperitoneal application of 0.1, 0.25 and 0.5 mg/kg doses. Combining different application periods with different current densities, in a manner that resulted in the same total current (1.6 mA*min) application, did not produce similar therapeutic effects, but the antinociceptive effect was directly proportional to the current density. The ipsilateral iontophoresis (0.25 mA/cm2 x 10 min or 0.5 mA/cm2 x 4 min) of diclofenac produced an effect significantly greater than the same contralateral application (p<0.05). In conclusion, our results suggest that the therapeutic effect depends on the current density but not on the application time, and also that the iontophoretic, direct application to the inflamed knee-joint enhances the therapeutic effect probably as a result of the direct delivery of the drug.


Bone mass density, subsequent risk of colon cancer and survival in postmenopausal women.
To test the hypothesis that high bone mass density (BMD), a potential marker for cumulative exposure to endogenous estrogen, calcium and vitamin D intake, is associated with a lower risk of colon cancer, and that women with a lower BMD are likely to develop a more aggressive form of colon cancer, as defined by mortality. BMD was measured in three different sites (Ward's triangle, trochanter, femoral neck) in 1,471 women 60 years of age. All incident cases of colon cancers were identified through record-linkage of cancer registry. The women were followed for a mean of 9.5 years. Overall 31 cases of colon cancer were observed among 28.6 expected (standardized incidence ratio (SIR) = 1.09, 95% confidence interval: 0.79-1.25). The SIR decreased with increasing BMD showing a significantly decreasing risk of 20% for women who were at the higher BMD comparatively to women who were at the lower BMD in all the skeletal sites. The 10-year survival rates showed that survival was increasing with increased BMD, but not significantly. The findings suggest that postmenopausal women with lower BMD have an increased risk of colon cancer. The biological mechanisms linking bone mass to colon cancer risk are not clear.


Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial.
Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response. Three patients experience grade 3 dose-limiting toxicities. The pre-specified endpoints are met, and overall response rate is 93.8% [95%CI: 69.8-99.8%] with a 2-year PFS of 75% [95% CI: 56.5-99.5%]. Compared to patients with progressive disease (PD), progression-free (PF) subjects show a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3+ T cells to PD-L1+ tumor cells and of FOXP3+ T cells to proliferating CD11c+ myeloid cells. PF show higher baseline levels of PD-1 and ICOS-L on tumor-infiltrating EMRA CD4+ T cells and tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression on TAMs, higher peripheral frequencies of proliferating Tregs at baseline and higher PD-1 levels at week 6 post-treatment initiation on CD4 and CD8 T cell subsets. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of locally advanced cervical cancer displaying pre-existing, adaptive immune activation is warranted.


Brainstem tumors may increase the impairment of behavioral emotional cognition in children.
It remains unclear as to whether patients with brainstem tumor experience complex neuropsychiatric problems. In this cohort study, we specifically investigated behavioral, emotional and cognitive symptoms in pediatric patients with brainstem glioma and healthy individuals. A total of 146 patients with pediatric brainstem tumors (aged 4-18 years old) and 46 age-matched healthy children were recruited to assess their behaviors and emotions examined by the Child Behavior Checklist. A variety of clinical factors were also analyzed. There were significant differences in most behavioral and emotional symptoms between pediatric patients and healthy subjects. Moreover, patients with pons tumors exhibited significantly higher scores than patients with medulla oblongata tumors (p = 0.012), particularly in concerning the syndrome categories of Withdrawn (p = 0.043), Anxious/depressed symptoms (p = 0.046), Thought Problems (p = 0.004), Attention deficits (p = 0.008), Externalizing problems (p = 0.013), and Aggressive behavior (p = 0.004). A tumor body located in the pontine (p = 0.01, OR = 4.5, 95% CI = 1.4-14.059) or DIPG in the midbrain (p = 0.002, OR = 3.818, 95% CI = 1.629-8.948) appears to act as a risk factor that is associated with more problems in patients with neuropsychiatric symptoms. Pediatric patients with brainstem tumors exhibit severe behavioral and emotional problems. Tumor invades the pontine and midbrain act a risk factor with more problems. It suggests that structural and functional abnormalities in the brainstem will cause prolonged behavioral problems and emotional-cognitive dysfunctions in young children.


Factors influencing direct clinical costs of outpatient arthroscopic rotator cuff repair surgery.
Very limited information exists about factors affecting direct clinical costs of rotator cuff repair surgery. The purpose of this study was to determine the direct cost of outpatient arthroscopic rotator cuff repair surgery using a unique value-driven outcomes tool and to identify patient- and treatment-related variables affecting cost. Cost data were derived for arthroscopic rotator cuff repairs performed by 3 surgeons from March 2014 to June 2015 using the value-driven outcomes tool. Costs included overall total direct cost, which included facility utilization costs, medication costs, supply costs, and other ancillary costs. Univariate and multivariate regressions were performed to determine the effect of various patient-related and surgical-related factors on costs. There were 170 arthroscopic rotator cuff repairs performed during the study period. Multivariate analysis showed significant correlations between higher total direct cost and the presence of a subscapularis repair being performed (P = .015) and total number of anchors used (P < .0001). Higher body mass index, severe systemic illness, 1 of the 3 surgeons, biceps tenodesis using an anchor, and total sum of anchors were correlated with higher facility utilization costs (P < .04). Severe systemic illness, addition of a subscapularis repair, 1 of the 3 surgeons, and additional subacromial decompression were correlated with higher pharmacy costs (P < .006). The addition of a subscapularis repair, total sum of anchors, and severe muscle changes to the supraspinatus were correlated with higher supply costs (P < .015). From a direct cost perspective, implementation of strategies to reduce overall costs should focus on reducing overall anchor quantity or price.


Preliminary study of fibrin glue combined with pingyangmycin for the treatment of venous malformations in the oral and maxillofacial region.
To observe the outcome of using fibrin glue (FG) combined with Pingyangmycin (Tianjin Taihe Pharmaceutical Co Ltd, Tianjin, China) in the treatment of venous malformations (VMs) in the oral and maxillofacial region. The treatment data of 7 patients with VMs from January 2005 to January 2006 were reviewed. All these patients were injected with FG combined with Pingyangmycin. The vital signs and symptoms were observed and recorded immediately after injections. Radiographic examination was used for the evaluation of pulmonary conditions. The therapeutic effect was evaluated by clinical examination and Doppler ultrasonography. The follow-up time was from 1 to 2 years. Of the 7 patients, 4 were male and 3 were female, with ages ranging from 10 to 62 years. Four of the 7 recovered to near-normal appearance, without any abnormal bloodstream detectable within the lesions. Two lesions were slightly asymmetrical in appearance, but no abnormal bloodstream could be detected in the lesions. Two patients had a fever during treatment, and one of them stopped treatment because of continuous high fever. No allergic reactions, pulmonary embolisms, or other complications were found during or after treatment. The therapeutic modality of FG combined with Pingyangmycin for VMs in the oral and maxillofacial region was effective, and the extent of morbidity was acceptable. However, the further long-term observation of severe complications such as deep venous thrombosis and pulmonary embolism should be performed in additional biological and clinical studies.


Reliability of an accelerometer-based system for quantifying multiregional spinal range of motion.
The purpose of this study was to investigate the reliability of a novel motion analysis device for measuring the regional breakdown of spinal motion and describing the relative motion of different segments of the thoracolumbar (TL) spine. Two protocols were applied to 18 healthy participants. In protocol 1, 2 sensors were placed on the forehead and T1 to measure cervical range of motion (ROM). In protocol 2, 6 sensors were placed on the spinous processes of T1, T4, T8, T12, L3, and S1 to measure TL regional ROM. Intraclass correlation coefficients were used to evaluate the repeatability of movement, whereas SEM was used to define the extent of error. Ranges of motion were demonstrated in flexion extension, right-left lateral flexion, and right-left rotation of the head-cervical, upper thoracic, middle thoracic, lower thoracic, upper lumbar, and lower lumbar. The intraclass correlation coefficient values, for all regions, were found to be high, ranging from 0.88 to 0.99 for all movements, and regions of the spine and SEM values ranged from 0.4° to 5.2°. Multiregional spine ROM ranged from 3° in the upper thoracic and mid-thoracic during flexion and 80° at head cervical during right rotation. The described methodology was reliable for assessing regional spinal ROM across multiple spinal regions while providing the relative motions of different segments of the TL spine.


Idiopathic hemochromatosis in a young female. A case study and review of the syndrome in young people.
Idiopathic hemochromatosis (iH) is typically a disease of older males. The case presented here describes a 26-yr-old woman with problems presenting heart failure, insulin-dependent diabetes, hepatomegaly, and secondary amenorrhea. The diagnosis was established by serum iron and transferrin saturation measurements, liver biopsy, and bone marrow examination for iron. Twenty grams of iron were removed by phlebotomy over 30 mo, and the patient's symptoms improved. A review of the literature pertinent to people with symptomatic onset of IH before age 30 yr revealed 52 young people in addition to this case. In contrast to IH patients older than 30, there was an almost equal ratio between the sexes, a greater frequency of cardiomyopathy and hypogonadism, and a lower frequency of diabetes mellitus and hepatic involvement. An autosomal recessive mode of inheritance appears to be most likely in this young group.


Operative transluminal laser angioplasty as the sole treatment for late stenoses of femorodistal artery bypass graft: experimental and clinical studies.
To determine the role of Nd:YAG laser thermal angioplasty as the sole treatment for late stenoses of femorodistal artery bypass graft, the lasing effect of a larger size of hot-tip probe (3, 4, and 5 mm) was experimentally studied in vitro. For an adequate lasing effect, 30 watts of laser power output for 3 seconds was needed for the 3 mm probe, 40 watts for the 4 mm probe, and 50 watts for the 5 mm probe, respectively. Based on these results, we used Nd:YAG laser thermal angioplasty alone for 25 grafts, including 16 polytetrafluoroethylene (PTFE) grafts, eight saphenous vein grafts, and one externally supported (EXS) Dacron graft in which the stenotic lesions were detected by deterioration of the Doppler flow waveform pattern or a significant fall in the ankle/brachial pressure index (ABPI). Follow-up was from 3 to 24 months (average of 9 months) for PTFE grafts, from 5 to 21 months (average of 11 months) for saphenous vein grafts, and 13 months for the EXS Dacron graft following femorodistal artery reconstructions. Stenotic lesions were most common in the distal anastomotic sites: 11 PTFE grafts, three saphenous vein grafts, and one EXS Dacron graft. Among these, 13 grafts showed a type II flow waveform pattern at the time of surgery. Clinical success was achieved in 12 of the PTFE grafts (75%), in five of the vein grafts (62.5%), and in the single EXS Dacron graft. Four PTFE and three saphenous vein grafts failed subsequent to repeat intraoperative balloon angioplasty in three and graft extension in three and one graft interposition.(ABSTRACT TRUNCATED AT 250 WORDS)


Regional patterns of blood-brain barrier breakdown during epileptiform seizures induced by various convulsive agents.
In unrestrained rabbits with generalized epileptic seizures induced by systemic application of convulsant drugs, regional changes in blood-brain barrier (BBB) permeability to macromolecules were investigated using Evans Blue (EB) as indicator. BBB leakage due to seizures was present only in animals in which the mean arterial blood pressure rose about 50 mm Hg with the onset of convulsive motor activity. However, a blood pressure increase was not necessarily associated with the occurrence of BBB opening. Pentylenetetrazole-induced seizures resulted in bilateral EB leakage mainly in the hypothalamus, with exception of the mammillary bodies, and the preoptic area, and they were associated, in most cases, with an intensive staining of the cerebellum and also of the midbrain tegmentum. In contrast, seizures due to the GABA receptor blocker bicuculline brought about a penetration of the dye in the region of the pallidum, whereas the GABA synthesis inhibitor methoxypyridoxine produced BBB breakdown in the hippocampus. Methionine-sulfoximine convulsions resulted in a selective stain of the corpora mammillaria, and kainic acid induced a diffuse leakage in neocortical brain areas. As a rule, BBB breakdown was bilateral and confined to anatomically limited brain areas, suggesting that BBB integrity was not only disturbed by abrupt increases in the intraluminal pressure, but was also influenced from the brain tissue. The fluorescence microscopic observations revealed that the tracer penetrated into the neuropil through larger vessels. It had the tendency to accumulate in neurons. In case of the hippocampus, CA2 pyramidal cells revealed more intense uptake of EB than those of the adjacent fields.


Differential immunomodulatory effects of six pesticides of different chemical classes on human monocyte-derived macrophage functions.
Exposure to pesticides through eyes, skin, ingestion and inhalation may affects human health by interfering with immune cells, such as macrophages. We evaluated, in vitro, the effect of six pesticides widely used in apple arboriculture on the functions of human monocyte-derived macrophages (hMDMs). hMDMs were cultured for 4 or 24 h with or without pesticides (0.01, 0.1, 1, 10 μmol.L-1). We showed that chlorpyrifos, thiacloprid, thiophanate, boscalid, and captan had little toxic effect at the tested concentrations, while dithianon had low-cytotoxicity at 10 μmol.L-1. While boscalid showed no effect on hMDMs function, thiophanate (0.01 μmol.L-1) stimulated with TPA and thiacloprid (1, 10 μmol.L-1) stimulated with zymosan activated ROS production. Chlorpyrifos, dithianon, and captan inhibited ROS production and TNF-α, IL-1β pro-inflammatory cytokines. We established that dithianon (0.01-1 μmol.L-1) and captan (0.1, 1 μmol.L-1) induced mRNA expression of NQO1 and HMOX1 antioxidant enzymes. Dithianon also induced the mRNA expression of catalase, superoxide dismutase-2 at 10 μmol.L-1. Together, these results show that exposure to chlorpyrifos, dithianon, and captan induce immunomodulatory effects that may influence the disease fighting properties of monocytes/macrophages while pesticides such as thiacloprid, thiophanate and boscalid have little influence.


The involvement of polyamine uptake and synthesis pathways in the proliferation of neonatal astrocytes.
Polyamines (PAs), such as spermidine (SPD) and spermine (SPM), are essential to promote cell growth, survival, proliferation, and longevity. In the adult central nervous system (CNS), SPD and SPM are accumulated predominantly in healthy adult glial cells where PA synthesis is not present. To date, the accumulation and biosynthesis of PAs in developing astrocytes are not well understood. The purpose of the present study was to determine the contribution of uptake and/or synthesis of PAs using proliferation of neonatal astrocytes as an endpoint. We inhibited synthesis of PAs using α-difluoromethylornithine (DFMO; an inhibitor of the PA biosynthetic enzyme ornithine decarboxylase (ODC)) and inhibited uptake of PAs using trimer44NMe (PTI; a novel polyamine transport inhibitor). DFMO, but not PTI alone, blocked proliferation, suggesting that PA biosynthesis was present. Furthermore, exogenous administration of SPD rescued cell proliferation when PA synthesis was blocked by DFMO. When both synthesis and uptake of PAs were inhibited (DFMO + PTI), exogenous SPD no longer supported proliferation. These data indicate that neonatal astrocytes synthesize sufficient quantities of PAs de novo to support cell proliferation, but are also able to import exogenous PAs. This suggests that the PA uptake mechanism is present in both neonates as well as in adults and can support cell proliferation in neonatal astrocytes when ODC is blocked.


Meta-Analysis of the SLCO1B1 c.521T>C Variant Reveals Slight Influence on the Lipid-Lowering Efficacy of Statins.
Several studies have focused on the association between the lipid-lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism; however, the results are conflicting. The effects of statins show significant variability between individuals. This meta-analysis aimed to investigate the effects of the SLCO1B1 c.521T>C polymorphism on the lipid-lowering effects of statins. We systematically searched PubMed and Web of Science to screen relevant studies. Meta-analysis was performed to identify the association between SLCO1B1 c.521 polymorphisms and the lipid-lowering effects of statins on the basis of the standard mean difference (SMD) and 95% confidence intervals (CIs). Additionally, we checked for heterogeneity (I(2)) among studies and evidence of publication bias. We obtained eight studies including 2,012 wild genotype (T/T) and 526 variant genotype (T/C and C/C) cases. No significant difference was observed in the lipid-lowering efficacy of statins between the wild and variant genotypes of SLCO1B1, with a pooled SMD of 0.03 (95% CI: -0.07-0.13). Furthermore, there was no significant effect in the meta-analyses of the variant heterozygote, homozygote, and Chinese populations. Subgroup meta-analysis indicated that the time required for the statin to take effect did not significantly affect the association between lipid-lowering efficacy of statins and SLCO1B1 c.521T>C polymorphism. However, the wild genotype improved the lipid-lowering efficacy of simvastatin with a pooled SMD of -0.26 (95% CI: -0.47- -0.05). No significant association was detected between the lipid-lowering efficacy of statins and the SLCO1B1 c.521T>C polymorphism, with the exception of simvastatin.


Binding of C1q and DNA to support materials by means of a new coupling procedure.
Since several years matrix-bound biologically active substances are widely used in biosciences, biotechnology and medicine. We are presenting a simple and inexpensive activation procedure for support materials which allows stable binding of C1q and DNA. We could not found a remarkable leakage of the bound ligands. In connection with the good biocompatibility of our procedure, both are important for the application in extracorporeal immunoadsorption. The method is technologically simple and represents an alternative to the activation methods applied so far.


The complexity of the gapped consecutive-ones property problem for matrices of bounded maximum degree.
The Gapped Consecutive-Ones Property (C1P) Problem, or the (k, δ)-C1P Problem is: given a binary matrix M and integers k and δ, decide if the columns of M can be ordered such that each row contains at most k blocks of 1's, and no two neighboring blocks of 1's are separated by a gap of more than δ 0's. This problem was introduced by Chauve et al. ( 2009b ). The classical polynomial-time solvable C1P Problem is equivalent to the (1, 0)-C1P problem. It has been shown that, for every unbounded or bounded k ≥ 2 and unbounded or bounded δ ≥ 1, except when (k, δ) = (2, 1), the (k, δ)-C1P Problem is NP-complete (Maňuch et al., 2011 ; Goldberg et al., 1995 ). In this article, we study the Gapped C1P Problem with a third parameter d, namely the bound on the maximum number of 1's in any row of M, or the bound on the maximum degree of M. This is motivated by the reconstruction of ancestral genomes (Ma et al., 2006 ; Chauve and Tannier, 2008 ), where, in binary matrices obtained from the experiments of Chauve and Tannier ( 2008 ), we have observed that the majority of the rows have low degree, while each high degree row contains many rows of low degree. The (d, k, δ)-C1P Problem has been shown to be polynomial-time solvable when all three parameters are fixed (Chauve et al., 2009b ). Since fixing d also fixes k (k ≤ d), the only case left to consider is the case when δ is unbounded, or the (d, k, ∞)-C1P Problem. Here we show that for every d > k ≥ 2, the (d, k, ∞)-C1P Problem is NP-complete.


Prediction, prevention, and management of right ventricular failure after left ventricular assist device implantation: A comprehensive review.
Left ventricular assist devices (LVADs) are increasingly common across the heart failure population. Right ventricular failure (RVF) is a feared complication that can occur in the early post-operative phase or during the outpatient follow-up. Multiple tools are available to the clinician to carefully estimate the individual risk of developing RVF after LVAD implantation. This review will provide a comprehensive overview of available tools for RVF prognostication, including patient-specific and right ventricle (RV)-specific echocardiographic and hemodynamic parameters, to provide guidance in patient selection during LVAD candidacy. We also offer a multidisciplinary approach to the management of early RVF, including indications and management of right ventricular assist devices in this setting to provide tools that help managing the failing RV.


A comparative bioavailability study of carbamazepine tablets and a chewable tablet formulation.
Differences in product formulations have been shown to affect the therapeutic response by altering the relative bioavailability and pharmacokinetics of a drug. The relative bioavailability and pharmacokinetics of carbamazepine tablets (CBZ) and a chewable tablet formulation were evaluated in 10 normal healthy subjects (five men and five women). The study utilized a randomized, crossover design with a 4-week washout period between doses. Blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 14, 24, 30, 36, and 48 h following a 200-mg dose. Plasma samples were assayed by fluorescence polarization immunoassay. Ke, Cmax, Tmax, area under the curve (AUC), and relative bioavailability were estimated using traditional pharmacokinetic methods and compared by paired t test. A statistically significant higher Cmax (3.81 +/- 81 vs. 4.64 +/- .80 mg/L) was observed with the chewable tablet formulation but was not thought to be clinically relevant. No significant differences between formulations for Ke (0.022 +/- 0.007 vs. 0.025 +/- 0.008 h-1 h), Tmax (7.49 +/- 2.69 vs. 6.04 +/- 2.7 h), AUC 48 h (119 +/- 22 vs. 133 +/- 13 mg/h/L), or AUCO--infinity ( 221 +/- 40 vs. 203 +/- 41 mg/h/L) were noted. Absorption was variable for both preparations. The relative bioavailability using the tablet as the standard formulation was (0.92 +/- 0.22). Transient, mild side effects were noted in three subjects with the chewable tablet alone, and one subject experienced side effects with both formulations. It was concluded that CBZ tablets and chewable tablets may be used interchangeably; however, considerable intra- and intersubject variability exists, and the need for patient monitoring is emphasized.


Targeting inflammatory cytokine storm to fight against COVID-19 associated severe complications.
Such testing and trying time probably never seen before in the human history. The novel coronavirus disease abbreviated as COVID-19 is the ongoing health crisis which entered into human life in late December 2019. The ease of transmission between humans and the undetectability in early stage makes COVID-19 frightening and unprecedented. The disease is characterised by pneumonia progressing to breathing difficulty, acute respiratory distress syndrome (ARDS) and multi-organ failure. Clinical studies suggest excessive release of inflammatory mediators leads to cytokine storm, a phenomenon which appears to be potentially life-threatening in COVID-19. Across the globe, when the world authorities are grappling to contain the virus, our review provides a glimpse on structure, pathophysiology of the virus and further sheds light on various clinical complications associated with the disease in order to open up/raise new horizons to explore various possible theoretical targets for COVID-19. The review also portrays a question and debates: Can targeting cytokine storm can be a feasible approach to combat COVID-19?


Oxoisoaporphine alkaloid derivatives: synthesis, DNA binding affinity and cytotoxicity.
A series of novel oxoisoaporphine alkaloid derivatives, 9-aminoalkanamido-1-azabenzanthrone (general formula Ar-NHCO(CH(2))(n)NR(2), Ar=1-azabenzanthrone, n=1, 2 or 3), had been synthesized. Compared with 1-azabenzanthrone, the derivatives had significantly higher DNA binding affinity with calf thymus DNA, and higher potent cytotoxicity against different tumor cell lines. The cytotoxicity and the structure-activity relationship of the prepared compounds were studied. The derivatives with two methylene groups (n=2), and piperidine or ethanolamine functional group in the side chain exhibited highest DNA binding affinity and cytotoxicity.


Forefoot injuries in dancers.
Dancers, particularly ballet dancers, are artists and athletes. In dance, the choreographer acts as a sculptor, using the dancer as a medium of expression. This often entails placing the dancer's body in positions that require extraordinary flexibility and movement, which requires controlled power and endurance. Ballet and other forms of dance can be highly demanding activities, with a lifetime injury incidence of up to 90%. Ballet is stressful particularly on the dancer's forefoot. The en pointe position of maximal plantarflexion through the forefoot, midfoot, and hindfoot requires tremendous flexibility and strength that only can be attained safely through many years of training. The forces experienced by the toes and metatarsals are extraordinary.


A knowledge-resonance (KRES) model of category learning.
This article introduces a connectionist model of category learning that takes into account the prior knowledge that people bring to new learning situations. In contrast to connectionist learning models that assume a feedforward network and learn by the delta rule or backpropagation, this model, the knowledge-resonance model, or KRES, employs a recurrent network with bidirectional symmetric connection whose weights are updated according to a contrastive Hebbian learning rule. We demonstrate that when prior knowledge is represented in the network, KRES accounts for a considerable range of empirical results regarding the effects of prior knowledge on category learning, including (1) the accelerated learning that occurs in the presence of knowledge, (2) the better learning in the presence of knowledge of category features that are not related to prior knowledge, (3) the reinterpretation of features with ambiguous interpretations in light of error-corrective feedback, and (4) the unlearning of prior knowledge when that knowledge is inappropriate in the context of a particular category.


Role of zinc in blockade of excitotoxic action of quinolinic acid by picolinic acid.
This study examined whether picolinic acid (PIC) inhibits quinolinic acid (QUIN)-induced excitotoxicity through zinc chelation. Injection of QUIN into the nucleus basalis magnocellularis significantly depleted cortical choline acetyltransferase activity 7 days post injection and PIC inhibited this response. Zinc augmented the QUIN- but not NMDA-induced response. When PIC was co-administered with zinc, PIC failed to attenuate the QUIN-induced response. The inhibition of QUIN-induced cholinergic toxicity by PIC may involve chelation of zinc.


Applications of PET/CT and PET/MR Imaging in Primary Bone Malignancies.
Primary bone malignancies are characterized with anatomic imaging. However, in recent years, there has been an increased interest in PET/computed tomography scanning and PET/MRI with fludeoxyglucose F 18 for evaluating and staging musculoskeletal neoplasms. These hybrid imaging modalities have shown promise largely owing to their high sensitivity, ability to perform more thorough staging, and ability to monitor treatment response. This article reviews the current role of PET/computed tomography scanning and PET/MRI in primary malignancies of bone, with an emphasis on imaging characteristics, clinical usefulness, and current limitations.


Topical antifungal drug products for over-the-counter human use; amendment of final monograph. Final rule.
The Food and Drug Administration (FDA) is issuing a final rule amending the final monograph for over-the-counter (OTC) topical antifungal drug products to add the ingredient clotrimazole as generally recognized as safe and effective for the treatment of athlete's foot, jock itch, and ringworm. This final rule is part of FDA's ongoing review of OTC drug products.


Long-term potentiation in the hippocampal CA1 region in the presence of N-methyl-D-aspartate receptor antagonists.
The present study deals with the question of whether L-type voltage-gated calcium channels can support the induction of input specific long-term potentiation. Tetanus-induced potentiation of synaptic transmission was examined in the CA1 region of normal and disinhibited guinea-pig hippocampal slices. It was found that afferent tetanization in the presence of 50 microM of the N-methyl-D-aspartate receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid led to a prolonged input specific potentiation. This potentiation was found only in disinhibited slices, its induction required cooperativity, and it was associated with an increase in the early part of the field excitatory postsynaptic potential initial slope. It was not affected by the L-type voltage-gated calcium channel blocker nifedipine, but it was reduced when D(-)-2-amino-5-phosphonopentanoic acid was supplemented with other N-methyl-D-aspartate receptor antagonists. The present study also examined a potentiation that was not restricted to the activated synapses and that was not associated with an increase in the early part of the field excitatory postsynaptic potential initial slope. This potentiation was blocked by the L-type voltage-gated calcium channel antagonist nifedipine. It is concluded that calcium influx through L-type voltage-gated calcium channels participates in the generation of a prolonged potentiation, but not of the input specific N-methyl-D-aspartate receptor-dependent long-term potentiation. The results also suggest that high concentrations of D(-)-2-amino-5-phosphonopentanoic acid can be insufficient to fully prevent N-methyl-D-aspartate receptor activation by strong afferent tetanization in the disinhibited slice.


Tumor necrosis factor receptor 1 induces interleukin-6 upregulation through NF-kappaB in a rat neuropathic pain model.
Peripheral nerve injury resulting in neuropathic pain induces the upregulation of interleukin (IL)-6 and tumor necrosis factor-alpha, which binds to tumor necrosis factor receptor 1 (TNFR1) and induces NF-kappaB and p38 MAPK activation in the spinal cord and dorsal root ganglia (DRG). We here investigated whether TNFR1 regulates IL-6 expression through NF-kappaB or p38 MAPK activations in the spinal cord and DRG in rats with chronic constriction injury (CCI) of the sciatic nerve. Intrathecal treatment with a TNFR1 antisense oligonucleotide (ASO) significantly inhibited CCI-elevated IKKs phosphorylation, IkB-alpha degradation, the nuclear translocation, phosphorylation, and DNA-binding activity of NF-kappaB, p38 MAPK activation, and IL-6 mRNA and protein expression in the spinal cord and DRG. Interestingly, CCI remarkably elevated IKKalpha and p65 phosphorylations in the spinal cord rather than in the DRG. In addition, NF-kappaB decoy, but not p38 MAPK inhibitor, SB203580 reduced CCI-elevated IL-6 expression in the spinal cord and DRG. Therefore, these data suggest that TNFR1 induces IL-6 upregulation and neuropathic pain through NF-kappaB, but not p38 MAPK activation in the spinal cord and DRG and that the NF-kappaB/IL-6 pathways in the DRG may be less dependent on TNFR1 than the spinal cord pathway.


Detection of infectious symptoms from VA emergency department and primary care clinical documentation.
The majority of clinical symptoms are stored as free text in the clinical record, and this information can inform clinical decision support and automated surveillance efforts if it can be accurately processed into computer interpretable data. We developed rule-based algorithms and evaluated a natural language processing (NLP) system for infectious symptom detection using clinical narratives. Training (60) and testing (444) documents were randomly selected from VA emergency department, urgent care, and primary care records. Each document was processed with NLP and independently manually reviewed by two clinicians with adjudication by referee. Infectious symptom detection rules were developed in the training set using keywords and SNOMED-CT concepts, and subsequently evaluated using the testing set. Overall symptom detection performance was measured with a precision of 0.91, a recall of 0.84, and an F measure of 0.87. Overall symptom detection with assertion performance was measured with a precision of 0.67, a recall of 0.62, and an F measure of 0.64. Among those instances in which the automated system matched the reference set determination for symptom, the system correctly detected 84.7% of positive assertions, 75.1% of negative assertions, and 0.7% of uncertain assertions. This work demonstrates how processed text could enable detection of non-specific symptom clusters for use in automated surveillance activities.


Orientation of the bacteriochlorophyll triplet and the primary ubiquinone acceptor of Rhodospirillum rubrum in membrane multilayers determined by ESR spectroscopy (I).
Chromatophores from Rhodospirillum rubrum were oriented as multilayers on quartz slides under reducing conditions. Irradiation of these multilayers in the resonance cavity of an ESR spectrometer at 6 K yielded the spectrum of the bacteriochlorophyll dimer triplet. The relative intesities of the main six lines of the triplet were dependent on the angle subtended by the direction of the external magnetic field with plane of the multilayers. The angular dependence of the intensities of these transitions can best be interpreted in terms of one of the principal axes of the triplet lying along the plane of the membrane while the other two axes are titled 10--20 degrees away from the parallel to and normal to the membrane directions. If we assume the porphyrin planes of the dimer to be parallel and the largest splitting of the triplet transitions to correspond to those transitions in a direction normal to this plane, then these data imply that the dimer planes are nearly perpendicular to the membrane plane. Purified iron-depleted phototrap complexes were similarly oriented in reconstituted phosphatidylcholine multilayers and the angular dependence of the light-induced spectrum recorded at room temperature. A computer analysis of this angular dependence suggests that the plane of the primary ubiquinone acceptor molecule is parallel to the plane of the membrane and therefore perpendicular to the donor.


Dynamics and temperature field analysis of piezoelectric driven three-stator multi-degree-of-freedom ultrasonic motor.
Since the temperature has a great effect on the service behavior of the ultrasonic motor, high temperature will affect its mechanical characteristics and service life. This article is on a model of a piezoelectric driven three-stator multi-degree-of-freedom ultrasonic motor. Firstly, the motion mechanism is analyzed, and the main causes of temperature rise are determined to be friction heat generation and vibration heat generation. Then, the theoretical model of temperature rise is built, and the temperature rise characteristics of the ultrasonic motor are simulated and analyzed by establishing a three-dimensional transient temperature field model. Finally, it is verified by temperature test experiment. The results show that the simulation analyses are consistent with the experimental results, and this analysis can correctly reflect the temperature rise characteristics of the motor. It provides a reference for further seeking the effect of the body temperature rise on the service behavior of the ultrasonic motor and improving the operating characteristics of the ultrasonic motor.


AIDS-related stigma and homophobia: implications for nursing education.
Healthcare workers' attitudes about acquired immune deficiency syndrome (AIDS) are influenced by two major types of fears: AIDS-related stigma refers to irrational fears about contracting the virus and about death and dying issues, whereas homophobia refers to irrational fears or negative attitudes about same-sex sexual behaviors or relationships. In this study, open-ended responses of nursing students to a videotape about an AIDS hospice were examined for the prevalence of these two types of fears. Most of the negative themes could be classified as AIDS-related stigma or homophobia. Implications for nursing education are discussed.


Regulation by thyroxine of the mRNA encoding the alpha subunit of mouse thyrotropin.
Thyrotropin (TSH), a glycoprotein hormone of the pituitary consisting of two subunits (alpha and beta), regulates thyroxine (T4) production by the thyroid gland. T4, in turn, regulates TSH biosynthesis and release. We have studied the regulation of the messenger RNA encoding the alpha subunit of TSH by T4 in pituitaries and in a transplantable thyrotropic tumor in mice. Hypothyroid male LAF1 mice bearing the TtT 97 thyrotropic tumor were injected daily with T4 for either 0, 1, 5, 12, or 33 days. Levels of TSH and its unassociated alpha (free alpha) and TSH-beta subunits in the plasma of these animals fell to less than 5% of control values after 33 days. Concentrations of TSH and TSH-beta in both tumor and pituitary also fell to low levels (less than 2% of control), while intracellular concentrations of free alpha subunit remained unchanged. Cellular levels of the mRNA encoding the precursor of the alpha subunit or pre-alpha (alpha mRNA) were measured by cell-free translation followed by electrophoretic analysis of immunoprecipitates of pre-alpha subunit and by nucleic acid hybridization to a radiolabeled cDNA probe specific for the alpha mRNA. In the pituitary, translatable and hybridizable alpha mRNA was decreased slightly after 1 day of T4 and decreased 40-50% after 5 and 12 days. In thyrotropic tumors, both translatable and total alpha mRNA showed a 60% decrease by 1 day and a maximum 85% decrease after 5, 12, and 33 days of T4. Therefore, T4 acts rapidly in vivo to decrease steady state alpha mRNA levels in the thyrotrope, and this decrease is maintained for the duration of treatment with thyroid hormone. This regulatory process is reflected in the sharp decreases in levels of TSH and free alpha subunit in plasma and in lower concentrations of the intact TSH in tissue. In contrast, the maintenance of high tissue concentrations of free alpha subunit after T4 treatment may be a reflection of alterations in a post-translational process specific for the free alpha subunit, as opposed to that of the intact TSH.


Behavioural and ERP evidence of the self-advantage of online self-relevant information.
The present study examined whether individuals experienced the same cognitive advantage for online self-relevant information (nickname) as that experienced for information encountered in real life (real name) through two experiments at both the behavioural and neural levels (event-related potential, ERP). The results indicated that individuals showed the same cognitive advantage for nicknames and real names. At the behavioural level, a nickname was detected as quickly as the real name, and both were detected faster than a famous name; at the neural level, the P300 potential elicited by one's nickname was similar to that elicited by one's real name, and both the P300 amplitudes and latencies were larger and more prolonged than those elicited by other name stimuli. These results not only confirmed the cognitive advantage for one's own nickname and indicated that this self-advantage can be extended to online information, but also indicated that the virtual self could be integrated into the self and further expanded individuals' self-concept.


The other-race effect in face processing among African American and Caucasian individuals with schizophrenia.
Studies of emotion recognition abilities in schizophrenia show greater impairment for non-Caucasians with schizophrenia compared with Caucasians. These studies, however, included only Caucasian faces as stimuli. There is evidence from healthy individuals for a performance disadvantage on face memory and emotion recognition when processing faces from a different ethnicity. The authors sought to measure the "other-race effect" in schizophrenia, which could account for previous findings and provide information about sensitivity to such social cues in patients. The study included 540 participants from four groups: African Americans with schizophrenia (N=135), Caucasians with schizophrenia (N=135), African American community comparison subjects (N=135), and Caucasian community comparison subjects (N=135). All participants completed face recognition and facial emotion identification tasks that included both Caucasian and African American faces as stimuli. Although comparison participants performed better than individuals with schizophrenia across all tasks, both comparison participants and participants with schizophrenia exhibited a strong and significant other-race effect for face memory and emotion recognition. The magnitude of the other-race effect did not differ between these two groups. These findings reveal an intact other-race effect in patients with schizophrenia and highlight a methodological concern in the measurement of face processing abilities in schizophrenia, namely, that findings of greater impairment in African American patients are spurious when Caucasian faces are used as stimuli. Despite overall impairments in face memory and emotion recognition, the presence of a normative other-race effect in schizophrenia may reflect typical experiences with faces during development.


Colour and pattern change against visually heterogeneous backgrounds in the tree frog Hyla japonica.
Colour change in animals can be adaptive phenotypic plasticity in heterogeneous environments. Camouflage through background colour matching has been considered a primary force that drives the evolution of colour changing ability. However, the mechanism to which animals change their colour and patterns under visually heterogeneous backgrounds (i.e. consisting of more than one colour) has only been identified in limited taxa. Here, we investigated the colour change process of the Japanese tree frog (Hyla japonica) against patterned backgrounds and elucidated how the expression of dorsal patterns changes against various achromatic/chromatic backgrounds with/without patterns. Our main findings are i) frogs primarily responded to the achromatic differences in background, ii) their contrasting dorsal patterns were conditionally expressed dependent on the brightness of backgrounds, iii) against mixed coloured background, frogs adopted intermediate forms between two colours. Using predator (avian and snake) vision models, we determined that colour differences against different backgrounds yielded perceptible changes in dorsal colours. We also found substantial individual variation in colour changing ability and the levels of dorsal pattern expression between individuals. We discuss the possibility of correlational selection on colour changing ability and resting behaviour that maintains the high variation in colour changing ability within population.


Evaluation of coplanar partial left breast irradiation using tomotherapy-based topotherapy.
To investigate the use of topotherapy for accelerated partial breast irradiation through field-design optimization and dosimetric comparison to linear accelerator-based three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT). Hypothetical 3-cm lumpectomy sites were contoured in each quadrant of a left breast by using dosimetric guidelines from the National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Therapy Oncology Group 0413 protocol. Coplanar intensity-modulated topotherapy treatment plans were optimized by using two-, three-, four-, five-, and seven-field arrangements for delivery by the tomotherapy unit with fixed gantry angles. Optimized noncoplanar five-field 3D-CRT and IMRT were compared with corresponding topotherapy plans. On average, 99.5% +/- 0.5% of the target received 100% of the prescribed dose for all topotherapy plans. Average equivalent uniform doses ranged from 1.20-2.06, 0.79-1.76, and 0.10-0.29 Gy for heart, ipsilateral lung, and contralateral lung, respectively. Average volume of normal breast exceeding 90% of the prescription and average area of skin exceeding 35 Gy were lowest for five-field plans. Average uniformity indexes for five-field plans using 3D-CRT, IMRT, and topotherapy were 1.047, 1.050, and 1.040, respectively. Dose-volume histograms and calculated equivalent uniform doses of all three techniques illustrate clinically equivalent doses to ipsilateral breast, lung, and heart. This dosimetric evaluation for a single patient shows that coplanar partial breast topotherapy provides good target coverage with exceptionally low dose to organs at risk. Use of more than five fields provided no additional dosimetric advantage. A comparison of five-field topotherapy to 3D-CRT and IMRT for accelerated partial breast irradiation illustrates equivalent target conformality and uniformity.


Neuroimmune interactions: experimental and clinical strategies.
This historical mini-review is devoted to the 30th Anniversary of the research activities of the Neuroimmunomodulation Group at the Immunology Research Center of Belgrade. During the past 30 years, these scientists have contributed to: (a) the definition of the structural and functional complexity and the lymphoneuroendocrine web of the immune microenvironment; (b) the structural and functional dissection of the neuron, brain and mind by means of anti-neural antibodies; (c) the antigenic relationship among the multiple components of the nervous and lymphoid tissues; (d) the methodological and conceptual aspects of the influence of lesioning and stimulation of various brain structures on immune responsiveness; (e) the lymphoneuroendocrine relationships during embryonic development; (f) the definition of immunopsychiatric diseases, i.e., neural tissue immunologic hypersensitivity in psychiatric diseases; (g) the immunomodulating and regulating activity of methionine-enkephalin and leucine-enkephalin; (h) the correlations between associative learning and immunity (behavioral immunology). The theoretical, experimental and clinical devices created, and observations collected from 1957 to 1987 by the Belgrade group of neuroimmunologists proved to be useful for elucidation of the complex interactions between the immune system and the nervous system, and provided a broad perspective for research in neuroimmunomodulation.


BMI metrics and their association with adiposity, cardiometabolic risk factors, and biomarkers in children and adolescents.
There are limited data comparing the relative associations of various BMI metrics with adiposity and cardiometabolic risk factors in youth. Examine correlations of 7 different BMI metrics with adiposity, cardiometabolic risk factors, and biomarkers (i.e. blood pressure, waist circumference, cholesterol, leptin, insulin, high molecular weight adiponectin, high-sensitivity c-reactive protein (hsCRP)). This was a cross-sectional analysis of youth in all BMI categories. BMI metrics: BMI z-score (BMIz), extended BMIz (ext.BMIz), BMI percentile (BMIp), percent of the BMI 95th percentile (%BMIp95), percent of the BMI median (%BMIp50), triponderal mass index (TMI), and BMI (BMI). Correlations between these BMI metrics and adiposity, visceral adiposity, cardiometabolic risk factors and biomarkers were summarized using Pearson's correlations. Data from 371 children and adolescents ages 8-21 years old were included in our analysis: 52% were female; 20.2% with Class I obesity, 20.5% with Class II, and 14.3% with Class III obesity. BMIp consistently demonstrated lower correlations with adiposity, risk factors, and biomarkers (r = 0.190-0.768) than other BMI metrics. The %BMIp95 and %BMIp50 were marginally more strongly correlated with measures of adiposity as compared to other BMI metrics. The ext.BMIz did not meaningfully outperform BMIz. Out of all the BMI metrics evaluated, %BMIp95 and %BMIp50 were the most strongly correlated with measures of adiposity. %BMIp95 has the benefit of being used currently to define obesity and severe obesity in both clinical and research settings. BMIp consistently had the lowest correlations. Future research should evaluate the longitudinal stability of various BMI metrics and their relative associations with medium to long-term changes in adiposity and cardiometabolic outcomes in the context of intervention trials.


Melatonin Inhibits the Malignant Progression of Glioblastoma via Regulating miR-16-5p/PIM1.
Melatonin (MT) is a pineal hormone with antineoplastic potential. This study aims to explore the therapeutic potential and mechanism of MT on glioblastoma (GBM). A human GBM cell line, LN229, was used to evaluate the function of MT. Cell viability, apoptosis, and migration were detected by CCK-8, flow cytometry, and transwell assays, respectively. The mRNA and protein expressions of specific genes were measured by qRT-PCR and western blot, respectively. The regulatory relationship between miR-16-5p and PIM1 was validated by dual luciferase reporter gene assay. A mouse xenograft model was established to prove the anti-tumor effect and related mechanisms of MT in vivo. MT inhibited the viability and migration and promoted the apoptosis of LN229 cells in a dose-dependent manner. MiR-16-5p was dose-dependently up-regulated by MT in LN229 cells, negatively regulating its target PIM1. MiR-16-5p inhibitor eliminated the anti-tumor effect of MT in LN229 cells, while si-PIM1 reversed the effect of miR-16-5p inhibitor in MT-treated cells. MT inhibited the tumor growth in vivo and MT-induced PIM1 down-regulation was reversed by miR- 16-5p inhibition in tumor tissues. MT inhibits the malignant progression of GBM via regulating miR-16-5p-mediated PIM1.


Persistent risk of tuberculosis in migrants a decade after arrival in Australia.
To examine the risk of tuberculosis (TB) in migrants a decade after their arrival in Australia. Retrospective review of laboratory-confirmed cases of TB in migrants diagnosed between 1990 and 2004 by the state TB reference laboratory in Victoria, analysed by a multivariate model comparing migrants diagnosed 10 or more years after arrival with those diagnosed within 10 years of arrival. Time to diagnosis; characteristics of migrants diagnosed with TB, including age, sex, region of birth, site of infection, and drug resistance. A third of migrants (734/1924) were diagnosed with TB 10 or more years after arrival in Australia. This group was more likely to be European-born (adjusted odds ratio [AOR], 3.4; 95% CI, 2.4-5.0) and older than 34 years (35-49 years: AOR, 3.8; 95% CI, 2.0-7.0), reflecting the longer time European migrants have been in Australia. There were two distinct European groups: European Union (EU)/Western and Central/Eastern. The Central/Eastern group were from countries with current high TB rates and, compared with the EU/Western group, were younger (mean age, 50 v 64 years) and more likely to be diagnosed within 10 years of arrival (47% v 14%; P < 0.001). European migrants were more likely to be diagnosed a decade or more after arrival in Australia. Once migrants from the currently high TB incidence areas of Asia and Africa have been in Australia for a similar period of time, their timing of diagnosis may resemble that for migrants from Europe. The current screening policy should be complemented with more sensitive techniques to detect latent TB.


Depletion of norepinephrine of the central nervous system Down-regulates the blood glucose level in d-glucose-fed and restraint stress models.
DSP-4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] is a neurotoxin that depletes norepinephrine. The catecholaminergic system has been implicated in the regulation of blood glucose level. In the present study, the effect of DSP-4 administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on blood glucose level was examined in d-glucose-fed and restraint stress mice models. Mice were pretreated once i.c.v. or i.t. with DSP-4 (10-40μg) for 3days, and d-glucose (2g/kg) was fed orally. Blood glucose level was measured 0 (prior to glucose feeding or restraint stress), 30, 60, and 120min after d-glucose feeding or restraint stress. The i.c.v. or i.t. pretreatment with DSP-4 attenuated blood glucose level in the d-glucose-fed model. Plasma corticosterone level was downregulated in the d-glucose-fed model, whereas plasma insulin level increased in the d-glucose-fed group. The i.c.v. or i.t. pretreatment with DSP-4 reversed the downregulation of plasma corticosterone induced by feeding d-glucose. In addition, the d-glucose-induced increase in plasma insulin was attenuated by the DSP-4 pretreatment. Furthermore, i.c.v. or i.t. pretreatment with DSP-4 reduced restraint stress-induced increases in blood glucose levels. Restraint stress increased plasma corticosterone and insulin levels. The i.c.v. pretreatment with DSP-4 attenuated restraint stress-induced plasma corticosterone and insulin levels. Our results suggest that depleting norepinephrine at the supraspinal and spinal levels appears to be responsible for downregulating blood glucose levels in both d-glucose-fed and restraint stress models.


The Biomedical Mutual Organization: a new approach to developing new medical treatments.
Self-experimentation is an efficient, productive and proven way to generate new treatments for mild and serious disease. But it is limited by materials available to the individual and the amount of testing one person can do. I advocate the formation of Biomedical Mutual Organizations, self-funded groups of individuals that provide mutual support for exploring new ideas in medical treatment. Such groups could achieve three things. Firstly, they could pool analytical services to validate the quality of materials and analytical services used in self-testing and self-medication, including verification of the identity and purity of medicine ingredients sourced from non-traditional sources. Secondly, they could pool resources to conduct group experiments in new treatments, interpret the results, and generate new hypotheses which could in turn be tested. Thirdly they could conduct more formal clinical trials on the group as a whole of new, indeed radical, therapies, in effect becoming a self-funded biotechnology company. While many practical objections remain to all of these, especially the last, and the last option may actually be illegal in some countries, some of the ethical objections that prevent such arrangements outside the context of a Mutual Organizations are overcome by the alignment of interests of those involved.


Targeting of Scavenger Receptors Stabilin-1 and Stabilin-2 Ameliorates Atherosclerosis by a Plasma Proteome Switch Mediating Monocyte/Macrophage Suppression.
Scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are preferentially expressed by liver sinusoidal endothelial cells. They mediate the clearance of circulating plasma molecules controlling distant organ homeostasis. Studies suggest that Stab1 and Stab2 may affect atherosclerosis. Although subsets of tissue macrophages also express Stab1, hematopoietic Stab1 deficiency does not modulate atherogenesis. Here, we comprehensively studied how targeting Stab1 and Stab2 affects atherosclerosis. ApoE-KO mice were interbred with Stab1-KO and Stab2-KO mice and fed a Western diet. For antibody targeting, Ldlr-KO mice were also used. Unbiased plasma proteomics were performed and independently confirmed. Ligand binding studies comprised glutathione-S-transferase-pulldown and endocytosis assays. Plasma proteome effects on monocytes were studied by single-cell RNA sequencing in vivo, and by gene expression analyses of Stabilin ligand-stimulated and plasma-stimulated bone marrow-derived monocytes/macrophages in vitro. Spontaneous and Western diet-associated atherogenesis was significantly reduced in ApoE-Stab1-KO and ApoE-Stab2-KO mice. Similarly, inhibition of Stab1 or Stab2 by monoclonal antibodies significantly reduced Western diet-associated atherosclerosis in ApoE-KO and Ldlr-KO mice. Although neither plasma lipid levels nor circulating immune cell numbers were decisively altered, plasma proteomics revealed a switch in the plasma proteome, consisting of 231 dysregulated proteins comparing wildtype with Stab1/2-single and Stab1/2-double KO, and of 41 proteins comparing ApoE-, ApoE-Stab1-, and ApoE-Stab2-KO. Among this broad spectrum of common, but also disparate scavenger receptor ligand candidates, periostin, reelin, and TGFBi (transforming growth factor, β-induced), known to modulate atherosclerosis, were independently confirmed as novel circulating ligands of Stab1/2. Single-cell RNA sequencing of circulating myeloid cells of ApoE-, ApoE-Stab1-, and ApoE-Stab2-KO mice showed transcriptomic alterations in patrolling (Ccr2-/Cx3cr1++/Ly6Clo) and inflammatory (Ccr2+/Cx3cr1+/Ly6Chi) monocytes, including downregulation of proatherogenic transcription factor Egr1. In wildtype bone marrow-derived monocytes/macrophages, ligand exposure alone did not alter Egr1 expression in vitro. However, exposure to plasma from ApoE-Stab1-KO and ApoE-Stab2-KO mice showed a reverted proatherogenic macrophage activation compared with ApoE-KO plasma, including downregulation of Egr1 in vitro. Inhibition of Stab1/Stab2 mediates an anti-inflammatory switch in the plasma proteome, including direct Stabilin ligands. The altered plasma proteome suppresses both patrolling and inflammatory monocytes and, thus, systemically protects against atherogenesis. Altogether, anti-Stab1- and anti-Stab2-targeted therapies provide a novel approach for the future treatment of atherosclerosis.


Veterinary public health activities aiming at prevention of chemical and other residues in food of animal origin. Action at the processing level.
The present situation regarding chemical residues in food products of animal origin is discussed. Some suggestions are given for sanitary judgement of such products and for preventive actions to be taken by the veterinary services.


Production of mycelial biomass by the Amazonian edible mushroom Pleurotus albidus.
Edible mushroom species are considered as an adequate source of food in a healthy diet due to high content of protein, fiber, vitamins, and a variety of minerals. The representatives of Pleurotus genus are characterized by distinct gastronomic, nutritional, and medicinal properties among the edible mushrooms commercialized worldwide. In the present study, the growth of mycelial biomass of Pleurotus albidus cultivated in submerged fermentation was evaluated. Saccharose, fructose, and maltose were the three main carbon sources for mycelial biomass formation with corresponding yields of 7.28gL(-1), 7.07gL(-1), and 6.99gL(-1). Inorganic nitrogen sources did not stimulate growth and the optimal yield was significantly higher with yeast extract (7.98gL(-1)). The factorial design used to evaluate the influence of saccharose and yeast extract concentration, agitation speed, and initial pH indicated that all variables significantly influenced the production of biomass, especially the concentration of saccharose. The greater amount of saccharose resulted in the production of significantly more biomass. The highest mycelial biomass production (9.81gL(-1)) was reached in the medium formulated with 30.0gL(-1) saccharose, 2.5gL(-1) yeast extract, pH 7.0, and a speed of agitation at 180rpm. Furthermore, P. albidus manifested different aspects of morphology and physiology under the growth conditions employed. Media composition affected mycelial biomass production indicating that the diversification of carbon sources promoted its improvement and can be used as food or supplement.


[Evaluation of quality of life after simultaneous pancreas-kidney transplantation].
To evaluate the influence of simultaneous pancreas-kidney (SPK) transplantation on the quality of life of diabetic recipients with end-stage renal disease. We performed a retrospective analysis of the data of diabetic patients with end-stage renal disease and evaluated the quality of life of the recipients using SF-36 health survey. One patient died of cerebrovascular accident, and 7 patients recovered smoothly. During the follow-up lasting for a mean of 23.3 months, the blood glucose, C-peptide and creatine levels of the patients remained stable. The score of 8 domains of SF-36 of the diabetic recipient at 2 years after SPK transplantation showed a significant improvement compared with that before the operation, similar to that of Chinese normal population(P > 0.05). SPK transplantation can achieve a significant improvement of the quality of life of diabetic patients with end-stage renal disease.


Appropriate use criteria for transthoracic echocardiography at a tertiary care center.
The American College of Cardiology and American Society of Echocardiography have developed appropriate use criteria for echocardiography. The objective of this study was to assess the rate of appropriate requests for transthoracic echocardiography at a Portuguese tertiary care center and to identify the factors associated with lower adherence to the appropriate use criteria. All transthoracic echocardiograms (in- and outpatient) performed over a period of one month were analyzed by two independent imaging cardiologists, who matched each request to a specific indication in the appropriate use criteria document. Overall, 799 echocardiograms were included in the analysis. In 97.5% of cases it was possible to determine an indication listed in the criteria, according to which 78.7% of classifiable echocardiograms were appropriate, 15.3% inappropriate and 6.0% of uncertain appropriateness. The most common appropriate indication (111 echocardiograms) was initial evaluation of patients with symptoms or conditions potentially related to cardiac etiology, while the main inappropriate indication (59 echocardiograms) was routine surveillance of ventricular function in patients with known coronary artery disease and no change in clinical status or cardiac exam. The proportion of inappropriate echocardiograms was significantly higher among outpatients than among inpatients (18.8 vs. 4.3%, p<0.05) and among cardiologists compared to other specialties (19.3% vs. 10.9%, p<0.05). The majority of requests for transthoracic echocardiograms at a Portuguese tertiary care center were appropriate. Requests by cardiologists and outpatient referrals presented the highest rates of inappropriateness.


Regulation of EZH2 by SMYD2-Mediated Lysine Methylation Is Implicated in Tumorigenesis.
The histone methyl transferase enhancer of zeste homolog 2 (EZH2) is a master transcriptional regulator involved in histone H3 lysine 27 trimethylation. We aimed to elucidate the precise post-translational regulations of EZH2 and their role in cancer pathogenesis. Here, we show that SET and MYND domain containing 2 (SMYD2) directly methylates EZH2 at lysine 307 (K307) and enhances its stability, which can be relieved by the histone H3K4 demethylase lysine-specific demethylase 1 (LSD1). SMYD2 is critical for EZH2 function in repressing a cohort of genes governing several cancer-associated pathways. In addition, SMYD2 promotes breast cancer cell proliferation, epithelial-mesenchymal transition, and invasion through EZH2 K307 methylation, and it is markedly upregulated in various human cancers. Our data suggest that dynamic crosstalk between SMYD2-mediated EZH2 methylation plays an important role in fine-tuning EZH2 functions in chromatin recruitment and transcriptional repression.


Transcriptionally active nitrogen fixation and biosynthesis of diverse secondary metabolites by Dolichospermum and Aphanizomenon-like Cyanobacteria in western Lake Erie Microcystis blooms.
Cyanobacterial harmful algal blooms (cyanoHABs) in the western basin of Lake Erie are dominated by microcystin producing Microcystis spp., but other cyanobacterial taxa that coexist in these communities may play important roles in production of toxins and shaping bloom dynamics and community function. In this study, we used metagenomic and metatranscriptomic data from the 2014 western Lake Erie cyanoHAB to explore the genetic diversity and biosynthetic potential of cyanobacteria belonging to the Anabaena, Dolichospermum, Aphanizomenon (ADA) clade. We reconstructed two near-complete metagenome-assembled genomes from two distinct ADA clade species, each containing biosynthetic gene clusters that encode novel and known secondary metabolites, including those with toxic and/or known taste and odor properties, that were transcriptionally active. However, neither ADA metagenome-assembled genome contained genes encoding guanitoxins, anatoxins, or saxitoxins, which are known to be produced by ADA. The ADA cyanobacteria accounted for most of the metagenomic and metatranscriptomic reads from nitrogen fixation genes, suggesting they were the dominant N-fixers at the times and stations sampled. Despite their relatively low abundance, our results highlight the possibility that ADA taxa could influence the water quality and ecology of Microcystis blooms, although the extent of these impacts remains to be quantified.


Demonstration of simultaneous experiments using thin crystal multiplexing at the Linac Coherent Light Source.
Multiplexing of the Linac Coherent Light Source beam was demonstrated for hard X-rays by spectral division using a near-perfect diamond thin-crystal monochromator operating in the Bragg geometry. The wavefront and coherence properties of both the reflected and transmitted beams were well preserved, thus allowing simultaneous measurements at two separate instruments. In this report, the structure determination of a prototypical protein was performed using serial femtosecond crystallography simultaneously with a femtosecond time-resolved XANES studies of photoexcited spin transition dynamics in an iron spin-crossover system. The results of both experiments using the multiplexed beams are similar to those obtained separately, using a dedicated beam, with no significant differences in quality.


Surgical Management of Breast Cancer Liver Metastasis.
Hepatic resection for patients with isolated breast cancer liver metastases (BCLM) is associated with prolonged disease-free interval and better overall survival in highly selected patients. Patients with limited disease who are not candidates for surgery benefit from ablative therapies for isolated breast cancer metastasis in addition to systemic chemotherapy. In the era of modern effective systemic chemotherapy for BCLM, local regional therapies are warranted, yet only in well-selected patients following discussion in a multidisciplinary setting. This article reviews data related to hepatic resection and ablative therapies of BCLM, as well as long-term outcomes of women treated with these approaches.


Fine structural and immunohistochemical properties of dysplastic melanocytic nevi: comparison with malignant melanoma.
This study will review the clinical features of dysplastic melanocytic nevi (DMN) in Japanese cases, and then show the fine structure of melanosomes/melanogenesis in the dysplastic melanocytes and the immunohistochemical property of DMN as identified by monoclonal antibodies against human melanosome specific antigen (HMSA). The incidence of DMN is quite low in the Japanese. It is indicated that this fact may partly explain the low incidence of malignant melanoma in Japanese; in particular, low incidence in sun-exposed areas. The patients with DMN were largely males. They were different from ordinary Japanese in that they usually burn and tan poorly after sun exposure. In addition, the synthesis of melanosomes in the dysplastic melanocytes was found to be abnormal and characterized by a significant alteration in the fine structure of the melanosomal matrix and the pattern of melanization. These abnormal melanosomes reacted positively with MoAb HMSA-1 and HMSA-2, which identify the structural matrix protein of melanosomes unique to neoplastic melanocytes. Importantly, HMSA was present in both dysplastic melanocytes and melanoma cells, but not in epidermal melanocytes (nevus cells) of common melanocytic nevi.


Do different foot types affect the 6-min walk test capacity of younths with Charcot-Marie-Tooth neuropathy ?
The present study aimed to assess the gait capacity of youths with Charcot Marie Tooth disease (CMT), considering the different foot postures as a grouping variable. METHODS: The total distance, the predicted distance, and gait velocity obtained during the six-minute walking test (6MWT) were compared between participants with and without CMT. In addition, part of the CMT group completed a 12-month follow-up. The study evaluated 63 participants (CMT group = 31; Non-CMT group = 32) aged 6 to 18, both sexes. Data included anthropometric measures, foot posture index (FPI), the distance (D6), percentage of predicted distance (%D6), and walking velocity(V) in 6MWT. The D6% presented no significant difference between the types of feet in CMT or Non-CMT (p < 0.05, Kruskal Wallis test). CMT presented reduced values of D6, %D6, and V when compared to Non-CMT. These findings indicate that gait performance was decreased in youths with CMT in comparison to non-CMT. Contrary to what was expected, the cavus foot type did not show lower gait capacity than the flatfoot, suggesting that the types of feet alone did not determine differences in gait capacity within the CMT group.


Erythropoietin reduces epileptogenic processes following status epilepticus.
Erythropoietin (EPO) has neuron and astroglial protective effects via reduction of tissue-injuring molecules such as reactive oxygen species, glutamate, inflammatory cytokines, and other damaging molecules. Although EPO may constitute an effective therapeutic modality in cases of epileptic insult, no study has been performed on the effects of exogenous EPO on the chronic seizure formation. In this study, we attempted to investigate if EPO could modulate the altered microenvironment in the epileptic rat brain. Morphological changes in the hippocampi of rats subjected to lithium-pilocarpine-induced status epilepticus (SE) were examined with respect to neuronal loss, inflammation, blood-brain barrier (BBB) leakage, and cell genesis. Spontaneous recurrent seizures (SRSs) were investigated by long-term video-EEG monitoring. EPO receptor (EPOR) was found to be increased in the hippocampus after SE. Administered EPO prevented, during the latent period following SE, BBB leakage, neuronal death, and microglia activation in the dentate hilus, CA1, and CA3, and inhibited the generation of ectopic granule cells in the hilus and new glia in CA1. Moreover, EPO reduced the risk of SRS development. These findings suggest that EPO has a potential therapeutic role in the setting of acute epileptic insults.


Molecular characterization and chromosomal mapping of porcine adipose differentiation-related protein (ADRP).
ADRP plays an important role in regulating lipid storage in various cells. We investigated the ADRP gene as a candidate gene for intramuscular fat deposition and marbling traits in pigs. A full-length transcript of porcine ADRP was cloned by RT-PCR and RACE. The porcine ADRP cDNA (1848 bp) contains a 1377-bp open reading frame, encoding a deduced protein of 459 amino acids, which has amino acid sequence identities of 89, 89, 82 and 81% with cattle, human, mouse and rat ADRP genes respectively. The genomic structure and sequence of the porcine ADRP were also analysed using a BAC clone of a Korean native pig. Pig ADRP comprises eight exons spanning approximately 13 kb and is located on chromosome 1 q2.3-q2.7 between microsatellite markers SW2185 and SW974. Several sequence variations were detected from nine different pig breeds. The biological role of this gene and the mapping localization indicated that the porcine ADRP is a possible candidate gene for fat deposition and marbling traits.


Quantitative photoacoustic spectroscopy of cataractous human lenses.
Quantitative photoacoustic spectra of the nuclei of cataractous human lenses with various degrees of colouration and opacification were measured in the spectral range 250-600 nm. The lens nuclei were obtained from 20 cataractous patients through extracapsular cataract extraction. These measurements yield the light loss per unit path length in the nucleus of cataractous lenses.


Entropic segregation of short polymers to the surface of a polydisperse melt.
Chain ends are known to have an entropic preference for the surface of a polymer melt, which in turn is expected to cause the short chains of a polydisperse melt to segregate to the surface. Here, we examine this entropic segregation for a bidisperse melt of short and long polymers, using self-consistent field theory (SCFT). The individual polymers are modeled by discrete monomers connected by freely-jointed bonds of statistical length a , and the field is adjusted so as to produce a specified surface profile of width [Formula: see text]. Semi-analytical expressions for the excess concentration of short polymers, [Formula: see text], the integrated excess, [Formula: see text] , and the entropic effect on the surface tension, [Formula: see text], are derived and tested against the numerical SCFT. The expressions exhibit universal dependences on the molecular-weight distribution with model-dependent coefficients. In general, the coefficients have to be evaluated numerically, but they can be approximated analytically once [Formula: see text]. We illustrate how this can be used to derive a simple expression for the interfacial tension between immiscible A- and B-type polydisperse homopolymers.


LiGRO: a graphical user interface for protein-ligand molecular dynamics.
To speed up the drug-discovery process, molecular dynamics (MD) calculations performed in GROMACS can be coupled to docking simulations for the post-screening analyses of large compound libraries. This requires generating the topology of the ligands in different software, some basic knowledge of Linux command lines, and a certain familiarity in handling the output files. LiGRO-the python-based graphical interface introduced here-was designed to overcome these protein-ligand parameterization challenges by allowing the graphical (non command line-based) control of GROMACS (MD and analysis), ACPYPE (ligand topology builder) and PLIP (protein-binder interactions monitor)-programs that can be used together to fully perform and analyze the outputs of complex MD simulations (including energy minimization and NVT/NPT equilibration). By allowing the calculation of linear interaction energies in a simple and quick fashion, LiGRO can be used in the drug-discovery pipeline to select compounds with a better protein-binding interaction profile. The design of LiGRO allows researchers to freely download and modify the software, with the source code being available under the terms of a GPLv3 license from http://www.ufrgs.br/lasomfarmacia/ligro/ .


Long-lasting desensitization of bladder afferents following intravesical resiniferatoxin and capsaicin in the rat.
The present study was conducted to determine whether long-lasting desensitization of bladder afferents could be achieved using a single local application of the capsaicin (CAP)-like irritant resiniferatoxin (RTX), and to compare the effects of RTX and CAP on behavioral and histological endpoints. While rats were anesthetized, vehicle (VEH), RTX (10-100 nmol) or CAP (10-100 mumol) was instilled in the bladder (intravesical, i.ves.) via a cannula surgically implanted into the bladder dome. Beginning 1 week after treatment, once per week for 4 weeks, rats were tested behaviorally for desensitization to i.ves. RTX (10 nmol) using the abdominal lick test. Rats pretreated with low doses of RTX and CAP were partially desensitized at week 1; desensitization diminished over weeks 2-3. In contrast, rats pretreated with high doses of RTX or CAP were more completely desensitized at week 1, and desensitization did not diminish by week 4. Separate groups of rats tested 8 weeks after treatment showed substantial recovery. Rats pretreated with RTX but tested only with VEH for the first 3 weeks showed desensitization at week 4 approximately equivalent to that of RTX-treated rats tested with RTX every week. Sensitivity of corneal afferents to RTX (1.0 microgram/ml) at week 4 was not different between VEH- and RTX- or CAP-treated rats. Gross and histological examination of bladder tissue indicated that both RTX and CAP produced inflammation, which diminished in a dose- and time-dependent manner (1-8 weeks post-treatment).(ABSTRACT TRUNCATED AT 250 WORDS)


The influence of subacute dyflos administration on the sensitivity to agonists of longitudinal and circular muscle preparations of the guinea-pig ileum.
1. Changes in the EC50 values to various agonists in longitudinal and circular muscle preparations of guinea-pig ileum were investigated following daily pretreatment of the animals for 10 days with dyflos (1.2 mg/kg, s.c.). 2. In the longitudinal muscle no significant change in sensitivity to acetylcholine and potassium chloride was noted following dyflos treatment. Marked subsensitivity to carbachol and histamine was observed. 3. In circular muscle a marked supersensitivity to acetylcholine occurred and there was no change in sensitivity to carbachol. 4. Dyflos treatment induced an increase in the slope of the log concentration-response curve and the maximal contractile response obtained to agonists in both longitudinal and circular muscle preparations. An increase in tissue mass was also associated with dyflos pretreatment. 5. Subsensitivity development was not attributable to changes in affinity for agonists at the receptor site but rather to changes at the post-receptor level leading to a nonspecific subsensitivity.


[Contribution of GIGA I3 (GIGA-Infection, Immunity and Inflammation) to the understanding of the complex pathogen-host-environment interplay].
COVID-19 has highlighted the necessary synergy between clinicians and researchers. Such synergy constitutes the DNA of GIGA I3 (GIGA-Infection, Immunity and Inflammation) and makes its wealth. It ensures the translational nature of the research projects on pathologies involving the immune system in an infectious or non-infectious context.


Mechanisms of Congenital Malformations in Pregnancies with Pre-existing Diabetes.
Fetuses of diabetic mothers are at increased risk for congenital malformations. Research in recent decades using animal and embryonic stem cell models has revealed many embryonic developmental processes that are disturbed by maternal diabetes. The aim of this review is to give clinicians a better understanding of the reasons for rigorous glycemic control in early pregnancy, and to provide background to guide future research. Mouse models of diabetic pregnancy have revealed mechanisms for altered expression of tissue-specific genes that lead to malformations that are more common in diabetic pregnancies, such as neural tube defects (NTDs) and congenital heart defects (CHDs), and how altered gene expression causes apoptosis that leads to malformations. Embryos express the glucose transporter, GLUT2, which confers susceptibility to malformation, due to high rates of glucose uptake during maternal hyperglycemia and subsequent oxidative stress; however, the teleological function of GLUT2 for mammalian embryos may be to transport the amino sugar glucosamine (GlcN) from maternal circulation to be used as substrate for glycosylation reactions and to promote embryo cell growth. Malformations in diabetic pregnancy may be not only due to excess glucose uptake but also due to insufficient GlcN uptake. Avoiding maternal hyperglycemia during early pregnancy should prevent excess glucose uptake via GLUT2 into embryo cells, and also permit sufficient GLUT2-mediated GlcN uptake.


WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells.
Development of metastases and drug resistance are still a challenge for a successful systemic treatment in breast cancer (BC) patients. One of the mechanisms that confer metastatic properties to the cell relies in the epithelial-to-mesenchymal transition (EMT). Moreover, both EMT and metastasis are partly modulated through epigenetic mechanisms, by repression or induction of specific related genes. We applied shRNAs and drug targeting approaches in BC cell lines and metastatic patient-derived xenograft (PDX) models to inhibit WDR5, the core subunit of histone H3 K4 methyltransferase complexes, and evaluate its role in metastasis regulation. We report that WDR5 is crucial in regulating tumorigenesis and metastasis spreading during BC progression. In particular, WDR5 loss reduces the metastatic properties of the cells by reverting the mesenchymal phenotype of triple negative- and luminal B-derived cells, thus inducing an epithelial trait. We also suggest that this regulation is mediated by TGFβ1, implying a prominent role of WDR5 in driving EMT through TGFβ1 activation. Moreover, such EMT reversion can be induced by drug targeting of WDR5 as well, leading to BC cell sensitization to chemotherapy and enhancement of paclitaxel-dependent effects. We suggest that WDR5 inhibition could be a promising pharmacologic approach to reduce cell migration, revert EMT, and block metastasis formation in BC, thus overcoming resistance to standard treatments.


Pre-operative and post-operative psychiatric manifestations in patients with supratentorial meningiomas.
In the present study, we have tried to delineate the nature of psychiatric abnormalities caused by supratentorial meningiomas and the effect of surgery on them. We have tried to find the patient and tumor characters influencing the psychiatric abnormalities and their post-operative outcome. This is a prospective study conducted on patients with supratentorial meningiomas, admitted and operated in neurosurgery department, Nizam's Institute of Medical Sciences, India, from July 2006 to July 2009. We have included fifty-seven patients aged between 15 and 65 years with a clinico-radiological diagnosis of supratentorial meningioma in our study. We later confirmed the diagnosis by histopathological examination of the tumor. We have evaluated the patients for psychiatric manifestations before and after surgery and also analyzed the various clinical and radiological factors influencing the psychiatric status. We have enrolled 57 patients into the study. Frontal group had 22 patients (38.6%), parietal group had 10 patients (17.5%), temporal group had 10 patients (17.5%), occipital group had 6 patients (10.5%), and suprasellar group had 9 patients (15.8%). Twenty patients (35.1%) presented with psychiatric symptoms. The frequency of psychiatric symptoms was highest in the temporal group (60%) followed by the frontal group (45.5%). Frontal convexity meningiomas presented predominantly with depression, basifrontal and sphenoid wing meningiomas presented with mania or depressive symptoms, Suprasellar lesions and temporal convexity lesions presented with organic delusional disorder. Basifrontal meningiomas also caused organic personality disorders. The frequency of psychiatric symptoms was much higher in meningiomas with volume greater than 35cc compared to the smaller ones, in the frontal group. None of the patients developed new psychiatric symptoms after surgery. Among the twenty patients with psychiatric symptoms, 3 (15%) didnot improve, 8 (40%) improved partly and 9 (45%) improved completely. Meningiomas, although extra-axial, cause significant psychiatric symptoms up to 35.1%. Frontal and temporal group of meningiomas have the highest frequency of psychiatric symptoms. The frequency of psychiatric symptoms was significantly higher in meningiomas with volume greater than 35cc compared to the smaller ones, in the frontal group. Surgical excision of meningiomas ameliorates the psychiatric symptoms, either completely or partly, in the majority of the patients.


The chemosensitizing and cytotoxic effects of RSU 1164 and RSU 1165 in a murine tumor model.
RSU 1069, the lead compound in a series of nitroimidazoles containing an alkylating aziridine function, has been shown to be a potent radiosensitizer and chemopotentiator both in vitro and in vivo. However, this agent also demonstrates significant in situ toxicity. Recently it has been shown that less toxic analogues of RSU 1069 can be produced by the introduction of alkyl substituents to moderate the reactivity of the aziridine function. The present investigations were undertaken to evaluate the in vivo cytotoxicity and chemosensitizing efficacy of two such analogues, RSU 1164 and RSU 1165. All experiments were performed with KHT sarcomas grown intra-muscularly. In the cytotoxicity studies, a range of sensitizer doses was utilized whereas in the chemopotentiation investigations a fixed sensitizer exposure was combined simultaneously with a range of doses of the nitrosourea CCNU. In both studies, tumor cell survival was determined 22-24 hr after treatment using a soft agar clonogenic assay. Normal tissue toxicity in the chemopotentiation studies was assessed by bone marrow CFU-S assay. Both analogues were found to be significantly less cytotoxic to KHT sarcoma cells than RSU 1169 (a factor of 4-6 in dose at 50% cell survival). Combining a 1.0 to 2.0 mmol/kg dose of RSU 1164 or RSU 1165 with a range of doses of CCNU increased tumor cell killing by a factor of 1.5-1.6 but did not enhance bone marrow stem cell toxicity. The addition of either sensitizer to CCNU treatment therefore led to a significant therapeutic benefit.


15N-NMR studies of Methanobacterium thermoautotrophicum: comparison of assimilation of different nitrogen sources.
Methanobacterium thermoautotrophicum can utilize glutamine and urea as well as ammonia as the sole nitrogen source during growth on H2 and CO2. High-field 15N-NMR has been used to compare the assimilation of these different nitrogen sources by this organism. The 15N-NMR spectra of extracts of cells grown in media containing [delta-15N]glutamine as the nitrogen source show that the glutamine amide nitrogen is rapidly converted to glutamate. The 15N-NMR spectra of cell extracts from cells grown on [15N]urea show a marked increase in the labeling of the alpha-NH2 of glutamate concurrent with a decrease in the urea resonance. These two nitrogen sources do not show the metabolic shift to alanine as the major resonance in stationary phase as is seen with 15NH4Cl. This behavior is discussed in terms of the enzymes of nitrogen metabolism.


Regulation of neutrophils by interferon-γ limits lung inflammation during tuberculosis infection.
Resistance to Mycobacterium tuberculosis requires the host to restrict bacterial replication while preventing an over-exuberant inflammatory response. Interferon (IFN) γ is crucial for activating macrophages and also regulates tissue inflammation. We dissociate these two functions and show that IFN-γ(-/-) memory CD4(+) T cells retain their antimicrobial activity but are unable to suppress inflammation. IFN-γ inhibits CD4(+) T cell production of IL-17, which regulates neutrophil recruitment. In addition, IFN-γ directly inhibits pathogenic neutrophil accumulation in the infected lung and impairs neutrophil survival. Regulation of neutrophils is important because their accumulation is detrimental to the host. We suggest that neutrophilia during tuberculosis indicates failed Th1 immunity or loss of IFN-γ responsiveness. These results establish an important antiinflammatory role for IFN-γ in host protection against tuberculosis.


The association between health professionals' international experience and the academic output of their students in Harbin, China.
It is common practice for health professionals in China to have international experience. However, the association between such experience and these professionals' students' scientific research ability has not previously been evaluated. Our study aimed to quantify this association among the students of health professionals in China. We constructed a self-administered questionnaire and distributed it to all students at Harbin Medical University and its affiliated hospitals, including 257 students (Group A) of health professionals who had studied overseas ("returning" professionals) and 257 age-, enrollment year-, and specialty-matched students (Group B) of health professionals who had not studied overseas ("resident" professionals). SPSS software was used for the data entry and analysis. The total impact factor (IF) for articles published during their PhD study was 1031.68 in Group A and 727.65 in Group B (P = 0.001), and the number of articles was 297 in Group A and 228 in Group B (P = 0.040). The total IF for articles published by the 151 clinical medicine students of returning professionals during their PhD study was positively correlated with their advisor's total IF for articles published while abroad (P = 0.019). This study indicates that medical students may benefit from their advisors' international experience. Medical education administrators and the government could encourage clinical professionals to study overseas and to prolong the duration of their study abroad. Medical students should consider potential advisors' overseas experience when choosing a mentor.


Methods and basic data of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria.
To examine whether the observed excess of childhood leukaemia and lymphoma near the Sellafield nuclear plant is associated with established risk factors or with factors related to the plant. A case-control study. West Cumbria health district. 52 Cases of leukaemia, 22 of non-Hodgkin's lymphoma, and 23 of Hodgkin's disease occurring in people born in the area and diagnosed there in 1950-85 under the age of 25 and 1001 controls matched for sex and date of birth taken from the same birth registers as the cases. Antenatal abdominal x ray examinations, viral infections, habit factors, proximity to and employment characteristics of parents at Sellafield. Ascertainment of cases through multiple sources was as complete as possible, and the diagnosis was established for nearly all cases from hospital records and by independent pathological review when suitable material (60% (58) of cases) was available. Identification and tracing of the parents of cases and controls enabled questionnaires to be forwarded to 730 (66%), and 467 (64%) of the questionnaires were returned completed. Obstetric records were located for 481 (44%) of the relevant births, more frequently in recent years. Linkage of study subjects to the Sellafield workforce file enabled dates of employment and records on external doses of whole body ionising radiation to be obtained. Concordance of information from duplicate sources (when available) was reasonably high with no indications of bias. Overall the collected data were sufficiently reliable for detailed analysis and careful interpretation.


A twist in Pitx2 regulation of gut looping.
Asymmetric expression of the transcription factor Pitx2 is important for correct asymmetry in organs during development. In a recent issue of Science, Sanketi et al. find Pitx2 expression directing gut tilting is independent of Nodal and acts as a "brake" to counteract BMP4 signaling on the right.


Evaluating Cellular Viability by iTRAQ Proteomic Profiling.
Cellular health, functionality, response to environment, and other variables affecting cell, tissue, or organ viability are reflected in the cellular proteomes and metabolomes. These "omic" profiles are in constant flux even during normal cellular functioning, to maintain cellular homeostasis, in response to small environmental changes and maintenance of optimal cell viability. However proteomic "fingerprints" can also provide insight into cellular ageing, response to disease, adjustment to environmental changes, and other variables that impact cellular viability. A variety of proteomic methods can be used to determine qualitative and quantitative proteomic change. In this chapter, we will focus on a labeling method called isobaric tags for relative and absolute quantification (iTRAQ), which is frequently used to identify and quantify proteomic expression changes in cells and tissues.