Experimental and clinical evaluation of incision size and shape following forceps and injector implantation of a three-piece high-refractive-index silicone intraocular lens.
Previous studies have demonstrated that incision sizes required for insertion of various foldable intraocular lenses (IOLs) vary according to the IOL/inserter combination. The purpose of this study was to compare incision sizes and wound shape for both forceps and injector implantation of high-refractive-index silicone IOLs. In fresh human cadaver eyes, limbal corneal tunnel incisions were created, and 12 foldable high-refractive-index silicone (dimethyldiphenylsiloxane) IOLs were inserted in a randomized fashion using either a forceps or an injector. Using incision calipers, internal and external measurements of the tunnel incisions were obtained before and after IOL insertion. Scanning electron microscopy (SEM) was performed on selected corneas following IOL insertion. Additionally, in 12 cataract procedures, the incision sizes following forceps or injector implantation were evaluated intraoperatively. In the experimental setting, the external and internal tunnel widths (in mm) before insertion were 3.05 mm (+/-0.07) and 3.02 mm (+/-0.03), respectively, with the forceps and 3.06 mm (+/-0.04) and 3.01 mm (+/-0.04) with the injector. Following IOL implantation, the external and internal incision sizes were 3.33 mm (+/-0.07) and 3.33 mm (+/-0.04) with the forceps and 3.32 mm (+/-0.08) and 3.33 mm (+/-0.07) with the injector. SEM showed tearing of corneal structures after implantation through the smallest possible incisions with both devices. In the clinical study, the incision sizes before and after implantation were 3.23 mm (+/-0.10) and 3.36 mm (+/-0.06) with the forceps and 3.11 mm (+/-0.08) and 3.21 mm (+/-0.10) with the injector. This study confirms that high-refractive-index silicone IOLs provide one of the smallest currently achievable incisions before and after IOL implantation. In clinical use, the new injector reduces the mean incision size required by approximately 0.1 mm.


The effect of changes in afterload on Doppler echocardiographic indexes of left ventricular performance.
To investigate the influence of changes in afterload on Doppler echocardiographic determination of peak aortic blood velocity, mean acceleration, and systolic velocity integral, eight dogs with their chests opened were studied in four inotropic states at varying levels of heart rate and mean aortic blood pressure. Data were collected in the control state, at two different levels of dobutamine administration (5 and 10 micrograms/kg/min intravenously), and after administration of propranolol (0.5 mg/kg intravenously). In each inotropic state, phenylephrine was infused intravenously to produce at least two successive steady state increases of 10 mm Hg or more in mean aortic blood pressure. Within a given animal, peak velocity emerged as the Doppler index most closely correlated with changes in Qmax, dQ/dt, and dP/dt (r = 0.94, 0.91, and 0.89, respectively). Mean acceleration also correlated closely with the invasive indexes (r = 0.87, 0.89, and 0.89). The effect of changes in mean aortic blood pressure on Doppler index measurements was not statistically significant in any of the inotropic states and did not affect the closeness of their correlation with the invasive indexes. We conclude that Doppler echocardiographic measurements of aortic blood peak velocity and mean acceleration remained as sensitive to changes in the inotropic state under conditions of varying increases in afterload as did the conventional invasive indexes tested.


Introducing fluorescence guided surgery into orthopedic oncology: A systematic review of candidate protein targets for Ewing sarcoma.
Ewing sarcoma (ES), an aggressive bone and soft-tissue tumor, is treated with chemotherapy, radiotherapy, and surgery. Intra-operative distinction between healthy and tumorous tissue is of paramount importance but challenging, especially after chemotherapy and at complex anatomical locations. Near infrared (NIR) fluorescence-guided surgery (FGS) is able to facilitate the determination of tumor boundaries intra-operatively, improving complete resection and therefore survival. This review evaluates potential ES-specific proteins from the literature as targets for NIR FGS.


The impact of COVID-19 on oral squamous cell carcinoma's diagnostic stage-A retrospective study.
The COVID-19 pandemic has had an impact on patients' access to primary care services. A timely diagnosis of oral squamosa cell carcinoma is paramount. This study aims to quantify the pandemic's effect on tumor volume at the time of initial diagnosis. In a retrospective study, all primarily diagnosed cancer patients between March 2018 and March 2022 were compiled; the TNM stage and the tumor volume were evaluated. Tumor volumes were calculated using pathology or radiology reports. In total, 162 newly diagnosed tumor cases were included in this study. Of these, 76 (46.9%) cases were allocated in the "pre-COVID-19" group and 86 (53.1%) in the "COVID-19" group. Patients diagnosed during the "COVID-19" period showed a significantly advanced T stage (p < 0.001) and larger mean tumor volumes (53.16 ± 73.55 cm3 vs. 39.89 ± 102.42 cm3 ; p = 0.002) when compared to the control group. Tumor volume and T stage were significantly advanced in the "COVID-19" group when compared to prepandemic data. We hypothesize that the postponement of routine dental check-ups may explain this finding. Hence, dentists and primary care providers are encouraged to place particular emphasis on screening during routine check-ups.


It's time to choose the study design!: net benefit analysis of alternative study designs to acquire information for evaluation of health technologies.
Uncertainty in the decision-making process for reimbursement of health technologies could be reduced if additional information were available. Although methods to evaluate the monetary value of the uncertainty have been previously described, an economic evaluation of alternative methods to acquire additional information has not yet been thoroughly explored. Should resources be allocated to a retrospective study design or to a randomised controlled trial (RCT) when additional information is deemed justified? We propose an approach for cost-effectiveness analysis of designs of future studies that are required to evaluate health technologies for reimbursement. Biases inherent in study designs are the main factor that differentiates the ability of the studies to predict the technology's benefit. By quantifying this inherent-bias effect, the incremental effectiveness of future studies can be evaluated. Economic consequences of decisions regarding prioritization of the technologies, along with the expected costs incurred by the study's execution, account for the cost component of the equation. Deducting the result retrieved for the retrospective design from that of the RCT design gives the net information benefit.


Thioridazine interacts with the membrane of mitochondria acquiring antioxidant activity toward apoptosis--potentially implicated mechanisms.
We evaluated the effects of the phenothiazine derivative thioridazine on mechanisms of mitochondria potentially implicated in apoptosis, such as those involving reactive oxygen species (ROS) and cytochrome c release, as well as the involvement of drug interaction with mitochondrial membrane in these effects. Within the 0 - 100 microM range thioridazine did not reduce the free radical 1,1-diphenyl-2-picryl-hydrazyl (DPPH) nor did it chelate iron. However, at 10 microM thioridazine showed important antioxidant activity on mitochondria, characterized by inhibition of accumulation of mitochondria-generated O2*-, assayed as lucigenin-derived chemiluminescence, inhibition of Fe2+/citrate-mediated lipid peroxidation of the mitochondrial membrane (LPO), assayed as malondialdehyde generation, and inhibition of Ca2+/t-butyl hydroperoxide (t-BOOH)-induced mitochondrial permeability transition (MPT)/protein-thiol oxidation, assayed as mitochondrial swelling. Thioridazine respectively increased and decreased the fluorescence responses of mitochondria labelled with 1-aniline-8-naphthalene sulfonate (ANS) and 1-(4-trimethylammonium phenyl)-6 phenyl 1,3,5-hexatriene (TMA-DPH). The inhibition of LPO and MPT onset correlated well with the inhibition of cytochrome c release from mitochondria. We conclude that thioridazine interacts with the inner membrane of mitochondria, more likely close to its surface, acquiring antioxidant activity toward processes with potential implications in apoptosis such as O2*- accumulation, as well as LPO, MPT and associated release of cytochrome c.


Large airway constriction in allergic rhinitis: response to inhalation of helium-oxygen.
Pulmonary function results were compared in 15 allergic rhinitis and 30 normal subjects. Airways resistance (RAW) was higher (p less than 0.01) and specific conductance (SGAW) and lower (p less than 0.01) in the rhinitis group. Maximal expiratory flow (VeMax), lung volumes, and results of tests measuring airways closure, distribution of ventilation, diffusing capacity, volume of isoflow, and density-dependence of VeMax at 50% of vital capacity (deltaVeMax50) did not differ significantly between the two groups. Following inhalation of isoproterenol, RAW decreased and SGAW and VeMax increased significantly in both groups. On the other hand, delta-VeMax50 decreased significantly in the rhinitis group (p less than 0.01) and increased significantly in the control group (p less than 0.05). In addition to comparing pulmonary function in rhinitis patients and control subjects, physiologic measurements were also made on two separate occasions in the rhinitis subjects (minimal or no symptoms; very symptomatic). Although rhinitis symptomatology varied considerably (p less than 0.001), pulmonary function results were not significantly different. Hence we conclude that: (1) Rhinitis subjects have large airway constriction which does not vary with season or symptoms. (2) As in normal control subjects, airflow limitation occurs in the large airways of rhinitis subjects. (3) The predominant site of isoproterenol-associated bronchodilatation differs between allergic rhinitis and normal subjects.


Arginine administration decreases cerebral cortex acetylcholinesterase and serum butyrylcholinesterase probably by oxidative stress induction.
In the present study we investigated the action of vitamins E and C on the inhibition of acetylcholinesterase and butyrylcholinesterase activities provoked by arginine in cerebral cortex and serum of 60-day-old rats. Animals were pretreated for 1 week with daily intraperitoneal administration of saline (control) or vitamins E (40 mg/kg) and C (100 mg/kg). Twelve hours after the last injection, animals received one injection of arginine (0.8 microM/g of body weight) or saline. Results showed that acetylcholinesterase and butyrylcholinesterase activities were decreased in the arginine-treated rats. Furthermore, pretreatment with vitamins E and C prevented these effects. The data indicate that the reduction of acetylcholinesterase and butyrylcholinesterase activities caused by arginine was probably mediated by oxidative stress. Assuming the possibility that these effects might also occur in the human condition, our findings may be relevant to explain, at least in part, the neurological dysfunction associated with hyperargininemia and might support a novel therapeutic strategy to slow the progression of neurodegeneration in this disorder.


[Prokhor and Iakym Charukivs'ki brothers--physicians and scientists].
The authors have studied scientific and professional life of Prokhor and Yakim Charukovsky brothers, who were physicians and came from Poltava province.


NMDA-induced nitric oxide generation and CREB activation in central nervous system is dependent on eukaryotic elongation factor 2 kinase.
The NMDA receptor is crucial to several functions in CNS physiology and some of its effects are mediated by promoting nitric oxide production from L-arginine and activation of signaling pathways and the transcription factor CREB. Our previous work demonstrated in retinal cells that increasing intracellular free L-arginine levels directly correlates to nitric oxide (NO) generation and can be promoted by protein synthesis inhibition and increase of free L-arginine concentration. Eukaryotic elongation factor 2 kinase (eEF2K), a calcium/calmodulin-dependent kinase, is also known to be activated by NMDA receptors leading to protein synthesis inhibition. Here we explored how does eEF2K participate in NMDA-induced NO signaling. We found that when this enzyme is inhibited, NMDA loses its ability to promote NO synthesis. On the other hand, when NO synthesis is increased by protein synthesis inhibition with cycloheximide or addition of exogenous L-arginine, eEF2K has no participation, showcasing a specific link between this enzyme and NMDA-induced NO signaling. We have previously shown that inhibition of the canonical NO signaling pathway (guanylyl cyclase/cGMP/cGK) blocks CREB activation by glutamate in retinal cells. Interestingly, pharmacological inhibition of eEF2K fully prevents CREB activation by NMDA, once again demonstrating the importance of eEF2K in NMDA receptor signaling. In summary, we demonstrated here a new role for eEF2K, directly controlling NMDA-dependent nitrergic signaling and modulating L-arginine availability in neurons, which can potentially be a new target for the study of physiological and pathological processes involving NMDA receptors in the central nervous system.


DHOEM: a statistical simulation software for simulating new markers in real SNP marker data.
Numerous simulation tools based on specific assumptions have been proposed to simulate populations. Here we present a simulation tool named DHOEM (densification of haplotypes by loess regression and maximum likelihood) which is free from population assumptions and simulates new markers in real SNP marker data. The main objective of DHOEM is to generate a new population, which incorporates real and simulated SNP by statistical learning from an initial population, which match the realized features of the latter. To demonstrate DHOEM's abilities, we used a sample of 704 haplotypes for 12 chromosomes with 8336 SNP from a synthetic population, used for breeding upland rice in Latin America. The distributions of allele frequencies, pairwise SNP LD coefficients and data structures, before and after marker densification of the associated marker data set, were shown to be in relatively good agreement at moderate degrees of marker densification. DHOEM is a user-friendly tool that allows the user to specify the level of marker density desired, with a user defined minor allele frequency (MAF) limit, which is produced in a reasonable computation time. DHOEM is a user-friendly and useful tool for simulation and methodological studies in quantitative genetics and breeding.


Autoradiographic localization of angiotensin II receptor binding sites on noradrenergic neurons of the locus coeruleus of the rat.
The locus coeruleus (LC) of the rat was lesioned by microinjection of selective neurotoxins into the brainstem. 6-Hydroxydopamine (6-OHDA), 3 micrograms/microliter, given unilaterally at two sites 0.6 mm apart on the rostro-caudal axis of the LC, was used to lesion catecholamine-containing neuronal elements. Ibotenic acid, 2.5 micrograms/0.5 microliters, administered similarly was used to lesion nerve cell bodies. Two weeks after administration of the neurotoxin, lesion efficacy was determined based on the norepinephrine content of the cerebral cortex ipsi- and contralateral to the lesion. 6-OHDA lesions of the LC caused a 46% reduction in ipsilateral cortical norepinephrine and a 60% reduction in specific 125I-[Sar1, Ile8]-angiotensin II (125I-SIAII) binding in the LC. Ibotenic acid lesions of the LC caused a 73% reduction in ipsilateral cortical norepinephrine and a 81% reduction in specific 125I-SIAII binding in the LC. These results indicate that AII receptor binding sites in the LC are localized on noradrenergic nerve cell bodies or their dendritic and axonal ramifications within the LC.


Anoxia-reoxygenation-induced cytochrome c and cardiolipin release from rat brain mitochondria.
Rat brain mitochondria were successively submitted to anoxia and reoxygenation. The main mitochondrial functions were assessed at different reoxygenation times. Although the respiratory control ratio decreased, the activity for each one of the enzymes participating in the respiratory chain was not affected. However, during reoxygenation, mitochondrial membrane lipoperoxidation quickly increased and was proportional to the decrease seen in membrane fluidity. Under the same conditions, cytochrome c and cardiolipin were released from mitochondria and their rate of release increased with reoxygenation time. The release of cytochrome c and cardiolipin was followed by the collapse of the membrane potential and it was not inhibited by cyclosporin A. Addition of the antioxidant alpha-tocopherol abolished all these reoxygenation-induced changes. These data indicate that, in this model, reoxygenation promotes the uncoupling of respiratory chain, and cytochrome c and cardiolipin releases. These events are not related to the membrane potential collapse but to an oxidative stress.


Health care overbooking cost minimization model.
Challenges in the health care industry have confounded the provision of quality services for patients. Among many relevant concerns, the drive for cost-effectiveness and efficient care have placed considerable pressure on public health care systems and insurance coverage, amid existing barriers to restructuring entrenched systems. This study closely examines the factors impacting disruptions in health care scheduling systems using a structured case study in the health care industry. The study introduces a novel model to identify optimal overbooking capacity and minimize no-show costs. To address the complexity of this issue on a smaller scale, the model is implemented using a private hospital clinical platform in Jeddah, Saudi Arabia, instituting an overbooking reservation and queuing system in 14 departments to investigate the factors that influence disruptions and inefficacy of service provision, while also introducing a strategy for covering costs. The results identify the maximum amount of overbooking that can be made for each clinic. The cost-saving plan developed is expected to save each clinic a considerable sum, as opposed to randomly overbooking without any cost assumptions. Overall, if the clinics studied implemented this strategy, a total loss of no more than SAR. 2, 408 would be incurred from overbooking, in contrast to the exponentially growing amount of SAR. 10,000 that is currently lost on scheduling errors per year. The loss model developed has practical application as a tool for decision-making that includes no-show cost minimization variables.


Vascular basis of late-onset depressive disorder.
Growing evidence suggests that there may be a subtype of depression arising in later life that is characterised by a distinct clinical presentation and an association with cerebrovascular disease. This has been termed 'vascular depression'. To review the evidence for associations between cardiovascular disease and depression and between cerebrovascular disease and depression, and to examine implications for clinical practice and research. The authors reviewed the medical literature covering the past 5 years. There is strong evidence for an association between cardiovascular disease and depression, but this is not confined to older people. The causal pathway may be bi-directional. There is also a convergence of evidence suggesting a causal link between cerebrovascular disease and depression, especially that occurring later in life. The major focus has been on neuroradiological findings thought to be due to vascular disease, although the pathology may be heterogeneous. Although there are gaps in the evidence there is strong support for the concept of vascular depression, characterised by reduced depression ideation, subcortical neurological dysfunction, apathy and psychomotor change. This has implications for both treatment and prevention.


The impact of geography on hospital electronic health records implementation in alabama: implications for meaningful use.
Given relatively less favorable health outcomes in rural Alabama, electronic health records (EHRs) have an even greater potential to improve quality and alleviate disparities if meaningfully used. We examined rural-urban differences as it pertained to perceived barriers, benefits, and motivating factors of EHR implementation. We used multivariate logistic models to analyze data collected from a state-wide, self-completed survey of health information management directors in Alabama hospitals. Findings from our analyses indicate that fewer rural hospitals (8%) have implemented EHRs as compared with urban hospitals (18%). Rural hospitals were 71% less likely to consider reduction in costs as a benefit of EHRs (OR = 0.29), and were 75% less likely to consider lack of structured technology as a challenge factor of EHR implementation (OR = 0.25). Promotion of EHRs in rural areas is challenging but necessary. Understanding perceived barriers and motivating factors of EHR implementation among rural hospitals can inform policy decisions, especially in light of recent meaningful use initiatives.


Adult-Onset Epilepsy in Presymptomatic Alzheimer's Disease: A Retrospective Study.
The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumulation of brain damage. However, a significant proportion of patients experience seizures of unknown cause. Alzheimer's disease (AD) is associated with an increased risk of seizures. Seizure activity is interpreted as a secondary event related to hyperexcitability caused by amyloid-β aggregation. Since neurodegenerative processes begin several years before clinical symptoms, epilepsy could be more frequent in the presymptomatic stages of dementia. We retrospectively reviewed the prevalence of epilepsy of unknown origin with adult onset before cognitive decline in a large cohort of AD patients (EPS-AD) recruited based on clinical and neuropsychological data. Data of patients with epilepsy followed by AD were compared with two control groups: patients with AD without seizures (no EPS-AD) and a large reference population (RP). In AD patients, the prevalence of epilepsy of unknown origin, with onset in the adulthood before cognitive decline is 17.1 times higher compared with the RP (95% CI: 10.3-28.3). In EPS-AD, seizures begin on average 4.6 years (median 2.0) before the onset of cognitive symptoms and cognitive decline starts 3.6 years earlier compared with noEPS-AD. Neurodegenerative processes of dementia could play a key role in the pathogenesis of epilepsy in a subgroup of individuals intended to develop cognitive decline. Adult-onset epilepsy of undefined cause could thus represent a risk factor for the ongoing neurodegenerative damage, even preceding by years the onset of clinical symptoms of dementia.


Relationship between soluble MICA and the MICA A5.1 homozygous genotype in patients with oral squamous cell carcinoma.
NK and cytotoxic T cells play an important role in the elimination of virus-infected and tumor cells through NKG2D activating receptors, which can promote the lysis of target cells by binding to the major histocompatibility complex class I-related chain A (MICA) proteins. Polymorphisms in MICA may influence its binding to the NKG2D. The soluble form of MICA is released from the surface of tumor cells of epithelial origin. Whereas MICA expressed on the cell surface stimulates the immunoreceptor natural killer group 2, member D (NKG2D), the secreted form down-regulates NKG2D activity, thus allowing the tumor to escape immunosurveillance by NKG2D-expressing cells. In this study, we examined the association between MICA gene microsatellite polymorphisms and serum levels of soluble MICA in patients with oral squamous cell carcinoma (OSCC). We found that patients with OSCC were more likely to have the A5.1 allele when compared to healthy subjects and also more likely to be homozygous for this allele (p=0.041). Patients with the homozygous A5.1 genotype had higher levels of soluble MICA (p=0.031) and a lower survival rate (p=0.026).


Cholinesterases in development: AChE as a firewall to inhibit cell proliferation and support differentiation.
Acetylcholinesterase (AChE) is a most remarkable protein, not only because it is one of the fastest enzymes in nature, but also since it appears in many molecular forms and is regulated by elaborate genetic networks. AChE is expressed in many tissues during development and in mature organisms, as well as in healthy and diseased states. In search for alternative, "non-classical" functions of cholinesterases (ChEs), AChE could either work within the frame of classic cholinergic systems, but in non-neural tissues ("non-synaptic function"), or act non-enzymatically. Here, we review briefly some of the major ideas and advances of this field, and report on some recent progress from our own experimental work, e.g. that (i) non-neural ChEs have pronounced, predominantly enzymatic effects on early embryonic (limb) development in chick and mouse, that (ii) retinal R28 cells of the rat overexpressing synaptic AChE present a significantly decreased cell proliferation, and that (iii) in developing chick retina ACh-synthesizing and ACh-degrading cells originate from the same postmitotic precursor cells, which later form two locally opposing cell populations. We suggest that such distinct distributions of ChAT(+) vs. AChE(+) cells in the inner half retina provide graded distributions of ACh, which can direct cell differentiation and network formation. Thus, as corroborated by works from many labs, AChE can be considered a highly co-opting protein, which can combine enzymatic and non-enzymatic functions within one molecule.


Involvement of the Bcl2 gene family in the signaling and control of retinal ganglion cell death.
Retinal ganglion cell death by apoptosis is a well-established outcome in the glaucomatous pathology of the retina. Extensive research into the molecular events underlying this process show us that members of the Bcl2 gene family play a critical role in the activation and control of ganglion cell death. Perhaps the most critical molecule at play is the pro-apoptotic protein BAX. Without BAX, ganglion cell somas appear to survive an optic nerve insult indefinitely. Once BAX is activated, however, the cell death program reaches an irreversible point, where the process cannot be blocked. Interacting with BAX are other members of this larger gene family, including the anti-apoptotic protein BCL-X, and several members of the BH3-only proteins that serve as sensors and activators of the cell death program. A hypothetical model of how all these molecules interact in glaucoma is presented.


Renal Angiomyxolipoma: Its First Appearance!
Angiomyxolipoma is considered a very rare subtype of lipoma, with the latter being the most common type of mesenchymal neoplasm. Only 17 cases have been described in English medical literature. Angiomyxolipomas have been described in many locations, mostly in the subcutaneous tissue. In this report, we present the first case of renal angiomyxolipoma ever encountered. Diagnosis was made after many differential diagnoses had been ruled out. Subsequent management and follow-up are illustrated along with a discussion and review of literature.


Arteriovenous malformation of the ear optimized with cinematic rendering images: A case presentation and review of literature.
Arteriovenous malformations (AVMs) define rare aberrations in vascular morphogenesis. AVMs are typically present at birth, and unless they are stimulated to grow quickly by trauma, illness, or hormonal effects, they enlarge in proportion to an individual's growth. Clinical manifestations of AVMs are often linked to abnormal mass effects and blood perfusion. In this report, we describe a unique case of AVM of the left ear in a 24-year-old male, employing cinematic rendering along with a review of differential diagnosis and treatment options.


Patient-maintained propofol sedation: a follow up safety study using a modified system in volunteers.
Patient-maintained sedation is a mode of patient-controlled sedation during which propofol is administered using a target-controlled infusion, with patient demand increasing the target concentration. A system tested previously for safety in our institution resulted in oversedation. Aiming to improve safety, we modified the system by increasing the lockout period to 4 min,reducing the starting concentration to 0.5 microg x ml(-1) and the increments on demand to 0.1 microg x ml(-1). As in the previous study, healthy volunteers attempted to render themselves unconscious by frequently pressing the demand button. To assess effects on memory, volunteers were given keywords to remember every 15 min. The maximum target concentration reached varied between 1.0 and 2.5 microg x ml(-1). No volunteers lost consciousness, however, one volunteer had a brief period of apnoea and oxygen desaturation. The Cp50 for loss of memory for words was 1.26 microg x ml(-1). Although this version represents an improvement, we conclude that the system is not yet completely suitable for use without anaesthetic supervision.


Two promoters within the human LMO4 gene contribute to its overexpression in breast cancer cells.
LMO4, a member of the LIM-only family of zinc-finger proteins, is overexpressed in more than 50% of primary breast cancers and cell lines, implying a role in the pathogenesis of this cancer. Southern blot analysis of these cell lines did not reveal amplification or rearrangement of the LMO4 gene. To investigate further the mechanism underlying LMO4 overexpression and the generation of two patterns of transcripts, we isolated genomic clones spanning the human gene. Similar to the mouse Lmo4 gene, there are two 5' noncoding exons, exon 1a and exon 1b, which we show are differentially expressed in breast epithelial cells. This reflects differential promoter usage in combination with alternative splicing. Two promoter regions were defined, one upstream of exon 1a and the other upstream of exon 1b. Both promoters exhibited strong activity in breast cancer cells, with up to 400-fold activity above basal levels. These promoters were significantly more active in T-47D and MCF-7 cells relative to SKBR3 cells, consistent with RNA levels. Thus, overexpression of the LMO4 gene in breast cancer cells reflects increased promoter activity and appears to involve aberrant activation of the second promoter in a subset of these cells.


Effectiveness of Levoamlodipine Maleate for Hypertension Compared with Amlodipine Besylate: a Pragmatic Comparative Effectiveness Study.
Antihypertensive treatment is the most important method to reduce the risk of cardiovascular events in hypertensive patients. However, there is scant evidence of the benefits of levoamlodipine maleate for antihypertensive treatment using a head-to-head comparison in the real-world. This study aims to examine the effectiveness of levoamlodipine maleate used to treat outpatients with primary hypertension compared with amlodipine besylate in a real-world setting. This was a pragmatic comparative effectiveness study carried out at 110 centers across China in outpatients with primary hypertension treated with levoamlodipine maleate or amlodipine besylate, with 24 months of follow-up. The primary outcomes used for evaluating the effectiveness were composite major cardiovascular and cerebrovascular events (MACCE), adverse reactions, and cost-effectiveness. Among the included 10,031 patients, there were 482 MACCE, 223 (4.4%) in the levoamlodipine maleate group (n = 5018) and 259 (5.2%) in the amlodipine besylate group (n = 5013) (adjusted hazard ratio = 0.90, 95%CI: 0.75-1.08, P = 0.252). The levoamlodipine maleate group had lower overall incidences of any adverse reactions (6.0% vs. 8.4%, P < 0.001), lower extremity edema (1.1% vs. 3.0%, P < 0.001) and headache (0.7% vs. 1.1%, P = 0.045). There was a nearly 100% chance of the levoamlodipine maleate being cost-effective at a willingness to pay threshold of 150,000 Yuan per quality-adjusted life years (QALYs) gained, resulting in more QALYs (incremental QALYs: 0.00392) and cost savings (saving 2725 Yuan or 28.8% reduction in overall costs) per patient. In conclusion, levoamlodipine maleate could reduce cost by 29% with a similar MACCE incidence rate and lower occurrence of adverse reactions (especially edema and headache) compared with amlodipine besylate. Clinicaltrials.gov NCT01844570 registered at May 1, 2013.


Comprehensive panicle phenotyping reveals that qSrn7/FZP influences higher-order branching.
Rice grain number directly affects crop yield. Identifying alleles that improve panicle architecture would greatly aid the development of high-yield varieties. Here, we show that the quantitative trait locus qSrn7 contains rice FRIZZY PANICLE (FZP), a previously reported gene encoding an ERF transcription factor that promotes floral transition. Reduced expression of FZP in the reproductive stage increases the extent of higher order branching of the panicle, resulting in increased grain number. Genotype analysis of this gene in cultivars from the publicly available National Institute of Agrobiological Sciences (NIAS) Core Collection demonstrated that the extent of higher order branching, especially in the upper panicle, was increased in those cultivars carrying the FZP allele associated with qSrn7. Furthermore, chromosome segment substitution lines resulting from a cross between Koshihikari and Kasalath, the latter of which carries qSrn7/FZP, also showed that upper panicle higher order branching and grain yield were increased by qSrn7/FZP. Our findings indicate that qSrn7/FZP influences panicle branching pattern and is thus useful in the breeding of high-yield rice varieties.


Classification of LC columns based on the QSRR method and selectivity toward moclobemide and its metabolites.
This paper focuses on a comparative study of the column classification system based on the quantitative structure-retention relationships (QSRR method) and column performance in real biomedical analysis. The assay was carried out for the LC separation of moclobemide and its metabolites in human plasma, using a set of 24 stationary phases. The QSRR models established for the studied stationary phases were compared with the column test performance results under two chemometric techniques - the principal component analysis (PCA) and the hierarchical clustering analysis (HCA). The study confirmed that the stationary phase classes found closely related by the QSRR approach yielded comparable separation for moclobemide and its metabolites. Therefore, the QSRR method could be considered supportive in the selection of a suitable column for the biomedical analysis offering the selection of similar or dissimilar columns with a relatively higher certainty.


A system for counting endothelial cells from transparencies and negatives.
We have developed a system for endothelial cell density calculation and morphologic examination, which has proven to be convenient and reproducible, by using a currently available viewing unit, a few inexpensive materials, and simple arithmetic.


Cefuroxime-induced immune hemolysis.
Drug-induced immune hemolytic anemia (IHA) is rare but is being reported with increasing frequency. The most commonly cited cause of drug-induced IHA has been receipt of second and third generation cephalosporin antibiotics. We report the first case of IHA associated with cefuroxime administration.


Young men utilise limited neuromuscular preparation to regulate post-impact knee mechanics during step landing.
The neuromuscular mechanisms determining the mechanical behaviour of the knee during landing impact remain poorly understood. It was hypothesised that neuromuscular preparation is subject-specific and ranges along a continuum from passive to active. A group of healthy men (N=12) stepped-down from a knee-high platform for 60 consecutive trials. Surface EMG of the quadriceps and hamstrings was used to determine pre-impact onset timing, activation amplitude and cocontraction for each trial. Partial least squares regression was used to associate pre-impact preparation with post-impact knee stiffness and coordination. The group analysis revealed few significant changes in pre-impact preparation across trial blocks. Single-subject analyses revealed changes in muscle activity that varied in size and direction between individuals. Further, the association between pre-impact preparation and post-impact knee mechanics was subject-specific and ranged along a continuum of strategies. The findings suggest that neuromuscular preparation during step landing is subject-specific and its association to post-impact knee mechanics occurs along a continuum, ranging from passive to active control strategies. Further work should examine the implications of these strategies on the distribution of knee forces in vivo.


Effective Identification of Lynch Syndrome in Gastroenterology Practice.
Identification of Lynch syndrome is important from an individual patient and public health standpoint. As paradigms for Lynch syndrome diagnosis have shifted in recent years, this review will discuss rationale and limitations for current strategies as well as provide an overview of future directions in the field. In recent years, the use of clinical criteria and risk scores for identification of Lynch syndrome has been augmented by universal testing of all newly diagnosed colorectal cancers with molecular methods to screen for mismatch repair deficiency with high sensitivity and specificity. Studies of implementation and outcomes of universal testing in clinical practice have demonstrated significant heterogeneity that results in suboptimal uptake and contributes to disparities in diagnosis. Emerging technologies, such as next-generation sequencing, hold significant promise as a screening strategy for Lynch syndrome. Universal testing for Lynch syndrome is being performed with increasing frequency, although real-world outcomes have demonstrated room for improvement. Future directions in Lynch syndrome diagnosis will involve optimization of universal testing workflow and application of new genetics technologies.


Spermatozoa selection in discontinuous Percoll gradients for use in artificial insemination.
In a preliminary study of the ejaculate of 93 men, changes in motility and hypo-osmotic swelling before and after sperm separation by discontinuous Percoll gradients were evaluated. Both parameters improved significantly (P less than 0.01) in Percoll-separated spermatozoa. In a second stage, 99 couples underwent intrauterine insemination of separated semen by Percoll gradients. The population had infertility for a mean of 5.6 years. In a 1-year period, a total of 344 intrauterine insemination cycles were completed. Failure was considered when conception did not occur within four treatment cycles. The mean number of cycles per successful couple before pregnancy was 1.52. An overall 21% pregnancy rate was achieved (16% for oligoasthenospermia and 24% for asthenospermia). Sperm separation in Percoll gradients is a useful technique for intrauterine insemination in some cases of male subfertility.


Soft tissue coverage of the upper limb: A flap reconstruction overview.
Different opinions about the reconstructive choice for upper limb are described in literature: advancement or rotation flaps, regional flaps and free flaps are the most common reconstructive options. Local and regional flaps can be used to cover small defects while large wounds require the use of free flaps or distant pedicled flaps. The coverage of large wounds opens a discussion about when to use free flaps and when distant pedicled flaps. This review will describe the different methods used for the coverage of soft tissues injuries affecting hand and/or forearm (excluding fingers). The aim is to show all flap reconstructive options in order to support the inexperienced surgeon during the management of traumatic injuries of the upper limb.


Ethnic difference in inter-East Asian subjects with normal glucose tolerance and impaired glucose regulation: a systematic review and meta-analysis focusing on fasting serum insulin.
To investigate ethnic difference by focusing on fasting serum insulin (FSI) in inter-East Asian subjects with normal glucose tolerance (NGT) and impaired glucose regulation (IGR). Data sources included MEDLINE and EMBASE between 2001 and 2007. We conducted a search for articles containing mean or geometric mean values of FSI in East Asian subjects with NGT, IGR, or type 2 diabetes (T2DM). The Monte Carlo method was used for simulation of the mean and standard deviation of individual measures in each ethnic group; calculation of the median ratio and 95% confidence interval of individual measures between ethnic groups. Twenty-two articles fully met our pre-determined criteria and were included in the meta-analysis. Results of the meta-analysis revealed that FSI level is significantly lower in Japanese subjects with NGT, IGR, or T2DM than in Korean and Chinese subjects. Ethnic difference in FSI level between East Asians was observed in not only T2DM patients but also subjects with NGT or IGR. The lower FSI level in Japanese subjects was accompanied by lower triglyceride level. These results suggest that ethnic difference in dietary habit was one of the most influential factors for the ethnic difference in FSI.


Primary in vitro generation of cytotoxic cells specific for human minor histocompatibility antigens between HLA-identical siblings.
A limiting dilution culture system was developed for the primary in vitro detection of human minor histocompatibility antigens by cytotoxic T lymphocytes (CTL). CTL were generated in primary in vitro culture between two HLA-identical sibling pairs and propagated as stable CTL lines. Population and family studies indicate that these CTL lines recognize minor histocompatibility antigens in an HLA-restricted manner. The antigen recognized by one CTL line is detected on six (out of 37) HLA-B7-positive donors but not on 32 HLA-B7-negative donors. The cytotoxicity of this CTL line is mediated by T3+, T8+ effector cells. The antigen detected by this CTL population is different from all known human minor histocompatibility antigens. The data of this study, like those in the mouse system, suggest that a suppressor cell is diluted out in a limiting dilution culture, which allows the activation of the CTL precursors.


Older adults compensate for switch, but not mixing costs, relative to younger adults on an intrinsically cued task switching experiment.
Aging negatively impacts the ability to rapidly and successfully switch between two or more tasks that have different rules or objectives. However, previous work has shown that the context impacts the extent of this age-related impairment: while there is relative age-related invariance when participants must rapidly switch back and forth between two simple tasks (often called "switch costs"), age-related differences emerge when the contexts changes from one in which only one task must be performed to one in which multiple tasks must be performed, but a trial-level switch is not required (e.g., task repeat trials within dual task blocks, often called "mixing costs"). Here, we explored these two kinds of costs behaviorally, and also investigated the neural correlates of these effects. Seventy-one younger adults and 175 older adults completed a task-switching experiment while they underwent fMRI brain imaging. We investigated the impact of age on behavioral performance and neural activity considering two types of potential costs: switch costs (dual-task switch trials minus dual-task non-switch trials), and mixing costs (dual-task non-switch minus single-task trials). We replicated previous behavioral findings, with greater age associated with mixing, but not switch costs. Neurally, we found age-related compensatory activations for switch costs in the dorsal lateral prefrontal cortex, pars opercularis, superior temporal gyrus, and the posterior and anterior cingulate, but age-related under recruitment for mixing costs in fronto-parietal areas including the supramarginal gyrus and pre and supplemental motor areas. These results suggest an age-based dissociation between executive components that contribute to task switching.


Periodontal Microorganisms and Cardiovascular Risk Markers in Youth With Type 1 Diabetes and Without Diabetes.
A subset of periodontal microorganisms has been associated with cardiovascular disease (CVD), which is the leading complication of type 1 diabetes (t1DM). The authors therefore evaluated the association between periodontal microorganism groups and early markers of CVD in youth with t1DM. A cross-sectional analysis was conducted among youth aged 12 to 19 years at enrollment; 105 had t1DM for ≥5 years and were seeking care at the Barbara Davis Center, University of Colorado, from 2009 to 2011, and 71 did not have diabetes. Subgingival plaque samples were assessed for counts of 41 periodontal microorganisms using DNA-DNA hybridization. Microorganisms were classified using cluster analysis into four groups named red-orange, orange-green, blue/other, and yellow/other, modified from Socransky's color scheme for periodontal microorganisms. Subsamples (54 with t1DM and 48 without diabetes) also received a periodontal examination at the University of Colorado School of Dental Medicine. Participants were ≈15 years old on average, and 74% were white. Mean periodontal probing depth was 2 mm (SE 0.02), and 17% had bleeding on probing. In multivariable analyses, glycated hemoglobin (HbA1c) was inversely associated with the yellow/other cluster (microorganisms that are not associated with periodontal disease) among youth with t1DM. Blood pressure, triglycerides, low-density lipoprotein, high-density lipoprotein, and total cholesterol were not associated with microorganism clusters in this group. HbA1c was not associated with periodontal microorganism clusters among youth without diabetes. Among youth with t1DM who had good oral health, periodontal microorganisms were not associated with CVD risk factors.


The changes in adenine nucleotides measured in glucose-stimulated rodent islets occur in beta cells but not in alpha cells and are also observed in human islets.
Glucose metabolism by pancreatic beta and alpha cells is essential for stimulation of insulin secretion and inhibition of glucagon secretion. Studies using rodent islets have suggested that the ATP/ADP ratio serves as second messenger in beta cells. This study compared the effects of glucose on glucose oxidation ([U-14C]glucose) and adenine nucleotides (luminometric method) in purified rat alpha and beta cells. The rate of glucose oxidation at 1 mM glucose was higher in beta than alpha cells (4.5-fold, i.e. approximately 2-fold after normalization for cell size). It was more strongly stimulated by 10 mM glucose in beta cells (9-fold) than in alpha cells (5-fold). At 1 mM glucose, ATP levels were similar in both cell types, which corresponds to an approximately 2-fold higher concentration in alpha cells ( approximately 6.5 mM) than in beta cells ( approximately 3 mM). In beta cells, glucose dose-dependently increased ATP and decreased ADP levels, causing a rise in the ATP/ADP ratio from 2.4 to 11.6 at 1 and 10 mM, respectively. In alpha cells, glucose did not affect ATP and ADP levels, and the ATP/ADP ratio remained stable around 7.5. In human islets, the ATP/ADP ratio progressively increased between 1 and 10 mM glucose. In duct cells, which often contaminate human islet preparations, an increase in the ATP/ADP ratio sometimes occurred between 1 and 3 mM glucose. In conclusion, the present observations establish that the regulation of glucagon secretion by glucose does not involve changes in alpha cell adenine nucleotides and further support the role of the ATP/ADP ratio in the control of insulin secretion.


Pseudomonas aeruginosa Evolutionary Adaptation and Diversification in Cystic Fibrosis Chronic Lung Infections.
Pseudomonas aeruginosa populations undergo a characteristic evolutionary adaptation during chronic infection of the cystic fibrosis (CF) lung, including reduced production of virulence factors, transition to a biofilm-associated lifestyle, and evolution of high-level antibiotic resistance. Populations of P. aeruginosa in chronic CF lung infections typically exhibit high phenotypic diversity, including for clinically important traits such as antibiotic resistance and toxin production, and this diversity is dynamic over time, making accurate diagnosis and treatment challenging. Population genomics studies reveal extensive genetic diversity within patients, including for transmissible strains the coexistence of highly divergent lineages acquired by patient-to-patient transmission. The inherent spatial structure and spatial heterogeneity of selection in the CF lung appears to play a key role in driving P. aeruginosa diversification.


Derivatives of WAY 100635 as potential imaging agents for 5-HT1A receptors: syntheses, radiosyntheses, and in vitro and in vivo evaluation.
Analogues of the potent and selective 5-HT1A ligand, WAY 100635, were synthesized and examined as potential candidates for imaging 5-HT1A receptors by positron emission tomography (PET). Several of the analogues displayed nanomolar affinity for the 5-HT1A receptor, comparable to WAY 100635. Three of these were examined in a model of human liver metabolism vis-à-vis WAY 100635. All showed a markedly lower propensity for amide hydrolysis than WAY 100635. Radiolabelling of these three potential PET radiotracers with carbon-11 was readily achieved from [11C]-iodomethane, and the newly synthesized radioligands were tested in vivo in rats for binding to 5-HT1A receptors. Whereas two of the ligands failed to bind to 5-HT1A receptors in vivo, one was successful. The latter, [11C]-7 [4-(2'-methoxyphenyl)-1-[2'-[N-(2'-pyridinyl)-2-bicyclo[2.2.2]octanec arboxamido]ethyl]-piperazine], showed good brain penetration, hippocampal:cerebellar ratios of 10:1 at 45 min postinjection. Blocking studies with a variety of drugs demonstrated that the binding of [11C]-7 in vivo was selective for 5-HT1A receptors. [11C]-7 is a promising candidate as a ligand for imaging 5-HT1A receptors by PET.


Detection of specific IgE against linear epitopes from Gal d 1 has additional value in diagnosing hen's egg allergy in adults.
Although hen's egg allergy is more prevalent in children, up to 0.6% of adults from different European countries suffer from a persistent or newly onset hen's egg allergy, making accurate diagnosis in adults necessary. However, sensitization to hen's egg extracts, components and linear epitopes is solely studied in children. Hen's egg allergic (n = 16) and tolerant (n = 19) adults were selected by sensitization towards recombinant components rGal d 1 and/or 3. Sensitization profiles towards egg white and yolk extract and the native components Gal d 1, 2, 3 and 4 were respectively evaluated with the ImmunoCAP or the EUROLINE system. Characterization of linear epitopes was performed with a peptide microarray containing 15mer peptides representing the entire sequence of mature Gal d 1 and 3. Overall, sIgE titres against hen's egg extracts and single components overlapped largely between allergic and tolerant adults. Although the median sIgE/sIgG4 ratio to Gal d 1 was increased in allergic adults, the range was comparable between both groups. Clinically relevant sensitization to Gal d 1 was confirmed by sIgE-binding to the linear epitopes aa30-41, aa39-50 or aa84-95 in 6/13 allergic adults, mainly suffering from objective symptoms. In comparison, these epitopes were recognized by 1/15 tolerant patient. Only a few linear epitopes were detected for Gal d 3, suggesting a greater importance of conformational epitopes for the recognition of Gal d 3. Specific IgE-binding to linear epitopes of Gal d 1 is highly specific in identifying hen's egg allergic adults with objective symptoms.


Development of the AOSpine Patient Reported Outcome Spine Trauma (AOSpine PROST): a universal disease-specific outcome instrument for individuals with traumatic spinal column injury.
To report on the multi-phase process used in developing the AOSpine Patient Reported Outcome Spine Trauma (AOSpine PROST), as well as the results of its application in a pilot study. The International Classification of Functioning, Disability and Health (ICF) methodology was used as the basis for the development of this tool. Four preparatory studies and a consensus conference were performed, and resulted in the selection of 25 core ICF categories as well as the scale for use. The first draft of the Dutch version of AOSpine PROST was pilot tested among a consecutively selected representative sample of 25 spine trauma patients, using the 'think aloud' and 'probing' methods. Of the 25 core ICF categories, 9 related to body functions, 14 activities and participation, and 2 environmental factors. Those 25 core categories were implemented into the selected response scale, and resulted in a draft version of AOSpine PROST consisting of 19 items. From the pilot study, very satisfactory results were obtained for comprehensibility, relevance, acceptability, feasibility and completeness, as well as high internal consistency (Cronbach's α = 0.926). Following the ICF methodology and including the results of 4 different preparatory studies and a consensus conference, the AOSpine PROST is developed. Taking the results from the subsequent pilot study into account, a definite version to be further validated will be developed. The AOSpine PROST has the potential to be a helpful tool in clinical practice and research to compare various treatments and improve the quality of health care.


Design, Synthesis, and Antitumor Activity of a Series of Novel 4-(Aromatic Sulfonyl)-1-oxa-4-azaspiro[4.5]deca-6,9-dien-8-ones.
Many sulfonamides show anticancer activity. Based on benzenesulfonylazaspirodienone (HL-X9) identified in our previous work, we optimized the lead compound for better efficacy, thereby synthesizing a series of novel 4-(aromatic sulfonyl)-1-oxa-4-azaspiro[4.5]deca-6,9-dien-8-one derivatives through a key step of metal-catalyzed cascade cyclization. The preliminary antiproliferative tests have shown that the anticancer activities of acetyl-protected mannose-linked sulfonylazaspirodienone derivatives (7i-7l) have been greatly improved. Among them, 7j is the most potent derivative, with IC50 values of 0.17 µM, 0.05 µM, and 0.07 µM for A549, MDA-MB-231, and HeLa cell lines, respectively. Flow cytometry analysis shows that 7j arrests MDA-MB-231 cells in the G2/M phase and has a certain effect on the apoptosis of MDA-MB-231 cells. In addition, the acute toxicity of 7j was lower than that of adriamycin.


Structure-based assessment and druggability classification of protein-protein interaction sites.
The featureless interface formed by protein-protein interactions (PPIs) is notorious for being considered a difficult and poorly druggable target. However, recent advances have shown PPIs to be druggable, with the discovery of potent inhibitors and stabilizers, some of which are currently being clinically tested and approved for medical use. In this study, we assess the druggability of 12 commonly targeted PPIs using the computational tool, SiteMap. After evaluating 320 crystal structures, we find that the PPI binding sites have a wide range of druggability scores. This can be attributed to the unique structural and physiochemical features that influence their ligand binding and concomitantly, their druggability predictions. We then use these features to propose a specific classification system suitable for assessing PPI targets based on their druggability scores and measured binding-affinity. Interestingly, this system was able to distinguish between different PPIs and correctly categorize them into four classes (i.e. very druggable, druggable, moderately druggable, and difficult). We also studied the effects of protein flexibility on the computed druggability scores and found that protein conformational changes accompanying ligand binding in ligand-bound structures result in higher protein druggability scores due to more favorable structural features. Finally, the drug-likeness of many published PPI inhibitors was studied where it was found that the vast majority of the 221 ligands considered here, including orally tested/marketed drugs, violate the currently acceptable limits of compound size and hydrophobicity parameters. This outcome, combined with the lack of correlation observed between druggability and drug-likeness, reinforces the need to redefine drug-likeness for PPI drugs. This work proposes a PPI-specific classification scheme that will assist researchers in assessing the druggability and identifying inhibitors of the PPI interface.


Determining the consequences of maternal obesity for offspring health.
What is the topic of this review? Observational studies have highlighted the association of increasing maternal body mass index with offspring adiposity and the subsequent risk of cardiometabolic disorders in adulthood. The in utero environment has become a target for intervention in order to reduce the burden of obesity, despite the mechanistic pathways of this association remaining unclear. What advances does it highlight? This short review provides a critical appraisal of the recent literature, including biological pathways and strategies to address causal relationships. The global obesity epidemic has been causally linked to changes in diet and lifestyle. Observational data and animal studies have now highlighted associations between in utero environmental exposures and increased susceptibility to obesity and related cardiometabolic disorders in later life. Maternal body mass index has been reported to show an independent association with offspring adiposity from an early age and to play an important role in the predisposition to obesity and metabolic disease in later life. Thus, the in utero environment has been the focus of recent targeted interventions to improve public health. In this review, we summarize recent progress in this field, including the use of animal models to investigate mechanistic links between maternal obesity and offspring metabolic risk. We then assess the level of evidence and challenges in establishing causal inferences from present birth cohorts.


Generation of retinal cells in the wallaby, Setonix brachyurus (quokka).
We have examined the generation of retinal cells in the wallaby, Setonix brachyurus (quokka). Animals received a single injection of tritiated thymidine between postnatal days 1-85 and retinae were examined at postnatal day 100. Retinae were sectioned, processed for autoradiography and stained with Cresyl Violet. Ganglion cells were labelled by injection of horseradish peroxidase into the optic tracts and primary visual centres. Other cells were classified according to their morphology and location. Retinal cell generation takes place in two phases. During the first phase, which concludes by postnatal day 30, cells destined to lie in all three cellular layers of the retina are produced. In the second phase, which starts by postnatal day 50, cell generation is almost entirely restricted to the inner and outer nuclear layers. Cells produced in the first phase are orthotopic and displaced ganglion cells, displaced and orthotopic amacrine cells, horizontal cells and cones. Glia in the ganglion cell layer, orthotopic amacrine cells, bipolar and horizontal cells. Muller glia, and rods are generated in the second phase. Cells became heavily labelled with tritiated thymidine in the central retina before postnatal day 7, over the entire retina (panretinal) by postnatal day 7 and from postnatal day 18, only in the periphery. The second phase of cell generation is initiated at P50, in a region extending from the optic nerve head to mid-temporal retina. Subsequently, cells are generated in annuli, centred on mid-temporal retina, which are seen at progressively more peripheral locations. Therefore, cell addition to the inner and outer nuclear layers continues for longer in peripheral than in mid-temporal retina. We suggest that such later differential cell addition to the inner and outer nuclear layers contributes to an asymmetric increase in retinal area. This non-uniform growth presumably results in more expansion of the ganglion cell layer peripherally than in mid-temporal retina and may play a role in establishing density gradients of ganglion cells.


Preformulation Studies to Guide the Production of Medicines by Fused Deposition Modeling 3D Printing.
Fused deposition modeling (FDM) 3D printing has demonstrated high potential for the production of personalized medicines. However, the heating at high temperatures inherent to this process causes unknown risks to the drug product's stability. The present study aimed to assess the use of a tailored preformulation protocol involving physicochemical assessments, including the rheological profiles of the samples, to guide the development of medicines by FDM 3D printing. For this, polymers commonly used in FDM printing, i.e., high impact polystyrene (HIPS), polylactic acid (PLA), and polyvinyl alcohol (PVA), and their common plasticizers (mineral oil, triethyl citrate, and glycerol, respectively) were evaluated using the thermolabile model drug isoniazid (INH). Samples were analyzed by chemical and physical assays. The results showed that although the drug could produce polymorphs under thermal processing, the polymeric matrix can be a protective element, and no polymorphic transformation was observed. However, incompatibilities between materials might impact their chemical, thermal, and rheological performances. In fact, ternary mixtures of INH, PLA, and TEC showed a major alteration in their viscoelastic behavior besides the chemical changes. On the other hand, the use of plasticizers for HIPS and PVA exhibited positive consequences in drug solubility and rheologic behavior, probably improving sample printability. Thus, the optimization of the FDM 3D printing based on preformulation studies can assist the choice of compatible components and seek suitable processing conditions to obtain pharmaceutical products.


Terrorism-related trauma in Africa, an increasing problem.
Global terrorist activities have increased significantly over the past decade. The impact of terrorism-related trauma on the health of individuals in low- and middle-income countries is under-reported. Trauma management in African countries in particular is uncoordinated, with little or no infrastructure to cater for emergency surgical needs. This article highlights the need for education, training and research to mitigate the problems related to terrorism and surgical public health.


Application of new techniques for the detection of carcinogen adducts to human population monitoring.
Several techniques have recently been developed for the detection and quantitation of carcinogen-DNA or -protein adducts without the requirement for radioactive carcinogens. These assays can be used to detect adducts in animals or cultured cells exposed to test compounds or in humans exposed to environmental carcinogens. Immunologic, 32P-postlabeling and fluorescence techniques, used on human samples for DNA adduct measurement, are reviewed here. Methods for the detection of carcinogen-protein adducts on human samples are also summarized.


Parent-Implemented Interventions via Telepractice in Autism Research: A Review of Social Validity Assessments.
Parent-implemented autism interventions are considered empirically validated interventions and the use of telepractice in these interventions is reported as effective. However, little is known about the social validity assessments and outcomes of these interventions. The purpose of this review is to explore the current practices of conducting social validity assessment and reporting its outcomes within parent-implemented telepractice autism interventions. The 11 reviewed studies included caregivers as participants, telepractice intervention focusing on social communication outcomes of young autistic children, and were published in a peer-reviewed journal within the past five years. The researchers in the reviewed articles reported positive outcomes for parent-implemented telepractice autism interventions. Notably, however, information about social validity assessments of the interventions was limited. Researchers are encouraged to evaluate the social validity of interventions using multiple data sources and methods, and report on their findings as they relate to other types of data.


Relationship between lifestyle habits and cardiovascular risk factors in familial hypercholesterolemia.
Little is known about the cardioprotective potential of a healthy lifestyle in familial hypercholesterolemia (FH). The objective of this study was to evaluate the relationship between lifestyle and cardiovascular risk factors in adults with FH. This cross-sectional study leveraged data from the CARTaGENE Quebec population-based cohort (Canada). Participants with FH were identified using the validated Simplified Canadian Definition for FH. A healthy lifestyle score (HLS), ranging from 0 to 5, was calculated per adherence to 5 lifestyle habits: 1) not smoking; 2) being physically active (≥150 min/week of moderate or vigorous physical activity); 3) eating a healthy diet (Alternate Healthy Eating Index ≥50%); 4) having a light to moderate alcohol consumption (men: 1-30 g/day; women: 1-15 g/day); and 5) sleeping 7-8 h/day. Among the 122 included individuals (women, n = 78; men, n = 44; mean age ± SD: 57.3 ± 6.7 years), 92 (75.4%) had a HLS ≤3/5, while only 5 (4.1%) had a HLS of 5/5. After adjustments for sex, age, body mass index, and lipid-lowering medication use, we found no evidence of an association between the HLS and concentrations of LDL-cholesterol (β = 0.04, 95% CI = -0.08, 0.15 mmol/L; P = 0.54). However, the HLS was favorably associated with HbA1c levels (β = -0.07, 95% CI = -0.13, -0.01%; P = 0.02), and statistical trends suggested favorable associations with HDL-cholesterol (β = 0.06, 95% CI = -0.02, 0.14 mmol/L; P = 0.06) and waist circumference (β = -2.22, 95% CI = -4.62, 0.17 cm; P = 0.07). This study suggests that a healthy lifestyle is favorably associated with CVD risk factors in adults with FH.


Binding of thyrotropin to selected Mycoplasma species: detection of serum antibodies against a specific Mycoplasma membrane antigen in patients with autoimmune thyroid disease.
Radiolabeled human (hTSH) and bovine (bTSH) thyroid stimulating hormone was shown to bind to five species of Mycoplasma, the wall-less prokaryotes. The maximum binding capacity of 125I-bTSH to these five species was about 7.9 x 10(-13) moles-1.4 x 10(-12) moles for 50-100 micrograms protein with dissociation constants of approximately 1.7 to 2.2 x 10(-7)M. Approximately 50% of the 125I-bTSH binding was displaced by excess, unlabeled bTSH or hTSH, but labeled bTSH was not effectively displaced by growth hormone, LH, FSH, prolactin, or the beta subunit of hTSH, FSH and LH. Antisera prepared against Mycoplasma gallisepticum and Mycoplasma pneumoniae bound to human thyroid membranes and guinea pig fat cells, suggesting that receptors on human thyroid tissues and on Mycoplasma cells may have similarities in antigenicity. These findings were substantiated by the occurrence of TSH binding to Mycoplasma antisera. Further, sera from three of six patients with Graves' disease containing antibodies to thyroid tissues also reacted to a 108 Kd polypeptide of Mycoplasma gallisepticum.


Preparation of 57Co point sources for the performance evaluation of nuclear imaging instruments.
This paper describes the utility of electrodeposition method to prepare (57)Co point sources. A description of the electrolytic cell, the process of (57)Co electrodeposition, encapsulation and quality control of the sealed (57)Co sources is presented. Sources containing ~3.7-4.81 MBq (0.10-0.13 mCi) of (57)Co were prepared, encapsulated in miniature titanium capsules and subjected to quality control tests to ensure compliance with regulatory requirements. The encapsulated (57)Co sources prepared by the reported procedure were found to be effective in routine performance evaluation of nuclear medicine instruments.


Fate of 15N-labelled urea as affected by long-term manure substitution.
Quantifying the fate of fertilizer nitrogen (N) is essential to develop more sustainable agricultural fertilization practices. However, the fate of chemical fertilizer N, particularly in long-term manure substitution treatment regimes, is not fully understood. The present study aimed to investigate the fate of 15N-labelled urea in a chemical fertilizer treatment (CF, 240 kg 15N ha-1) and N manure 50 % substitution treatment (1/2N + M, 120 kg 15N ha-1 + 120 kg manure N ha-1) in two continuous crop seasons, based on a 10-year long-term experiment in the North China Plain (NCP). The results showed that manure substitution greatly enhanced 15N use efficiency (15NUE) (39.9 % vs. 31.3 %) and suppressed 15N loss (6.9 % vs. 7.5 %) compared with the CF treatment in the first crop. However, the N2O emissions factor in the 1/2N + M treatment was increased by 0.1 % (0.5 kg 15N ha-1 for CF vs. 0.4 kg 15N ha-1 for 1/2N + M) compared with the CF treatment, although N leaching and NH3 volatilization rates decreased by 0.2 % (10.8 kg 15N ha-1 for CF vs. 5.1 kg 15N ha-1 for 1/2N + M) and 0.5 % (6.6 kg 15N ha-1 for CF vs. 2.8 kg 15N ha-1 for 1/2N + M), respectively. In which, only NH3 volatilization presented significantly difference between treatments. It is important to note that in the second crop, the residual 15N in soil (0-20 cm) remained mostly in the soil for the CF (79.1 %) and the 1/2N + M treatment (85.3 %), and contributed less to crop N uptake (3.3 % vs. 0.8 %) and leached losses (2.2 % vs. 0.6 %). This proved that manure substitution could enhance the stabilization of chemical N. These results suggested that long-term manure substitution effectively increases NUE, suppresses N loss, and improves N stabilization in soil, but negative impacts such as N2O emissions due to climate change should be investigated further.


The Assessment of Cytotoxicity, Apoptosis Inducing Activity and Molecular Docking of a new Ciprofloxacin Derivative in Human Leukemic Cells.
The fluoroquinolone class of antibiotics includes derivatives of the drug ciprofloxacin. These substances have recently been advocated for the treatment of cancer. In the current study, we examined the cytotoxicity and apoptosis-inducing potential of a novel synthetic ciprofloxacin derivative in the human myeloid leukemia KG1-a cell line. With an IC50 of 25µM, this ciprofloxacin derivative, 7-(4-(2-(benzhydryloxy)-2-oxoethyl) piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4 dihydroquinoline-3- carboxylic acid (4-BHPCP), was an active drug. Through Hoechst 33,258 staining and Annexin V/PI double staining experiments, the apoptotic activity of the 4-BHPCP was assessed morphologically. Real-time quantitative PCR was used to assess changes in the expression level of certain apoptosis-related genes, including Bcl-2, Bax, and Survivin (qRT PCR). The results of the qRT PCR analysis demonstrated that 4-BHPCP promotes apoptosis in the KG1-a cell line by down-regulating Survivin and Bcl2, up-regulating Bax, and increasing the Bax/Bcl2 transcripts in a time-dependent manner. These results imply that this novel chemical may be a promising therapy option for acute myeloid leukemia.


[Effect of stimulation of the sensomotor cortex on the activity of the lumbar motor center in rats during ontogenesis].
In rats ageing up to 3 weeks, studies have been made on the reactions of the spinal motor center to long-lasting rhythmic stimulation of sensorimotor cortex. It was found that in 5-day old rats specific periodic pattern of the activity may be recorded similar to the autorhythmic spontaneous activity described in our earlier papers. In older animals periodic pattern of reaction can also be observed, but it may be modulated by stimulation. Beginning from the 12th day, periodic pattern of reaction is transformed into aperiodic one typical for adult animals. From the 3rd week of life, the inhibitory effect of motor cortex stimulation on locomotor activity could be observed.


Reversion of temperature sensitive transformation mutants of Rous sarcoma virus and its effect on the expression of tumour specific surface antigen.
Rous sarcoma virus (RSV) mutants, which bear temperature sensitive (ts) defects in both the maintenance of cell transformation and the expression of tumour specific cell surface antigen(s) (TSSA), have yielded a number of revertants. In seven revertants studied, the acquisition of wild type transforming capacities is always accompanied by a wild type TSSA expression. This strongly indicates that transformation and TSSA expression in RSV are affected by the same mutation.


Improved quantitative LC-MS/MS analysis of vitamin D metabolites in serum after one-pot double derivatization.
In this study, we report a one-pot double derivatization scheme, which used acetylation after a Diels-Alder reaction using 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) to improve separation efficiency and provide baseline separations of the five vitamin D metabolites 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), 3β-25-hydroxyvitamin D3 (3β-25(OH)D3), 3α-25-hydroxyvitamin D3 (3α-25(OH)D3) and vitamin D3 on a C-18 stationary phase. Vitamin D metabolites are often very challenging to measure quantitatively using mass spectrometry, due to their low serum concentration levels and low ionization efficiencies. Moreover, some of these species are isomers with virtually identical mass spectral dissociation behavior. To overcome the low ionization efficiency and unspecific fragmentation behavior, derivatization using Diels-Alder reactions with Cookson-type reagents such as PTAD are common. These derivatization reactions generally result in more complicated liquid chromatography separations, because both 6R- and 6S-isomers are formed during Diels-Alder reactions. It has been shown that separations have been particularly challenging for the 3α-25(OH)D3 and 3β-25(OH)D3 epimers. Here, we optimized the PTAD derivatization and the esterification using acetic anhydride. By utilizing the esterification catalyst 4-dimethylaminopyridine, we avoided quenching and evaporation between the two derivatization steps, but were also able to perform the esterification at room temperature without heating. The optimized one-pot double derivatization LC-MS/MS assay was validated with respect to inter/intra-day precision, accuracy, recovery and linear dynamic range and applied to metabolic fingerprinting of vitamin D3 metabolites in serum samples. The metabolites 3α-25(OH)D3, 3β-25(OH)D3 and 24,25(OH)2D3, were readily quantified in all investigated samples. The method was, in principle, also fit for purpose for quantification of the native vitamin D3 species; the relatively high blank concentration of the commercial vitamin D-depleted serum used for calibration, however, limited the limits of quantification for this metabolite. The method provided insufficient limits of quantification for serum levels of 1,25(OH)2D3.


Neurocysticercosis-related seizures in the post-partum period: two cases and a review of the literature.
Neurocysticercosis, the infection of the CNS with larval cysts of Taenia solium, is a leading cause of seizures in low-income countries. The clinical presentation of neurocysticercosis is variable and depends on the number, size, and location of cysticerci, and on the immune response of the host. In most patients, the affected site is the brain parenchyma, where cysts can precipitate seizures. Neurocysticercosis has seldom been described in pregnant women. In this Grand Round, we report two cases of pregnant women who immigrated to Italy from Bolivia and Ecuador, and who developed seizures in the early post-partum period, due to calcified parenchymal neurocysticercosis lesions. We discuss the complex interactions between neurocysticercosis and the immune system in pregnancy and the post-partum period. Building on this scenario, we propose practices for the management of neurocysticercosis in pregnancy and the post-partum period, highlighting important gaps in the literature that should be addressed.


Electron microscopical demonstration of nucleic acids in virus-like particles in the skeletal muscle of a traffic accident victim.
Picornavirus-like crystalline arrays were found in the skeletal muscle of a victim of a traffic accident. Individual particles measured approximately 22 nm in diameter and were arrayed in a hexagonal or triangular pattern. Cis-platinum (II) staining of these virus-like particles showed that these particles were not glycogen but contained nucleic acids, and the staining according to Bernhard also showed these particles contained RNA. Through the combination of the methods of Heinen (1977) and Bernhard (1969), we can confirm that virus-like crystalline structures found electron microscopically contain nucleic acids and possibly represent virions.


Role of prostaglandin deficiency in pathogenetic mechanism of gastric lesions induced by indomethacin in rats.
The present study was undertaken in rats using 2-deoxy-D-glucose (2DG) as a stimulator of gastric motility and a low dose of indomethacin as a prostaglandin (PG) synthesis inhibitor to investigate the roles of gastric motility and PG deficiency in the pathogenesis of indomethacin-induced gastric lesions. Subcutaneously administered indomethacin at 5 mg/kg did not induce any visible damage in the mucosa within 4 hr, but at 25 mg/kg produced linear hemorrhagic lesions along the long axis of the stomach. 2DG (100 mg/kg/hr), given intravenously, produced linear nonhemorrhagic lesions along the mucosal folds and, in the presence of 5 mg/kg of indomethacin, caused severe hemorrhagic lesions in the same areas of the stomach. Gastric motility was markedly enhanced by both indomethacin (25 mg/kg) and 2DG, while acid output and mucosal blood flow were increased only by the latter. Mucosal PGE2 levels were significantly reduced by indomethacin (25 mg/kg) but not by 2DG. Indomethacin at 5 mg/kg alone had no or little effect on any parameter except PG levels, which were reduced to similar degrees as caused by 25 mg/kg of the agent. Time-course development of the lesions was closely associated with those changes in gastric motility after administration of indomethacin (25 mg/kg) and 2DG. These results suggest that the enhanced gastric motility is, by itself, sufficient to induce damage (nonhemorrhagic) in the mucosa and that a PG deficiency alone does not induce any damage but is required for further extension to hemorrhagic lesions of nonhemorrhagic ones that are initially induced by enhanced gastric motility.(ABSTRACT TRUNCATED AT 250 WORDS)


"Designer drugs"--a current perspective.
Since the late 1970s, in an effort to quench the ever burgeoning appetite for pharmacological substances of abuse and to satiate their own need for profit, unscrupulous chemists have set up clandestine laboratories to produce and market new drugs for street sale. Using fairly common industrial chemicals, they have altered or modified preexisting controlled substances such as fentanyl, meperidine, mescaline, amphetamine, and phencyclidine, producing derivatives of these parent compounds that, up until 1986, were able to temporarily elude the guidelines of the Federal Controlled Substances Act due to their new and unique chemical structures. Unsuspecting users continue to use the drugs recreationally. This article will present a comprehensive review of these "Designer Drugs" looking at historical data, pharmacokinetics, treatment, abuse trends, and some of the more recent additions to the social pharmacopoeia.


Post traumatic growth among military enroute care nurses: A secondary analysis.
To date, little is known about the experience of military nurses and post traumatic growth (PTG). An analysis focusing on PTG was performed using data from the surveys and qualitative interviews of military enroute care nurses. In a mixed methods study designed to understand behavioral health symptoms experienced by military enroute care nurses, the qualitative data confirmed the experiences of nurses found in the quantitative data regarding the presence of PTG. Although the mean PTG total score was low in the quantitative findings, the qualitative data supported the presence of important factors comprising PTG. More research is needed to determine the experience of PTG among nurses.


Neurochemical bases of plasticity in the magnocellular oxytocin system during gestation.
The central and systemic release of oxytocin (OT) has been well documented during parturition and lactation. In preparation for the demands of these events, the magnocellular hypothalamic neurons of the central OT system undergo a variety of biochemical, molecular, electrophysiological, and anatomical adaptations during gestation. However, the mechanisms responsible for these changes have not been well established. A number of neurochemical mediators have been implicated in contributing to the plasticity in the OT magnocellular system during gestation, including ovarian hormones, as well as central neurotransmitters, such as glutamate, gamma-amino butyric acid (GABA), and central neurosteroids, e.g., allopregnanolone. In addition, several lines of evidence suggest that central OT release and subsequent OT receptor stimulation may contribute to adaptations of the OT system during gestation, and may be necessary for its subsequent functioning during lactation. Here, we review evidence for involvement of the neurochemical systems implicated in contributing to adaptations that occur in the OT system during the course of gestation.


INSOMNet: Automated insomnia detection using scalogram and deep neural networks with ECG signals.
Sleep is a natural state of rest for the body and mind. It is essential for a human's physical and mental health because it helps the body restore itself. Insomnia is a sleep disorder that causes difficulty falling asleep or staying asleep and can lead to several health problems. Conventional sleep monitoring and insomnia detection systems are expensive, laborious, and time-consuming. This is the first study that integrates an electrocardiogram (ECG) scalogram with a convolutional neural network (CNN) to develop a model for the accurate measurement of the quality of sleep in identifying insomnia. Continuous wavelet transform has been employed to convert 1-D time-domain ECG signals into 2-D scalograms. Obtained scalograms are fed to AlexNet, MobileNetV2, VGG16, and newly developed CNN for automated detection of insomnia. The proposed INSOMNet system is validated on the cyclic alternating pattern (CAP) and sleep disorder research center (SDRC) datasets. Six performance measures, accuracy (ACC), false omission rate (FOR), sensitivity (SEN), false discovery rate (FDR), specificity (SPE), and threat score (TS), have been calculated to evaluate the developed model. Our developed system attained the classifications ACC of 98.91%, 98.68%, FOR of 1.5, 0.66, SEN of 98.94%, 99.31%, FDR of 0.80, 2.00, SPE of 98.87%, 98.08%, and TS 0.98, 0.97 on CAP and SDRC datasets, respectively. The developed model is less complex and more accurate than transfer-learning networks. The prototype is ready to be tested with a huge dataset from diverse centers.


Fluorescently labeled therapeutic antibodies for detection of microscopic melanoma.
Detection of microscopic disease during surgical resection of melanoma remains a significant challenge. To assess real-time optical imaging for visualization of microscopic cancer, we evaluated three US Food and Drug Administration (FDA)-approved therapeutic monoclonal antibodies. Prospective, basic science. Melanoma cell lines (A375 and SKMEL5) were xenografted into the ears of immunodeficient mice. Bevacizumab, panitumumab, tocilizumab, or a nonspecific immunoglobin G (IgG) were covalently linked to a near-infrared (NIR) fluorescent probe (IRDye800CW) and systemically injected. Primary tumors were imaged and then resected under fluorescent guidance using the SPY (Novadaq, Toronto, Ontario, Canada), an NIR imaging system used in plastic and reconstructive surgeries to evaluate perfusion. Mice were also imaged with the Pearl Impulse small animal imager (LI-COR Biosciences, Lincoln, NE), an NIR imaging system designed for use with IRDye800CW. Postresection, small tissue fragments were fluorescently imaged and the presence of tumor subsequently confirmed by correlation with histology. All fluorescently labeled therapeutic monoclonal antibodies could adequately delineate tumor from normal tissue based on tumor-to-background ratios (TBR) compared to IgG-IRDye800CW. On serial imaging, panitumumab achieved the highest TBRs with both SPY and Pearl (3.8 and 6.6, respectively). When used to guide resections, the antibody-dye conjugates generated TBRs in the range of 1.3 to 2.2 (average, 1.6) using the SPY and 1.9 to 6.3 (average, 2.7) using the Pearl. There was no significant difference among the antibodies with either imaging modality or cell line (one-way analysis of variance). Our data suggest that FDA-approved antibodies may be suitable targeting agents for the intraoperative fluorescent detection of melanoma.


Functional roles of conserved amino acid residues surrounding the phosphorylatable histidine of the yeast phosphorelay protein YPD1.
The histidine-containing phosphotransfer (HPt) protein YPD1 is an osmoregulatory protein in yeast that facilitates phosphoryl transfer between the two response regulator domains associated with SLN1 and SSK1. Based on the crystal structure of YPD1 and the sequence alignment of YPD1 with other HPt domains, we site-specifically engineered and purified several YPD1 mutants in order to examine the role of conserved residues surrounding the phosphorylatable histidine (H64). Substitution of the positively charged residues K67 and R90 destabilized the phospho-imidazole linkage, whereas substitution of G68 apparently reduces accessibility of H64. These findings, together with the effect of other mutations, provide biochemical support of the proposed functional roles of conserved amino acid residues of HPt domains.


Disinfection of hands and tubing of CAPD patients.
During a 3 month study the effectiveness of two methods of handwashing was assessed in a group of 31 patients undergoing continuous ambulatory peritoneal dialysis. A defined, double rinse with alcohol, prior to bag exchange, was found to be more convenient and significantly more effective than povidone-iodine alone or povidone-iodine followed by alcohol. Spraying the tubing around the bag connector with 70 per cent ethanol reduced the numbers of adherent skin organisms so reducing the likelihood of bacteria being drawn into the dialysate. Although there was no difference in the overall incidence of peritonitis in the two groups of patients studied, there was an unexpected drop in the incidence of peritonitis caused by coagulase-negative skin staphylococci. This was attributed to an overall awareness of the importance of handwashing and aseptic procedures during bag exchange. Monitoring the bacteriology of the catheter exit site may give some prior indication as to the likelihood of subsequent peritonitis especially with Staphylococcus aureus and Gram-negative bacilli.


An evaluation of hepatobiliary scintigraphy with 99mTc-pyridoxylideneisoleucine.
From our experience with 30 cases, we conclude that 99mTc-PI is useful for assessment of hepatobiliary diseases and is much preferable to the 131I-labeled compounds.


Brain tryptophan metabolism on the 5-hydroxytryptamine and kynurenine pathways in a strain of rats with a deficiency in platelet 5-HT.
1 Brain 5-hydroxytryptamine (5-HT) metabolism has been compared in albino (Sprague-Dawley; SD) and in Fawn-Hooded (FH) rats, which have an inherited platelet 5-HT deficiency. 2 It was confirmed that blood 5-HT levels in the FH rats were about one quarter of those in the SD rats. 3 Brain 5-HT and 5-HIAA were however higher in FH rats on a per gram basis; there was no difference between the strains on a per brain basis, because of the smaller brain weights of the FH rats. 4 Brain and plasma tryptophan were not significantly different in the two strains. Plasma kynurenine was higher in the FH rats, and brain kynurenine was also higher either on a per gram or on a per brain basis. 5 The reserpine-releasable brain 5-HT was the same proportion of total brain 5-HT in the two strains. 6 Experiments with pargyline suggested that the turnover of 5-HT was somewhat higher in the FH rats on a per gram basis, but not significantly so on a per brain basis. 7 It is concluded that although brain tryptophan metabolism may be somewhat accelerated along both the 5-HT and kynurenine pathways in the FH rats there is no gross deficiency in the binding of 5-HT in their brains analogous to that found in their platelets.


[The role of temperament and emotional awareness in risk taking in adolescents].
Risk-taking behaviors among adolescents are now considered as a real public health issue. To investigate for potential vulnerability factors, adolescent risk-taking behavior can be analyzed from several different perspectives, based on biological, social or psychological variables. Risk-taking theories based on temperamental dimensions examine individual differences in propensity for engaging in such behaviors, whereas others focused on emotional processing disorder such as alexithymia or anhedonia with diverse conclusions. The aim of this study was to investigate the relationship between risk taking and two levels of psychological functioning: personality with reference to Cloninger's model of personality, and emotion with reference to Lane and Schwartz's level of emotional awareness theory. The sample consisted in 488 adolescents (m(age)=14.93, SD=1.44) with 257 boys (m(age)=15, SD=1.51) and 231 girls (m(age)=14.52, SD=1.23) who completed a set of three inventories: the Youth Risk Behavior Surveillance Scale (YRBSS), the Tridimensional Personality Questionnaire, and the Level of Emotional Awareness Scale. Risk-taking behaviors were also assessed indirectly with regards to teachers or school educators' evaluation. Moderate to weak significant correlations were found between temperament dimensions and risk-taking, and between level of emotional awareness and risk-taking. A positive moderate correlation was observed between novelty and risk-taking, whereas a negative weak correlation was observed between harm avoidance and risk-taking. Level of emotional awareness shows moderate negative correlations with risk-taking, as the two self and others dimensions. Finally, a model including the four temperament and the two emotional awareness dimensions was tested with risk-taking as the outcome variable. It accounted for 33% of the total variance (R(2)=0.33; F=30.78, p<0.0001), with novelty seeking (p<0.0001), self (p<0.0001) and others (p=0.0001), and level of emotional awareness as significant criteria. As hypothesized, temperamental dispositions of novelty seeking and harm avoidance, associated with weak emotional awareness, were associated with risk-taking. They may be considered as vulnerability factors for adolescents to engage in risk-taking behaviors. Several propositions may explain our results. First, risk-taking might be considered as an attempt to struggle against a sensation of emptiness due to a lack of emotion. Second, it may tend to replace emotion by sensations, which could be more controlled. Third, it could be an attempt - without success - to construct the complexity of subjective emotional experience.


Humoral factors released during trauma of Aplysia body wall. II. Effects of possible mediators.
1. Preliminary, general chemical characteristics of substances in artificial sea water (ASW) washed through stimulated body wall (SBW) and in hemolymph taken from noxiously stimulated animals (SHL) were consistent with those of classical neurotransmitters, amino acids, and small- to medium-sized peptides. 2. 5-Hydroxytryptamine (5HT) and acetylcholine (ACh), unlike SBW and SHL, caused relaxation when perfused into isolated body wall. FMRFamide produced a biphasic response--brief contraction followed by prolonged relaxation. 3. Small cardioactive peptide (SCPB) caused body wall contractions similar to those produced by SBW and SHL, except that SCPB contractions displayed more desensitization and were completely blocked by 30 mM CoCl2. SCPB and SBW contractions were synergistic. 4. Dopamine caused persistent body wall contractions similar to those of SBW and SHL. Dopamine contractions were reduced but not blocked by 30 mM CoCl2. Unlike SBW activity, dopamine activity was reduced by alkalinization. 5. Glutamate and taurine produced strong but usually short-lasting body wall contractions. Adenosine, octopamine, arginine vasotocin, and cholecystokinin (CCK-8) caused weak or variable contractions. Met-enkephalin and somatostatin caused no obvious body wall responses. 6. When superfused over the fully sheathed abdominal ganglion, FMRFamide, met-enkephalin, glutamate, aspartate, and taurine reduced the magnitude of the gill-withdrawal reflex elicited by siphon nerve stimulation. 7. Taken together with earlier results, these data suggest a preliminary framework for trauma signal pathways. It is proposed that stress hormones (perhaps including FMRFamide, SCPs, 5HT, and dopamine) are released into hemolymph from neuroendocrine cells. Effective amounts of active intracellular solutes such as amino acids may also be released by extensive cellular rupture. Various humoral signals produce slow effects that contribute to hemostasis, balling up, increased cardiac output, and reflex suppression.


Safety and feasibility of dobutamine stress echocardiography in symptomatic high gradient aortic stenosis patients scheduled for transcatheter aortic valve implantation.
We aimed to study the safety and feasibility of low-dose dobutamine stress echocardiography in a symptomatic high gradient aortic stenosis population scheduled for transfemoral transcatheter aortic valve implantation (TAVI) and to quantify left ventricular (LV) flow reserve. Fifty patients underwent dobutamine stress echocardiography with 5 minutes increments of 5 μg/kg/min up to 20 μg/kg/min until the heart rate increased ≥20 beats/min from baseline or exceeded 100 beats/min. Other criteria for discontinuing the infusion were major adverse events: ventricular arrhythmia, persistent supraventricular arrhythmia, pulmonary edema, chest pain with significant ST-changes, or minor events: ST-changes, drop in systolic blood pressure >30 mmHg, mild chest pain, and/or dyspnea. LV flow reserve was defined as an increase in stroke volume ≥20% during the test. Of 50 patients, 45 completed the test according to protocol. No patient had major adverse event. Five patients experienced minor side effects: mild chest pain/dyspnea in three, self-terminating atrial flutter in one, and decrease in blood pressure in one. Significant LV flow reserve was observed in 20 patients (40%). Low-dose dobutamine stress test appeared safe and feasible patients with high gradient aortic stenosis, and showed LV flow reserve in a minority of them.


An ATP synthase beta subunit is required for internalization of dsRNA into shrimp cells.
Extracellular double-stranded RNA (dsRNA) is an important modulator in innate immunity in both vertebrates and invertebrates. In shrimp, extracellular dsRNA can trigger RNAi pathway and serves as antiviral defense mechanism. However, the mechanism of dsRNA internalization into the cells has not yet known in shrimp cells. This study identified candidate cell surface proteins from shrimp hepatopancreatic cells that could interact with dsRNA by a ligand blot assay. Among the candidate proteins, a cell-surface beta subunit of ATP synthase was shown to be capable of internalizing dsRNA into shrimp hepatopancreatic cells that could rapidly occur in just 1 min upon dsRNA challenge. Colocalization between dsRNA and ATP synthase beta subunit implied correlation between dsRNA and ATP synthase beta subunit during dsRNA internalization. Furthermore, dsRNA showed colocalization with Ras-related endocytic proteins, Rab5 and Rab7 indicating that dsRNA was internalized via the receptor-mediated endocytosis. For the above evidences as well as the reduction of dsRNA internalization by angiostatin and antibodies against ATP synthase beta subunit, we propose that dsRNA interacts with ATP synthase via a nucleotide binding site in the beta subunit prior to internalize dsRNA into cells.


'Mind genomics': the experimental, inductive science of the ordinary, and its application to aspects of food and feeding.
The paper introduces the empirical science of 'mind genomics', whose objective is to understand the dimensions of ordinary, everyday experience, identify mind-set segments of people who value different aspects of that everyday experience, and then assign a new person to a mind-set by a statistically appropriate procedure. By studying different experiences using experimental design of ideas, 'mind genomics' constructs an empirical, inductive science of perception and experience, layer by layer. The ultimate objective of 'mind genomics' is a large-scale science of experience created using induction, with the science based upon emergent commonalities across many different types of daily experience. The particular topic investigated in the paper is the experience of healthful snacks, what makes a person 'want' them, and the dollar value of different sensory aspects of the healthful snack.


Keeping Order in Anaphase.
The critical components of chromosome segregation machinery are well established, but how they orchestrate the relative order of events during mitosis remains unclear. Kamenz et al. (2015) now report in Molecular Cell quantitative data suggesting competing networks and adaptive thresholds in the control of mitotic exit by the anaphase-promoting complex.