[Characteristics of postoperative healing in patients with stenoses of the hollow organs of the neck (clinico-morphologic study)].
In 160 patients, postoperative healing of stenoses of hollow neck organs of various etiology was examined clinically and morphologically. All the patients were divided into 4 groups in terms of the etiological factor as follows: Group 1 (60 patients)--patients with post-traumatic stenoses of the larynx and trachea; Group 2 (34 patients)--patients with post-resuscitation stenoses of the larynx and trachea; Group 3 (38 patients)--patients with bilateral laryngoparalysis that developed after strumectomy; Group 4 (28 patients)--patients with postburn deformation of the pharyngolarynx and esophagus. Pathomorphological changes typical of a chronic inflammatory process were detected in the frontal neck tissues (skin, muscles, cartilages, mucous membrane) of all the patients. Morphologically, the frontal neck tissues were similar in all the patients. In view of this, a large number of suppurative-necrotic complications seen after surgery of stenoses of hollow neck organs (up to 45%) can be attributed to pathological lesions in the frontal neck tissues.


Ceramide as a modulator of endocytosis.
The effects of ceramide analogs on the uptake of markers for fluid-phase (horseradish peroxidase, HRP) and receptor-mediated (low density lipoprotein, LDL) endocytosis were studied in Chinese hamster fibroblasts. N-Hexanoyl-D-erythro-sphingosine (C6-Cer) decreased the uptake of HRP in a dose-dependent manner. Internalization was inhibited > 40% with 25 microM C6-Cer, relative to controls, and was apparent within 5 min. Internalization of HRP was also inhibited by other Cer analogs and by treatment with agents that raise levels of endogenous Cer (sphingomyelinase or the glycosphingolipid synthesis inhibitor, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP)), but not by N-hexanoyl-D-erythrosphinganine (C6-dihydro-Cer) or sphingosine. Internalization of LDL was also inhibited by C6-Cer in a concentration-dependent manner, but was less pronounced than the effect on HRP internalization (10% versus 40% inhibition with 25 microM C6-Cer), suggesting that ceramide might affect fluid-phase and receptor-mediated endocytosis to different extents. C6-Cer also slowed HRP and LDL transport from endosomes to lysosomes as studied by analysis of endocytic vesicles on Percoll density gradients and induced a redistribution of endocytic organelles as determined by fluorescence microscopy of intact cells using appropriate markers. This resulted in decreased degradation of 125I-labeled LDL in the presence of C6-Cer. These results suggest that endogenous ceramide may modulate endocytosis.


Motivationally significant stimuli show visual prior entry: evidence for attentional capture.
Previous studies that have found attentional capture effects for stimuli of motivational significance do not directly measure initial attentional deployment, leaving it unclear to what extent these items produce attentional capture. Visual prior entry, as measured by temporal order judgments (TOJs), rests on the premise that allocated attention accelerates perception, that is, stimuli that receive attention first are perceived first; thus, this method is a sensitive and direct measure of the time course of initial attentional deployment. The authors demonstrate, using a novel TOJ paradigm without cues, that displays of faces and facial threat show visual prior entry effects, that is, these stimuli are prioritized by the perceptual-attentional system over other stimuli competing for awareness. This study provides direct evidence of the extent to which motivationally significant stimuli capture attention over other concurrently displayed items in the visual array.


Assessing the Effect of Low Calorie Soda Beverages on Primary Tooth Enamel: An In Vitro Study.
Objective: The purpose of this study was to evaluate the effect of low calorie soda beverages on the enamel of primary teeth. Study Design: Fifty enamel slabs were prepared from twenty primary extracted teeth and were equally divided into five groups: a) 0.9% NaCl (Control), b) Coca-Cola Classic (Sucrose), c) Diet Coke (Aspartame), d) Zevia Cola (Erythritol), e) Coca-Cola Life (Stevia). Each specimen was exposed to the beverage for a total of sixty minutes. Enamel surface roughness was measured before and after the exposures using a LEXT OLS4000 3D Laser Measuring Microscope. Results: All tested sodas resulted to a statistically significant change on the surface roughness of the enamel (p =.000). However, this effect did not differ significantly between the different treatment groups (p =.103). Conclusions: Both regular soda and low calorie soda containing different commercial sweeteners appear to have an effect on the surface morphology of primary tooth enamel. Thus, it is important to discourage the intake of any type of soda as part of the dietary advice provided in the dental office.


Rana catesbeiana ribonuclease inhibits Japanese encephalitis virus (JEV) replication and enhances apoptosis of JEV-infected BHK-21 cells.
Rana catesbeiana ribonuclease (RC-RNase) is a cytotoxic and antitumor RNase isolated from the oocyte yolk granules of the bullfrog R. catesbeiana. Our previous studies have shown that RC-RNase possesses antitumor activity by activating proapoptotic caspases. Here, we demonstrate that RC-RNase also possesses antiviral activity. By using cell viability and caspase activation assays, we show that RC-RNase largely enhances apoptosis of Japanese encephalitis virus (JEV)-infected BHK-21 cells by activating caspase-3, caspase-8, and caspase-9. In addition, immunoblotting experiments revealed that JEV infection enhances the internalization of RC-RNase by cells. In sum, these results indicate that RC-RNase provides a beneficial effect on JEV-infected cells by enhancing apoptosis.


Primary endoscopic endonasal dacryocystorhinostomy for pediatric nasolacrimal duct obstruction: A systematic review.
Epiphora secondary to nasolacrimal duct obstruction is common in the pediatric age group. The mainstay treatment among these young patients has been conservative. Once epiphora becomes recalcitrant, however, an external or an endonasal approach is considered. Endoscopic dacryocystorhinostomy (EDCR) entails creating an opening from the lacrimal sac directly into the nasal cavity to counteract nasolacrimal duct obstruction. We reviewed the literature to determine the effectiveness and the safety of primary EDCR to treat pediatric nasolacrimal duct obstruction. A literature search was conducted by using a number of medical literature data bases for the period from 1995 to 2016. The following search words were used either individually or in combination: epiphora, nasolacrimal duct obstruction, endoscopic dacryocystorhinostomy, powered endoscopic dacryocystorhinostomy, laser-assisted endoscopic dacryocystorhinostomy, children, congenital, acquired, presaccal obstruction, and postsaccal obstruction. In addition, a few articles were identified based on the experience and information provided by the senior authors (B.A., S.H., D.Y.W.). The search was conducted over a 1-month period (January 2017). Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews of Interventions were followed when possible. Only 10 original clinical research articles were selected based on our objectives and selection criteria. All the studies were at level of evidence III: nonrandomized and noncomparative prospective or retrospective case series. Altogether, 313 patients with ages that ranged from 4 months to 18 years were enrolled. A total of 352 EDCRs were performed that were either single sided (n = 313) or bilateral (n = 39). The most common causes of the obstruction were classified as congenital, followed by idiopathic, and then acquired. A meta-analysis was not performed because of the heterogeneity of the patient groups and variability of the methods used to measure outcomes. Analysis of the results indicated that EDCR was an effective, safe therapeutic approach to treating nasolacrimal duct obstruction in pediatric patients. It should be considered as an alternative procedure to external dacryocystorhinostomy after a failed conservative treatment.


Factors of importance in the hyperglycaemia induced by upper abdominal surgery.
The variation in the hyperglycaemic response, between different individuals, is large in the immediate postoperative period. In the present study, factors of possible importance in the hyperglycaemic response to standardized elective surgery (cholecystectomy) were determined by stepwise multiple linear regression analysis. The statistical analysis comprised 29 variables which included hormones (catecholamines, cortisol, insulin, thyroid hormones), blood-borne energy metabolites (glucose, lactate, free fatty acids (FFA), glycerol, 3-hydroxybutyrate, alanine) as well as anthropometric data and variables related to surgery and anaesthesia. In linear regression analysis, with one independent variable, the glucose concentration correlated significantly with: the duration of surgery, the dose of pancuronium bromide, the dose of fentanyl, the lactate, adrenaline and cortisol concentrations respectively. The variables which, when successively included in stepwise regression, significantly reduced the residual variance for glucose were, in order of introduction; the duration of surgery and the cortisol and adrenaline concentrations respectively. It is concluded that, in standardized surgical trauma the duration of surgery may influence the metabolic response to surgery. Duration of surgery has, thus, to be taken into account when interpreting results from studies where different treatments are compared. Our results confirm that there is a synergistic effect of cortisol and adrenaline in mediating the hyperglycaemic response to surgery.


Thyroid hormone stimulates progesterone release from human luteal cells by generating a proteinaceous factor.
Blood samples collected from 29 women (aged between 19 and 35 years) during the luteal phase of the menstrual cycle (between days 18 and 23 of the cycle) showed that deficiency in thyroid hormone level is related to a decrease in progesterone (P4) secretion. To observe the effect of thyroid hormone on human ovarian luteal cells, 3,5,3'-triiodothyronine (T3; 125 ng/ml) was added to luteal cells in vitro. T3 significantly stimulated progesterone release (P < 0.01) from luteal cells and this could be blocked by cycloheximide, indicating a protein mediator for the T3 effect. The T3 stimulatory effect was inhibited by anti-T3 antibody suggesting specificity of T3 action. Addition of T3 caused a more than threefold increase in cellular protein synthesis which was inhibited by cycloheximide. Preparation of partially purified thyroid hormone-induced factor (TIF) (from peak II of Sephadex G 100 chromatography of T3-incubated cells), and its addition to luteal cell incubations caused a significant increase in P4 release (P < 0.05). Incubation with trypsin or treatment with heat destroyed the stimulatory effect of TIF on P4 release, indicating the proteinaceous nature of TIF. Purified thyroid hormone-induced protein. (TIP) from rat granulosa cells and fish ovarian follicles greatly stimulated P4 release from human luteal cells. These results suggest that T3 stimulation of P4 release from human luteal cells is not direct, but is mediated through a putative protein factor, which appears to be a protein conserved through evolution as far as its biological activity is concerned.


Downregulation of CITED2 contributes to TGFβ-mediated senescence of tendon-derived stem cells.
Tendon-derived stem cells (TDSCs) are multipotent adult stem cells with potential applications in tendon and tendon-bone junction repair. However, cellular characteristics change during in vitro passaging. Therefore, elucidation of the molecular and cellular mechanisms of tendon aging will be essential for the development of TDSC-based therapies. The aim of this study is to investigate the effect of CITED2, a nuclear regulator and transforming growth factor β2 (TGFβ2) on TDSC proliferation and senescence by comparing cells derived from Achilles tendon biopsies of young individuals (Y-TDSC) with those of older patients (O-TDSC). Our results showed that CITED2 mRNA and protein expression levels were significantly higher in Y-TDSCs than in O-TDSCs and O-TDSCs displayed decreased proliferation and increased senescence compared with Y-TDSCs. Furthermore, high levels of CITED2 protein expression in Y-TDSCs correlated with the downregulation of SP1 and p21 and the upregulation of MYC, potentially indicating the mechanism by which CITED2 upregulates TDSC proliferation. TGFβ2 was found to downregulate the expression of the CITED2 gene and knockdown of CITED2 abolished the effect of TGFβ2 on TDSC proliferation and senescence. Thus, the downregulation of CITED2 contributes to TGFβ-mediated senescence providing an insight into the molecular and cellular mechanisms that contribute to tendon aging and degeneration. Our findings may aid the development of cell-based therapies for tendon repair.


Discontinuation of treatment among Italian diabetic patients treated by renal replacement therapy.
Death from dialysis termination has been extensively surveyed in Canada, the United States, and Australia. In the US old age and the presence of diabetes has been associated with treatment withdrawal. On the other hand, information for Europe is very scarce. We addressed the issue of dialysis termination in Italy in both a cohort of diabetic patients starting RRT in 1987, and two age-, sex-, type of RRT, and unit-matched cohorts of diabetic and non-diabetic patients alive on RRT treatment on 31 December 1987. Follow-up was available till 31 December 1991. Dialysis termination accounted for 1.1% of the known causes of death in the incident diabetic cohort and for only 0.5% and 0.9% of the prevalent diabetic and non-diabetic cohorts respectively. In Italy, diabetes is not associated with higher rates of dialysis termination and this cause of death seems uncommon among the overall Italian RRT population. We cannot, however, exclude a predialysis selection against patients presenting with an old age or comorbid conditions.


Analysis of neocortical grafts placed into focal ischemic lesions in adult rats.
This study investigated the viability of fetal neocortical block grafts transplanted into adult ischemic cortical lesions. Recipient rats sustained focal ischemic lesions by permanent occlusion of the middle cerebral artery 4-7 days prior to transplantation. Twenty days later, the animals were sacrificed and the brains examined using triphenyltetrazolium chloride, routine Nissl or acetylcholinesterase histochemistry. Ischemic infarctions were localized to the ipsilateral sensorimotor cortex and transplants were integrated with the host cerebral cortex or striatum. Cholinergic fibers were found crossing the host-transplant interface, presumably innervating the graft. This study demonstrates that fetal neocortical block grafts placed into adult focal ischemic lesions following permanent arterial occlusion can survive and establish connections with the host brain.


Snaps, Selfies, and Shares: How Three Popular Social Media Platforms Contribute to the Sociocultural Model of Disordered Eating Among Young Women.
The current study aimed to integrate and test the sociocultural model of disordered eating with theories explaining the impact of mass media on the development of disordered eating for users of three popular social networking platforms. Young women social networking site (SNS) users (age 18-24) who had never received an eating disorder diagnosis (N = 637) completed questions capturing their SNS gratifications and usage, body surveillance, social comparisons, body dissatisfaction, and eating pathology. Measures were administered in one online session. Model relationships were similar across users of all three SNS platforms: Facebook, Instagram, and Snapchat. Users of all platforms demonstrated a significant positive relationship between upward comparisons and disordered eating outcomes, and between body surveillance and disordered eating outcomes, although differences between models did emerge. Empirical findings support extending the sociocultural model of disordered eating to include SNS uses and gratifications.


Constraints on cardiac hypertrophy imposed by myocardial viscosity.
Laplace's law constrains how thin the ventricular wall may be without experiencing excessive stress. The present study investigated constraints, imposed by myocardial viscosity (resistance to internal rearrangement), on how thick the wall may be. The ventricle was modeled as a contracting, spherical shell. The analysis demonstrated that viscosity generates stress and energy dissipation with inverse fourth- and eighth-power dependence, respectively, on distance from the cavity center. This result derives from the combination of squared dependence of viscous forces on shearing velocity gradients and the greater shear rearrangement required for inner layers of a contracting sphere. These predictions are based solely on geometry and fundamentals of viscosity and are independent of material properties, cytoskeletal structure, and internal structural forces. Calculated values of energy and force required to overcome viscosity were clearly large enough to affect the extent of thickening of the left ventricle. It is concluded that load-independent viscous resistance to contraction is an important factor in cardiac mechanics, especially of the thickened ventricles of concentric hypertrophy.


Adverse effects from inappropriate medication administration via a jejunostomy feeding tube.
Numerous complications can arise when administering medications to patients receiving continuous enteral feeding. We report a case of a patient who could not be fed by mouth and was receiving continuous jejunal enteral feeding who had an adverse event associated with inappropriate administration of a medication via his jejunostomy tube. He had taken an extended-release niacin product before hospitalization for type IIb hyperlipidemia. The patient was inappropriately given a single dose of 750 mg of niacin as the short-acting tablets that were crushed and administered via the jejunostomy tube. He experienced severe cutaneous flushing, a feeling of warmth, itching, nausea, and emesis. He was noted to have "prickly heat" to the forehead, according to the nursing notes. A discussion of problems and guidelines for medication administration in adult patients receiving continuous tube feeding is provided.


Regression of femoral anteversion. A prospective study of intoeing children.
To study the spontaneous regression of femoral anteversion, 30 children referred to the outpatient clinic for intoeing were followed until at least 15 years of age. The mean observation time was 9 (7-12) years, and all the children were examined three times during the growth period. The mean radiographic angle at the first examination was 42 degrees, at the second examination 36 degrees, and at the last examination 28 degrees. The mean decrease of the AV angle per year was 1.5 degrees, with a considerable range (0.2-3.1 degrees). The mean internal rotation of the hip decreased from 74 degrees to 53 degrees during the observation period, and the external rotation increased from 19 degrees to 37 degrees. While all 30 children had an intoeing gait at the first examination, this disappeared in all but 5 children.


[Computerized tomography analysis of cement-free total hip endoprostheses].
16 patients with total hip endoprosthesis were investigated by high resolution computed tomography (CT) to analyse possible advantages of CT over conventional radiography. The quality of the examinations was good only in pure titanium systems: examinations of chromium-molybdenum alloys were severely deteriorated by strike artifacts. Positioning of implants is well defined in radiographs; CT provides better visualisation of the relation between implant and cortical bone. Evaluation of the contact of the shaft to the femoral corticalis is difficult in radiographs but facilitated in axial scans. Determination of relevance of CT analysis of total hip endoprosthesis remains subject to a future long-term follow-up study.


Interband recombination dynamics in resonantly excited single-walled carbon nanotubes.
Wavelength-dependent pump-probe spectroscopy of micelle-suspended single-walled carbon nanotubes reveals two-component dynamics. The slow component (5-20 ps), which has not been observed previously, is resonantly enhanced whenever the pump photon energy coincides with an absorption peak and we attribute it to interband carrier recombination, whereas we interpret the always-present fast component (0.3-1.2 ps) as intraband carrier relaxation in nonresonantly excited nanotubes. The slow component decreases drastically with decreasing pH (or increasing H+ doping), especially in large-diameter tubes. This can be explained as a consequence of the disappearance of absorption peaks at high doping due to the entrance of the Fermi energy into the valence band, i.e., a 1D manifestation of the Burstein-Moss effect.


Chaotic parameters extracted from fluorescence spectra to quantify sheep cheese whey in natural bodies of water.
Sheep cheese whey (SCW) is a by-product from the dairy industry, and due to its composition, it is very hazardous for natural bodies of water. However, illegal discharges of this product have been commonly reported in watercourses and reservoirs. To prevent this type of actions, a simple and affordable sensor has been designed and validated using diverse water samples from different sources containing SCW, such as water from two Spanish reservoirs and two Spanish rivers located in the province of Madrid. Using these waters, different SCW solutions (lower than 20% in weight) have been prepared and measured. The equipment used to sense the samples is based on combining fluorescence measurements, obtained with light emitting diodes (LEDs), and algorithms which rely on chaotic parameters. Every sample was measured by six different types of LEDs possessing distinct emission wavelengths (blue, orange, green, pink, white, and UV), leading to 1786 fluorescence spectra that were employed during the modeling phase. After the mathematical analysis, the dataset that generates the best statistical results was from the blue LED. This approach was dually validated via leave-one-out cross-validation as well as externally validation, and the results were very promising (error around 6.5% and 8% quantification error, respectively). Additionally, it is important to note that the sensor used has been designed and developed by a 3D printer and has the potential of being applied in situ for real-time and cost-effective analysis of natural bodies of water.


[Study of apocytochrome c from the horse heart by high resolution 1H NMR].
The horse heart apocytochrome c was investigated by high resolution 1H-NMR. The secondary chemical shifts of 1H-NMR spectra are not observed, which is typical for disordered molecules. However NOE is characterized by the appearance of spin diffusion which decreases with a temperature increase. The presence of spin diffusion assumes an existence of rigid sites and thus some ordered conformation of the molecule.


Early diagnosis of Hepatitis B by Dane particle associated DNA polymerase assay.
We have studied prospectively 178 subjects exposed to hepatitis B and 120 haemodialysed patients for the presence of HGs antigen, e antigen and DNA polymerase as well as for anti-HBs and anti-HBc antibodies. The results suggest that the DNA polymerase assay enables us to diagnose hepatitis B earlier than the radioimmunoassay for HGs and that DNA polymerase might be present in the blood in the absence of HBs in cases of confirmed hepatitis B. A posititive correlation between e antigen and DNA polymerase was observed in 83% of the patients on haemodialysis who developed hepatitis B but only in 9% of normal patients developing the same disease.


[Infantile and late-onset type of globoid cell leucodystrophy in one family (author's transl)].
Globoid cells leucodystrophy was diagnosed by specific enzyme assays in two siblings of one family. A male infant presented the typical symptoms of hyperirritability and progressive loss of psychomotor functions beginning at the age of 4 months. The progression of the disease lead to decerebration and death at 19 months of age. The elder sister had a normal development until her third year, when she developed exclusively symptoms of peripheral neuropathy. Up to the moment there are no symptoms of cortical function loss.


[From cradle to grave? Expectations from atypical antipsychotics].
Clinical expectations are high toward atypical, second generation antipsychotics (SGAs). Controlled clinical trials supporting the superiority of SGAs over traditional agents are scarce. Meta-analysis of existing data may come for the rescue but that kind of method has its limitations. One of the most meticulous approaches (Davis et al. 2003) reached the conclusion that some, but not all, SGAs are more efficacious than traditional ones. Within the group of distinguished drugs, clozapine and amisulpride have the highest efficacy. The present paper critically overviews the study of the Davis group. Based on in vivo D2 receptor binding data of the new SGAs and the usual post marketing changes of clinical dosing, it is expected that some of the currently and most recently marketed SGAs may show similar superiority.


[Incorporation of (32P)orthosphate into DNA of the mouse spleen under influence of antigen (author's transl)].
Antigens cause an increase of the DNA synthesis in the spleen of mice as shown by the incorporation of [32P]orthophosphate and [3H]thymidine. In the present paper, the incorporation of [32P]orthophosphate into the single deoxymononucletides has been studied under influence of the antigen bovine serum albumin. For this purpose, the labelled DNA was decomposed to the deoxymononucleotides and their specific activities determined. Using [32P]orthophosphate, it was found that the activity of the DNA increased continuously during an observation period of 8 h. While after one hour the relative specific activity of dTMP was highest and that of dAMP lowest, the relative specific activities of the deoxymononucleotides had become equal after 8 h. Under the influence of bovine serum albumin, the incorporation of [32P]orthophosphate increased in he main band DNA as well as in the satellite DNA. The antigen had no effect on the distribution of the specific activities of the deoxymononucleotides.


Intervention therapy for coronary artery disease in the elderly.
The central aim of this review was to examine the application of intervention therapy for CAD in the elderly population. The data reviewed indicates that it is no longer appropriate to use age 70 or 75 as the upper limit of eligibility for thrombolytic intervention in patients with acute myocardial infarction. Elderly who are physiologically active without contraindications to thrombolytic therapy should be considered eligible. Additional controlled trials specifically targeted at the elderly population are needed to better define the precise dosing regimen and the magnitude and extent of bleeding complications in this group. Nevertheless, it appears appropriate to recommend thrombolytic intervention for most eligible elderly patients presenting with acute myocardial infarction. This recommendation is based on the fact that the higher mortality in the elderly results in more lives saved per patient treated than for younger patients. It is important to reemphasize that this recommendation is for treating elderly patients with acute infarction as suggested by ST-segment elevation and/or Q waves, without contraindications to thrombolytic therapy. Those with non-Q-wave infarctions, hypertension, recent stroke, history of bleeding, or other contraindications are not candidates. Regarding intervention therapy in other elderly patients with acute and chronic manifestations of coronary disease, results also appear very encouraging. Elderly patients appearing to tolerate PTCA include those with all forms of angina from chronic stable angina to unstable angina. Although only observational data are on hand at present, our review suggests these elderly patients tolerate PTCA well and indeed may benefit. The elderly patients who have co-morbid factors that adversely influence the application of CABG for revascularization may be the best candidates for PTCA. At present, the challenge for the physician is to carefully assess each elderly patient on an individual basis for intervention therapy. This evaluation should be aimed at identifying factors that may permit application of intervention treatment to the elderly patients who are most likely to receive the greatest benefit.


Projections from the raphe nuclei to the phrenic motor nucleus in the cat.
The purpose of this study was to identify the projections from the brain to the phrenic motor nucleus in the cat by employing a retrogradely-transported fluorescent dye. Propidium iodide was iontophoresed into the phrenic motor nucleus which is located in the fourth, fifth and sixth segments of the cervical spinal cord. Retrogradely-labeled cell bodies were found in the brainstem within recognized respiratory areas. In addition, retrogradely-labeled cell bodies were found within the raphe nuclei, nuclear areas not previously associated with respiratory control. The results of this study suggest that the raphe nuclei may play a role in the central regulation of breathing.


Dissolution and Translational Modeling Strategies Toward Establishing an In Vitro-In Vivo Link-a Workshop Summary Report.
This publication summarizes the proceedings of day 2 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Patient-centric drug product development from a drug product quality perspective necessitates the establishment of clinically relevant drug product specifications via an in vitro-in vivo link. Modeling and simulation offer a path to establish this link; in this regard, physiologically based modeling has been implemented successfully to support regulatory decision-making and drug product labeling. In this manuscript, case studies of physiologically based biopharmaceutics modeling (PBBM) applied to drug product quality are presented and summarized. These case studies exemplify a possible path to achieve an in vitro-in vivo link and encompass (a) development of biopredictive dissolution methods to support biowaivers, (b) model-informed formulation selection, (c) predicting clinical formulation performance, and (d) defining a safe space for regulatory flexibility via virtual bioequivalence (BE). Workflows for the development and verification of absorption models/PBBM and for the establishment of a safe space using dissolution as an input are described with examples. Breakout session discussions on topics, such as current challenges and some best practices in model development and verification, are included as part of the Supplementary material.


Influence of direct and alternating current electric fields on efficiency promotion and leaching risk alleviation of chelator assisted phytoremediation.
Direct and alternating current electric fields with various voltages were used to improve the decontamination efficiency of chelator assisted phytoremediation for multi-metal polluted soil. The alleviation effect of electric field on leaching risk caused by chelator application during phytoremediation process was also evaluated. Biomass yield, pollutant uptake and metal leaching retardation under alternating current (AC) and direct current (DC) electric fields were compared. The biomass yield of Eucalyptus globulus under AC fields with various voltages (2, 4 and 10 V) were 3.91, 4.16 and 3.67kg, respectively, significantly higher than the chelator treatment without electric field (2.71kg). Besides growth stimulation, AC fields increased the metal concentrations of plant tissues especially in aerial parts manifested by the raised translocation factor of different metals. Direct current electric fields with low and moderate voltages increased the biomass production of the species to 3.45 and 3.12kg, respectively, while high voltage on the contrary suppressed the growth of the plants (2.66kg). Under DC fields, metal concentrations elevated obviously with increasing voltages and the metal translocation factors were similar under all voltages. Metal extraction per plant achieved the maximum value under moderate voltage due to the greatest biomass production. DC field with high voltage (10V) decreased the volume of leachate from the chelator treatment without electric field from 1224 to 56mL, while the leachate gathered from AC field treatments raised from 512 to 670mL. DC field can retard the downward movement of metals caused by chelator application more effectively relative to AC field due to the constant water flow and electroosmosis direction. Alternating current field had more promotive effect on chelator assisted phytoremediation efficiency than DC field illustrated by more metal accumulation in the species. However, with the consideration of leaching risk, DC field with moderate voltage was the optimal supplementary technique for phytoremediation.


An Improved Patient-Specific Mortality Risk Prediction in ICU in a Random Forest Classification Framework.
Dynamic and automatic patient specific prediction of the risk associated with ICU mortality may facilitate timely and appropriate intervention of health professionals in hospitals. In this work, patient information and time series measurements of vital signs and laboratory results from the first 48 hours of ICU stays of 4000 adult patients from a publicly available dataset are used to design and validate a mortality prediction system. An ensemble of decision trees are used to simultaneously predict and associate a risk score against each patient in a k-fold validation framework. Risk assessment prediction accuracy of 87% is achieved with our model and the results show significant improvement over a baseline algorithm of SAPS-I that is commonly used for mortality prediction in ICU. The performance of our model is further compared to other state-of-the-art algorithms evaluated on the same dataset.


Coupled quantum dots in a graphene-based two-dimensional semimetal.
We present an experimental demonstration of a graphene-based double quantum dot system, which exhibits single-electron transport of two lateral quantum dots coupled in series. Low-temperature transport measurements revealed honeycomb charge stability diagrams with a varied (from weak to strong) interdot tunnel-coupling regime, and we have extracted the relevant parameters associated with the double quantum dot system. These results are important for the realization of integrated quantum circuits in graphene-based electronics.


[Functional state of the sex glands in men with encephaloophthalmopathies pathogenetically associated with thyrotoxicosis].
In 36 young males with encephaloophthalmopathy, resultant of thyrotoxicosis, androgen and estrogen concentrations were studied using radioimmunoassay (for the blood determination) and physico-chemical methods (for the urine detection). The blood plasma and urine androgen levels decreased in the patients examined. The total 17-ketosteroid excretion remained unchanged, whereas the fraction ratio was disordered. The blood plasma and urine estrogen content increased. A tendency of normalizing the changed sex hormone levels was observed in patients with encephaloophthalmopathy after recovery.


Time course of phosphorylated CREB and Fos-like immunoreactivity in the hypothalamic supraoptic nucleus after salt loading.
Phosphorylation of the cAMP response element binding protein (CREB) precedes the induction of immediate early gene expression. Using antibodies that distinguish CREB from phosphorylated CREB (PCREB), we studied the appearance of PCREB-like immunoreactivity (PCREB-LI) and Fos-LI in the hypothalamic supraoptic nucleus (SON) of rats treated with hypertonic or normal saline and uninjected controls. Fifteen minutes after injection, increased numbers of PCREB-LI cells were seen in both normal and hypertonic saline-treated rats as compared with uninjected controls. Forty-five minutes after injection, levels of c-fos mRNA in the SON were elevated in hypertonic saline-treated rats as compared with normal saline-treated rats, and were minimally detectable in uninjected rats. At this time period, the hypertonic saline-treated rats showed increased number of Fos-LI cells in the SON, whereas normal saline-treated rats showed little or no Fos-LI cells. The discrepancy between levels of PCREB-LI and c-fos mRNA suggests that injection of hypertonic saline may activate additional transcriptional factors besides CREB. The lack of Fos-LI in the presence of modest increases in c-fos mRNA in normal saline-treated rats implies that levels of c-fos mRNA must exceed a threshold before increases in Fos-LI cells are detectable by immunostaining of the SON. Such a threshold might permit neuronal cells to activate diverse genes, through phosphorylation of CREB, without inducing the constellation of Fos-responsive genes.


Cerebellar projections to the red nucleus and inferior olive originate from separate populations of neurons in the rat: a non-fluorescent double labeling study.
In the rat, the extent of collateralization of projections from the cerebellar nuclei to the red nucleus and inferior olive was investigated using a retrograde double labeling technique. The combination of tracers selected, cholera toxin-beta-subunit and WGA-BSA-gold, not only enabled the use of small injection sites but also resulted in clearly distinguishable and permanently stained neurons that could be analyzed in counterstained sections.


[Effect of bacterial endotoxin on migration of gonadotropin-releasing, hormone producing neurons in rat embryogenesis].
The effect of bacterial lipopolysaccharide endotoxin (LPS), immune system activator, on differentiation and migration of gonadotropin-releasing, hormone producing neurons in rat embryogenesis has been studied. Intraperitoneal introduction of LPS (18 jg/kg) to pregnant rats on the 12th day of pregnancy led to 50% decrease in total number of GRH-neurons in the forebrain of 17-day-old embryos and 17% decrease in 19-day-old embryos. At the same time, the number of GRH-neurons in the nasal area of the head of 17- and 19-day-old embryos increased by 40 and 50%, respectively, whereas it increased by 20% in olfactory bulbs of 17-day-old embryos and did not changed in olfactory bulbs of 19-day-old embryos. Neither the total number of neurons nor their distribution patterns were affected by the introduction of LPS into pregnant rats on the 15th day of pregnancy. Singular localization of GRH-neurons in embryo forebrain was observed after LPS administration, whereas the neurons were located by groups of 3-4 cells in rostral areas. Therefore, at the early stages of pregnancy, LPS was shown to suppress initial stages of differentiation and migration of GRH producing neurons. The effects observed in our study may be mediated by LPS-induced, proinflammatory cytokines.


Pterygium recurrence related to its size and corneal involvement.
To establish the usefulness of grading system based on the size and extent of corneal involvement in predicting recurrence in patients undergoing primary pterygium excision with intraoperative use of adjunctive topical Mitomycin-C (MMC). A case series. Section of Ophthalmology, the Aga Khan University Hospital, Karachi, from 2005 till 2010. One hundred and twenty male patients (120 eyes) underwent surgical removal of pterygium using bare sclera method with MMC in concentration of 0.2 mg/ml (0.02%) with exposure time of 3 minutes. Classification of subjects was done according to the grading of pterygium. Patients were followed at 3 months interval for a minimum period of 1 year to record any recurrence. The pterygium recurrence rate was 6.7% at a follow-up of 1 year. There was no significant association of pterygium recurrence with younger age (p = 0.14). A higher level of corneal involvement by the pterygium at presentation correlated significantly with the recurrence (p = 0.01). These results suggest that a higher grade of pterygium at presentation in patients leads to increased rate of recurrence after surgical excision. Hence, early excision of pterygium is recommended to decrease its recurrence rate.


Influence of diet on trans fatty acids in human milk.
In two experiments on relations between diet and milk lipids, subjects recorded food intake for 1 week and saved duplicate portions of foods consumed on 3 days. Diet collections were analyzed for selected nutrients and percent fatty acids. In the first experiment, for 1 week five subjects took morning and evening milk samples for fatty acid analysis. Significant differences were found in percentages of trans- 18:1 and total trans fatty acids between subjects' milks but not between morning and evening samples. In the second experiment six additional subjects collected milk samples in the morning only. Subjects were significantly different in the percentages of trans- 18:1 and total trans acids in their milks. In nine of the 11 subjects the fluctuation of percent total trans acids in the milk appeared to follow dietary trans changes after a 12 to 36 hr lag period. A significant correlation was found for diet and evening milk of the same day. Polyunsaturated/saturated ratios of the fatty acids in the diet lipids were related to those for milk lipids from the same evening and the next morning. Although other factors are involved, diet lipids influence trans fatty acids and polyunsaturated/saturated ratios of the fatty acids in human milk.


[Contributions of ludic care in nursing to chemical detoxification due to the use of crack cocaine].
to understand the contributions of ludic care in nursing by stimulating the acceptance of chemical detoxification from crack on the perception of people in the detoxification process. an exploratory, descriptive study with a qualitative approach, performed with five people hospitalized for chemical detoxification from crack, from March to July 2013 in a chemical detox unit of a midsize hospital in the central region of Rio Grande do Sul. Data was collected using a semi-structured interview and was subjected to content analysis. Two categories emerged: Ludic care in nursing as a stimulus to the acceptance of chemical detoxification; Ludic care in nursing in the promotion for healthy living after chemical detoxification. ludic care in nursing proved to enhance the acceptance of chemical detoxification from crack in the reality investigated.


308-nm excimer laser for the treatment of psoriasis: induration-based dosimetry.
To determine the response of stubborn psoriatic plaques to the 308-nm excimer laser. Controlled study with a before-after design. A university-based clinical research center. Adult subjects with recalcitrant plaque psoriasis that have not responded to other therapies for at least 2 months. Selected psoriatic plaques were treated with the 308-nm excimer laser. One lesion was left as a control. Each plaque was treated 2 times a week, with an initial dose based solely on the induration component of the modified Psoriasis Area and Severity Index score for that lesion. Subsequent treatments were twice a week with dosage increments up to 50%, based on the change in induration. Four final consolidation doses were given once the induration score was reduced to zero. Eighteen subjects were treated. There were 4 dropouts because of various scheduling problems. In the remaining 14 subjects, 44 plaques received a mean of 10 treatments (range, 4-14). Treatments were quick and well tolerated. The mean cumulative dose was 8.8 J/cm2 (range, 2.2-22.8 J/cm2). Compared with controls, treated plaques showed significant improvement (P<.001). The only adverse event was a mild sunburn-like reaction in 2 subjects after 1 treatment. Selective targeting of laser-generated 308-nm excimer radiation with this convenient subblistering dosage schedule based on induration allows for individualized treatment plans for each plaque. Clearing of stubborn psoriatic lesions occurs rapidly and safely.


Transcriptional regulation of enniatins production by Fusarium avenaceum.
The aim of this study was to analyse the transcriptional regulation of enniatins (ENs) production in Fusarium avenaceum. We develop a new method to quantify ENs in FDM agar medium. We performed an LC/MS/MS analysis to evaluate enniatin A, A1, B, B1 and B4 production by seven F. avenaceum strains and, in a time-course experiment, by ITEM 3404 to analyse the transcriptional regulation of the esyn1 gene. The expression profile, achieved by Real time reverse transcriptase assay, showed an activation of gene transcription at the seventh day of incubation, corresponding to the higher increase of total ENs production. Enniatin B was the most abundant ENs analogues, representing the 90% of total ENs. The relative percentage of ENs remained unaltered during the experiment. We reported a transcriptional regulation of esyn1 responsible for the modulation of ENs biosynthesis. Enniatins are cyclic depsipeptides metabolites with a wide range of biological activities. They are also widespread contaminants in grains and cereals due to infection by enniatin-producing Fusarium species. This is the first article describing the transcriptional regulation of esyn1 gene that modulates ENs production in Fusarium avenaceum and provides new knowledge about the molecular mechanism underlying the biosynthesis of these important fungal metabolites in this toxigenic fungal species.


Leakage of protein into lungs of preterm ventilated rabbits is correlated with activation of clotting, complement, and polymorphonuclear leukocytes in plasma.
We investigated whether leakage of protein in lungs of preterm ventilated rabbits of 28- and 29-d gestational age is correlated with activation of clotting, complement, and polymorphonuclear leukocytes (PMN) in plasma. We found signs of systemic activation of clotting, complement and PMN in ventilated 28-d gestational age rabbits, as indicated, respectively, by increased median plasma fibrin monomer concentrations (83 versus 40% of normal adult rabbit plasma in nonventilated 28-d gestational age rabbits, p < 0.01), decreased median plasma CH50 activity (112 versus 122 U/L in nonventilated 28-d gestational age rabbits, p < 0.05), and increased median plasma beta-glucuronidase concentrations (159 versus 97% of maximal activated adult rabbit plasma in nonventilated 28-d gestational age rabbits p < 0.05). We did not find signs of systemic activation in the ventilated 29-d gestational age group. Higher median total protein concentrations in alveolar wash of the ventilated 28-d gestational age rabbits (2.7 versus 1.3 mg/mL in the nonventilated rabbits. p < 0.01) indicated protein leakage into the lungs, and this protein leakage was more pronounced in the lungs of ventilated 28-d gestational age rabbits than in those of ventilated 29-d gestational age rabbits (2.1 mg/mL, p < 0.01). The total protein concentration in the alveolar wash of all 28-d gestational age rabbits was correlated with the concentration of fibrin monomers (p = 0.51, p = 0.035) and beta-glucuronidase (p = 0.61, p = 0.011), and the CH50 activity (p = -0.73, p = 0.002) in plasma. We conclude that leakage of protein in lungs of preterm ventilated rabbits of 28-d gestational age is correlated with activation of clotting, complement, and PMN in plasma. This activation process may contribute to lung injury by intravascular and intraalveolar deposition of fibrin and formation of proteinaceous edema.


Polymyalgia rheumatica.
Polymyalgia rheumatica is a syndrome that occurs in the elderly and is characterized by pain and stiffness involving the neck, the shoulder girdle, and the hip girdle. The aching should be present for greater than one month. Polymyalgia rheumatica may be more common than reported. The etiology remains unknown. There is generally little found pathologically in this disease. The physical examination is often not impressive. Synovitis may be a main contributing factor to many of the symptoms seen in patients with polymyalgia rheumatica. Symptoms often do not correlate with physical findings. Polymyalgia rheumatica must be differentiated from many conditions since the diagnosis remains entirely clinical. Osteoarthritis, flu syndromes, inflammatory myopathies, fibromyalgia, and depression all have features that may mimic polymyalgia rheumatica. Malignancies and infections may also be difficult to separate from polymyalgia rheumatica. Polymyalgia rheumatica may also be extremely difficult to differentiate from seronegative rheumatoid arthritis in patients older than 50 years. Although some patients with polymyalgia rheumatica have underlying giant cell arteritis, the majority apparently do not. The distinction between polymyalgia rheumatica and giant cell arteritis cannot be made on the basis of laboratory studies and relies solely on clinical symptoms and physical findings. Although nonsteroidal antiinflammatory medications may control symptoms in patients with mild disease, most patients with polymyalgia rheumatica require low-dose corticosteroids. The tapering schedule for the corticosteroids is contingent upon the response of symptoms and laboratory parameters. Polymyalgia rheumatica usually follows a benign course with almost complete response to an adequate treatment program. Recently, there have been several studies suggesting that the course of polymyalgia rheumatica may not be as short and simple as once proposed. Nevertheless, many patients may be completely weaned from corticosteroids. Other agents have been used in this disease, but for the most part their use remains somewhat controversial. Patients must be monitored carefully. Most patients do well, and treatment is effective.


Role of natural killer cells in psychosocial stressor-induced changes in mouse mammary tumor growth.
We have shown that social housing conditions affect the growth rate of the androgen-responsive Shionogi mouse mammary tumor (SC115) and differentially stimulate splenic natural killer (NK) cell activity. Mice reared in a social group and then singly housed (GI) following tumor cell injection have increased tumor growth rates and increased NK cell activity, whereas mice reared individually and then group housed following tumor cell injection have decreased tumor growth rates and decreased NK cell activity compared to that in mice remaining in their rearing group. The present study was undertaken to determine whether NK cells are involved in mediating the effects of social housing conditions on SC115 tumor growth rates. We demonstrate that the presence of the SC115 tumor significantly stimulates the activity of NK cells at the tumor site in the first 7 days after tumor cell injection, and that, consistent with the data on splenic NK cells, mice of the GI group (largest tumors) have significantly greater levels of NK cell activity than mice reared individually and then group housed (smallest tumors). We further demonstrate that in mice of the GI group, in vivo stimulation of NK cell activity by polyinosinic:polyCMP correlates with a corresponding increase in tumor growth rate. These findings suggest that NK cell activity may play a role in mediating the increased tumor growth rate observed in mice of the GI housing condition.


Proteome reference map of Lactobacillus acidophilus NCFM and quantitative proteomics towards understanding the prebiotic action of lactitol.
Lactobacillus acidophilus NCFM is a probiotic bacterium adapted to survive in the gastrointestinal tract and with potential health benefits to the host. Lactitol is a synthetic sugar alcohol used as a sugar replacement in low calorie foods and selectively stimulating growth of L. acidophilus NCFM. In the present study the whole-cell extract proteome of L. acidophilus NCFM grown on glucose until late exponential phase was resolved by 2-DE (pH 3-7). A total of 275 unique proteins assigned to various physiological processes were identified from 650 spots. Differential 2-DE (DIGE) (pH 4-7) of L. acidophilus NCFM grown on glucose and lactitol, revealed 68 spots with modified relative intensity. Thirty-two unique proteins were identified in 41 of these spots changing 1.6-12.7-fold in relative abundance by adaptation of L. acidophilus NCFM to growth on lactitol. These proteins included β-galactosidase small subunit, galactokinase, galactose-1-phosphate uridylyltransferase and UDP-glucose-4-epimerase, which all are potentially involved in lactitol metabolism. This first comprehensive proteome analysis of L. acidophilus NCFM provides insights into protein abundance changes elicited by the prebiotic lactitol.


CD34+ cell enumeration by flow cytometry: a comparison of systems and methodologies.
An increasing number of medical centers can collect bone marrow, peripheral blood, or umbilical cord stem cells. Pathology laboratories should accommodate this trend, but investment in additional equipment may be impractical. To compare CD34(+) cell counting results by using 2 widely available flow cytometry systems, with and without the use of a separate hematology analyzer (ie, single-platform versus dual-platform methodologies). Whole blood and peripheral blood stem cell (PBSC) samples were analyzed from 13 healthy allogeneic PBSC donors and 46 autologous PBSC donors with various malignancies. The Cytomics FC500 (Beckman Coulter, Fullerton, California) was compared with the FACSCalibur (BD Biosciences, San Jose, California). Dual-platform CD34(+) cell counting incorporated data from a KX-21 hematology analyzer (Sysmex, Kobe, Japan). Subtle differences in CD34(+) cell counting between 2 systems and 2 methods did not achieve statistical significance. Different systems and methods for CD34(+) cell enumeration, properly validated, can support care for patients undergoing transplants and provide meaningful data for multicenter studies or meta-analyses.


Favorable long-term clinical outcome of uncovered D-weave stent placement as definitive palliative treatment for malignant colorectal obstruction.
Most self-expandable metallic stents for colorectal placement are uncovered because of the high migration rate of covered stents. However, the optimal stent design for colorectal use remains unclear. The purpose of this study was to evaluate the efficacy and safety of a double-wire woven uncovered stent for definitive palliative treatment of malignant colorectal obstruction. This study was a prospective, single-arm, observational clinical study of patients enrolled between December 2005 and September 2010. This study was conducted at a referral hospital in Japan. Twenty-four consecutive patients with malignant colorectal obstruction were included in the study. A double-wire woven uncovered stent was placed by use of a standard through-the-scope endoscopic placement technique. Technical, initial clinical, and long-term clinical success were measured. Long-term clinical success was defined as sustained relief of obstructive symptoms without reintervention until the patient's death. The Karnofsky performance status score before stent placement was 60 (median, interquartile range, 42.5-67.5). Twenty of 24 patients had primary colorectal cancer, and 4 had extracolorectal malignancies. The site of obstruction was the ascending colon in 10 patients, descending colon in 4 patients, sigmoid colon in 7 patients, and rectum in 3 patients. Technical, initial, and long-term clinical success rates were 100%, 100%, and 83%. Median stent patency time was 149 days (interquartile range, 45-198 days). Median survival time after stent placement was 155 days (interquartile range, 68-231 days). Four patients (17%) had negative outcomes including stent occlusion by tumor ingrowth (8%) and stent migration (8%). The highest Karnofsky performance status score after stent placement was 70 (median; interquartile range, 50-70). The Karnofsky performance status score improved after stent placement (p = 0.002). This study was limited because it was a single-arm, single-center study, and it had a small sample size. Endoscopic placement of double-wire woven uncovered stents is effective and safe as definitive palliative treatment for patients with malignant colorectal obstruction.


Continuous suction method in superficial temporal artery-middle cerebral artery anastomosis surgery. Technical note.
A new method was developed to maintain a bloodless microscopic operative field for superficial temporal artery-middle cerebral artery (MCA) anastomosis surgery. A silicone suction tube with multiple holes is placed circumferentially under the reflected dural flaps around the craniotomy. Blood and irrigated saline are continuously aspirated by the tube. Use of this method in nine patients significantly reduced the mean MCA trapping time (24.0 +/- 2.8 min) compared with nine patients treated using the conventional method (30.1 +/- 4.6 min). MCA trapping time is shortened because the surgery is not interrupted for manual suctioning of bloody cerebrospinal fluid.


[Organ lesions and chronobiologic structure of circadian rhythm in arterial blood pressure in persons with arterial hypertension].
The relation of 24-hour blood pressure monitoring indices with degree of target-organs damage in 114 non-natives of the Far North who had no previous antihypertensive treatment was studied. It was found out that mean BP influences on developing of chronic forms of vascular brain pathology, microalbuminuria degree correlates with pulse BP level, development of hypertensive retinopathy is associated with excessive variability of day BP.


Gastroduodenal disorders associated with emesis in infants.
Emesis is a common occurrence in newborns and infants. The causes are ubiquitous and unfortunately nonspecific. However, clues exist with respect to the timing of the onset of emesis as well as to its character. Emesis can be bilious or nonbilious, projectile or nonprojectile, and in some patients it is effortless. Newborns and infants with emesis of gastric origin may display a paucity of visible external signs. Ultrasound, contrast radiographic studies, and endoscopy coupled with physical examination are invaluable in the assessment of the emesis. Important in the management is prompt correction of fluid and electrolyte losses. Surgical correction, if warranted, can then be undertaken with significant lessening of morbidity.


[Role of C-type natriuretic peptide receptor and large-conductance calcium-activated potassium channels in brain natriuretic peptide-induced porcine coronary artery dilation].
To investigate the role of C-type natriuretic peptide receptor (NPR-C) and large-conductance calcium-activated potassium channels (BK(Ca)) in brain natriuretic peptide (BNP) induced porcine coronary artery dilation. Porcine coronary artery rings were obtained and treated with BNP (10(-6) mol/L), BNP + NPR-C antagonist cANF4-28 (10(-6) mol/L) and BNP + BK(Ca) blocker tetraethylammonium (TEA, 1 mmol/L). The vascular tone experiments were observed on 10 vessel segments. BK(Ca) current density was measured by the whole-cell patch clamp technique. The maximum diastolic rate was similar between BNP group (68.51% ± 11.50%) and cANF4-28 + BNP group (65.67% ± 11.90%, P > 0.05) while significantly reduced in TEA + BNP group (28.87% ± 4.55%, all P < 0.05). When the holding potential was set at +60 mV, the BK(Ca) current density of BNP group was (78.48 ± 5.86) pA/pF, which was significantly higher than control group [(53.84 ± 4.55) pA/pF, P < 0.05], which was equally reduced in the TEA group and TEA + BNP group [(28.80 ± 2.76) pA/pF and (30.60 ± 3.88) pA/pF respectively, all P < 0.05 vs. control group]. BNP could relax the porcine coronary arterial smooth muscles by increasing BK(Ca) current, and this effect is not mediated by NPR-C.


Agonist-receptor efficacy. I: Mechanisms of efficacy and receptor promiscuity.
The description of drug effects on receptor proteins is based on models and equations used to describe mass-action kinetics of molecules and inert surfaces. These models provide an adequate description of drug affinity, that is, how well a molecule binds to a receptor protein, but the way in which ligands change receptor populations to impart signals to cells remains to be determined. In the first of two articles, Terry Kenakin discusses a basic question in receptor pharmacology, namely the nature of ligand efficacy.


Outbreak of Salmonella Enteritidis phage type 13a: case-control investigation in Hertsmere, United Kingdom.
Cases of illness were reported to Hertsmere Borough Council among attendees of a children's charity event in June 2006. Initial laboratory investigation identified Salmonella Enteritidis PT13a as a possible cause of the outbreak. We carried out an unmatched case-control investigation. The population at risk included all individuals who attended the event. Self-completion questionnaires were sent to 53 presumptive cases and 212 randomly selected potential controls. Information was available for 49 cases and 128 controls (overall response rate=75%). We calculated odds ratios from single and multivariable analysis and tested for all two-way interactions. Risk factors for diarrhoea were eating egg mayonnaise bagels (OR=34.1, 95%CI 10.5 - 111.3) and drinking apple juice (OR=16.1, 95% CI 3.5 - 74.2). There was weak statistical evidence to suggest that the risk of diarrhoea after eating egg mayonnaise bagels was greater in the afternoon. No food samples were available to confirm which food item might have caused this outbreak. Eggs from Spain were used by the caterer. The ecology of salmonella, experience from previous outbreaks and epidemiological findings from this case-control investigation suggest that the most likely cause of the outbreak was contaminated eggs.


Effects of an anti-androgen in the laying hen (Gallus domesticus).
The daily injection of the anti-androgen, cyproterone acetate, into regularly laying hens failed to prevent ovulation immediately. The delayed response suggested that testosterone is not part of the ovarian positive feedback stimulus resulting from the presence of an ovulable follicle and leading to ovulation. Ovarian changes in treated birds, and their unimpaired response to LH-RH, suggested that the drug might be acting by altering ovarian steroid metabolism.


MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.
Feingold syndrome is characterized by variable combinations of esophageal and duodenal atresias, microcephaly, learning disability, syndactyly and cardiac defect. We show here that heterozygous mutations in the gene MYCN are present in Feingold syndrome. All mutations are predicted to disrupt both the full-length protein and a new shortened MYCN isoform, suggesting that multiple aspects of early embryogenesis and postnatal brain growth in humans are tightly regulated by MYCN dosage.


Case-Mix Adjustment of the Bereaved Family Survey.
Surveys of bereaved family members are increasingly being used to evaluate end-of-life (EOL) care and to measure organizational performance in EOL care quality. The Bereaved Family Survey (BFS) is used to monitor EOL care quality and benchmark performance in the Veterans Affairs (VA) health-care system. The objective of this study was to develop a case-mix adjustment model for the BFS and to examine changes in facility-level scores following adjustment, in order to provide fair comparisons across facilities. We conducted a cross-sectional secondary analysis of medical record and survey data from veterans and their family members across 146 VA medical centers. Following adjustment using model-based propensity weighting, the mean change in the BFS-Performance Measure score across facilities was -0.6 with a range of -2.6 to 0.6. Fifty-five (38%) facilities changed within ±0.5 percentage points of their unadjusted score. On average, facilities that benefited most from adjustment cared for patients with greater comorbidity burden and were located in urban areas in the Northwest and Midwestern regions of the country. Case-mix adjustment results in minor changes to facility-level BFS scores but allows for fairer comparisons of EOL care quality. Case-mix adjustment of the BFS positions this National Quality Forum-endorsed measure for use in public reporting and internal quality dashboards for VA leadership and may inform the development and refinement of case-mix adjustment models for other surveys of bereaved family members.


Strawberry vein banding virus isolates in eastern Canada are molecularly divergent from other isolates.
The complete sequence of a strawberry vein banding virus (SVBV) isolate collected in Nova Scotia, Canada, and designated NS8, was determined. The 7,856-nucleotide circular double-stranded DNA genome contains seven open-reading frames (ORFs), which is consistent with other SVBV isolates and other members of the genus Caulimovirus. Comparison of NS8 with other whole-genome sequences retrieved from databases revealed that NS8 shares the highest sequence similarity (96.5% identity) with isolate China (accession number HE681085) and the lowest (88.3% identity) with clone pSVBV-E3 (accession number X97304). Despite the overall high sequence similarity between NS8 and China, the coat protein encoding ORF IV of NS8 shares only 90.9% sequence identity with the China isolate. Phylogenetic analysis at the complete-genome level placed NS8 and all Chinese isolates in one clade and clone pSVBV-E3 in a separate clade. Interestingly, phylogenetic analysis of all available ORF IV sequences, including those retrieved from databases and newly sequenced samples in this study from Canada, revealed three distinct clades. All Canadian isolates grouped together as one clade, pSVBV-E3 and several others from Europe, Egypt and the USA grouped as a second clade, and isolates from China formed a third clade. These results demonstrate that SVBV is more divergent than previously reported.


Malignant transformation in craniopharyngioma after radiation therapy: a case report and review of the literature.
Craniopharyngioma is a benign epithelial tumor that is thought to arise from the remnant of the Rathke pouch. Malignant transformation in craniopharyngioma is extremely rare. Herein, we report a case of malignant transformation in craniopharyngioma after radiation therapy. Histopathological and immunohistochemical analyses were carried out for specimens of the suprasellar tumor (from three resections, with the third surgery performed after radiation therapy). The resected tumors from the first and second surgeries comprised islands of loosely cohesive aggregates of epithelial cells, so-called stellate reticulum. At the periphery of the nests, palisaded columnar epithelium was observed. Wet keratins were scattered, and few mitotic figures were seen. The third surgical specimen was composed of irregular large nests of basaloid cells that had large, round to oval nuclei with prominent nucleoli, and mitotic figures were frequently seen (21/10 high power fields). In the center of the nests, eosinophilic ghost cells, resembling wet keratin, were observed. Accordingly, the diagnosis of malignant transformation in craniopharyngioma was made. Immunohistochemical studies revealed that the p53 protein was over-expressed in the malignant component, whereas its expression was much lower in the benign component. Similar to the ten previously reported cases of malignant transformation in craniopharyngioma, the present case occurred after radiation therapy. p53 protein overexpression was also observed in the earlier cases of malignant craniopharyngioma as well as in the present case (6/6 cases). We concluded that radiation therapy and p53 mutations could be involved in malignant transformation in craniopharyngioma.


Antiparasitic activity of two Lavandula essential oils against Giardia duodenalis, Trichomonas vaginalis and Hexamita inflata.
Two essential oils derived from Lavandula angustifolia and Lavandula x intermedia were investigated for any antiparasitic activity against the human protozoal pathogens Giardia duodenalis and Trichomonas vaginalis and the fish pathogen Hexamita inflata: all of which have significant infection and economic impacts. The study has demonstrated that low (< or = 1%) concentrations of L. angustifolia and L. x intermedia oil can completely eliminate T. vaginalis, G. duodenalis and H. inflata in vitro. At 0.1% concentration, L. angustifolia oil was found to be slightly more effective than L x intermedia oil against G. duodenalis and H. inflata. The potential applications are discussed.


Genetic analysis of mefloquine-resistant mechanism of Plasmodium falciparum.
We studied DNA sequence polymorphism, expression level of pfmdr1 gene and sensitivity of major antimalarial drugs in both mefloquine sensitive and resistant strains to elucidate mechanism of mefloquine resistance. Mefloquine-resistant 523a R/24 strain exhibited decreased susceptibility to mefloquine, artemisinin and halofantrine whereas increased susceptibility to chloroquine. We found a novel point mutation in pfmdr1 gene of 523a R/24 strain. Moreover, overexpression of mRNA of pfmdr1 has been observed in this strain. In addition, functional analysis by pfmdr1 antisense revealed correlation of mefloquine sensitivity with expression level of pfmdr1. We suggest that gene mutation and overexpression of pfmdr1 may be associated with mechanism of mefloquine resistance.


Geminin in embryonic development: coordinating transcription and the cell cycle during differentiation.
Geminin was initially characterized as a bifunctional protein with roles in regulating the fidelity of DNA replication and in controlling cell fate during embryonic nervous system formation. More recently, Geminin's roles have expanded, encompassing regulation of cell proliferation and differentiation during retinogenesis, control of Hox transcription factor function during vertebrate axial patterning, and regulation of the timing of neuronal differentiation. Geminin interacts with homeodomain-containing transcription factors and with protein complexes that regulate chromatin structure, including Polycomb complexes and the catalytic subunits of the SWI/SNF chromatin remodeling complex, Brg1 and Brahma. Activities for Geminin in coordinating cellular events at the transition from proliferation to differentiation have recently emerged in multiple developmental contexts. This review will summarize Geminin's increasingly diverse roles as a developmental regulatory molecule.


A study on the in vitro percutaneous absorption of silver nanoparticles in combination with aluminum chloride, methyl paraben or di-n-butyl phthalate.
Some reports indicate that the silver released from dermally applied products containing silver nanoparticles (AgNP) (e.g. wound dressings or cosmetics) can penetrate the skin, particularly if damaged. AgNP were also shown to have cytotoxic and genotoxic activity. In the present study percutaneous absorption of AgNP of two different nominal sizes (Ag15nm or Ag45nm by STEM) and surface modification, i.e. citrate or PEG stabilized nanoparticles, in combination with cosmetic ingredients, i.e. aluminum chloride (AlCl3), methyl paraben (MPB), or di-n-butyl phthalate (DBPH) was assessed using in vitro model based on dermatomed pig skin. The inductively coupled plasma mass spectrometry (ICP-MS) measurements after 24h in receptor fluid indicated low, but detectable silver absorption and no statistically significant differences in the penetration between the 4 types of AgNP studied at 47, 470 or 750μg/ml. Similarly, no significant differences were observed for silver penetration when the AgNP were used in combinations with AlCl3 (500μM), MPB (1250μM) or DBPH (35μM). The measured highest amount of Ag that penetrated was 0.45ng/cm2 (0.365-0.974ng/cm2) for PEG stabilized Ag15nm+MPB.


[Effects of CCR5-delta32, CCR2-64I and SDF-1-3'A polymorphic alleles on human immunodeficiency virus 1 (HIV-1) infection in the Polish population].
Among many factors that can influence vulnerability to infection and disease progression are genetic host factors together with the phenotype/genotype of the transmitting virus and the route of infection. Each of these factors alone or in combination could determine susceptibility to infection and subsequent rate of progression towards AIDS. Between host genetic factors identified and analyzed for their role in HIV-1 transmission and disease progression are polymorphisms in the genes encoding chemokine receptors and CCR5, CCR2 and SDF-1 a natural ligand for CXCR4 receptor. It has been shown that the distribution of this genetic polymorphisms and their role in the course of disease varies between different racial, ethnic and risk groups. The aim of present study was to examine the frequencies of polymorphic alleles CCR5-delta32, CCR2-64I and SDF-1-3'A and their role in human immunodeficiency virus (HIV-1) transmission in Polish population. The allelic and genotype distribution was studied in 103 HIV-1 infected patients (group HIV+) and 59 seronegative participants (group HIV-). Genotyping was done by the use of polymerase chain reaction with sequence-specific primers and restriction fragment length polymorphism. We found higher prevalence of CCR5-delta32 mutant allele among seronegative participants (13.6%) compared with HIV-infected patients (9.7%), although this did not attain statistical significance (p = 0.29). The CCR2-64I allelic frequency was almost identical in the HIV- and HIV+ groups (12.7% vs. 12.6%; respectively; p = 0.98). In contrast, the SDF-1-3'A allelic frequency was slightly lower among seronegative participants (15.3%) compared with HIV-infected patients (16.5%), and observed difference was not statistically significant (p = 0.77). Furthermore, we found that the genotype or allelic frequencies among HIV-1 infected patients were independent on the participant's sex, age at HIV-1 infection and the transmission route. Our results showed no significant differences in the prevalence of examined alleles and genotypes between HIV-1 infected patients and seronegative participants, which indicates that in the examined population they are not influencing host susceptibility to the HIV-1 infection.


Bent spine syndrome as an early manifestation of myotonic dystrophy type 1.
Myotonic dystrophy type 1 (DM1) is highly variable systemic disorder with prominent myopathic involvement in distal limb, facial, and jaw muscles. Bent spine syndrome presents a diagnostic challenge, and usually, DM1 is not included in the differential. We report 2 cases of DM1 with bent spine syndrome. To further investigate this phenomenon, we compared weakness patterns in a cohort of DM1 with cohorts of amyotrophic lateral sclerosis and inclusion body myositis and found that neck extension weakness is most pronounced in DM1. Our findings emphasize the heterogeneity of DM1 and underscore the importance of considering DM1 as a cause of bent spine syndrome.


Effect of PGR5 impairment on photosynthesis and growth in Arabidopsis thaliana.
PGR5 has been reported as an important factor for the activity of the ferredoxin-dependent cyclic electron transport around PSI. To elucidate the role of PGR5 in C(3) photosynthesis, we characterized the photosynthetic electron transport rate (ETR), CO(2) assimilation and growth in the Arabidopsis thaliana pgr5 mutant at various irradiances and with CO(2) regimes. In low-light-grown pgr5, the CO(2) assimilation rate and ETR were similar to the those of the wild type at low irradiance, but decreased at saturating irradiance under photorespiratory conditions as well as non-photorespiratory conditions. Although non-photochemical quenching of chlorophyll fluorescence (NPQ) was not induced in the pgr5 mutant under steady-state photosynthesis, we show that it was induced under dark to light transition at low CO(2) concentration. Under low light conditions in air, pgr5 showed the same growth as the wild type, but a significant growth reduction compared with the wild type at >150 mumol photons m(-2) s(-1). This growth impairment was largely suppressed under high CO(2) concentrations. Based on the intercellular CO(2) concentration dependency of CO(2) assimilation, ETR and P700 oxidation measurements, we conclude that reduction of photosynthesis and growth result from (i) ATP deficiency and (ii) inactivation of PSI. We discuss these data in relation to the role of PGR5-dependent regulatory mechanisms in tuning the ATP/NADPH ratio and preventing inactivation of PSI, especially under conditions of high irradiance or enhanced photorespiration.


Does early ultrasonography affect management of pediatric appendicitis? A prospective analysis.
Appendicitis remains a difficult diagnosis in children. Ultrasonography is increasingly used for the diagnosis of appendicitis, although the proper clinical role for this test remains unclear. To evaluate the clinical utility of ultrasonography in appendicitis, the authors analyzed prospectively all children evaluated for possible appendicitis from January 1 through December 31, 1997. Children with a high clinical suspicion of appendicitis were referred for surgery (n = 122). Children with equivocal findings of appendicitis were referred for early ultrasonography (EUS) and formed the study cohort (n = 103). An initial management plan was made to operate or observe each patient, and a risk of appendicitis (doubtful, possible, probable) was assigned by a pediatric surgery fellow. EUS was then performed, and its effect on management was assessed. Using clinical judgment to operate at initial presentation, the sensitivity was 38% and specificity was 95%. Using EUS alone, the sensitivity was 87% and specificity was 88%. The management of 30 of 103 patients (30%) was changed after EUS, including a decision to operate in 28 patients and a decision not to operate in two patients. EUS appears to have substantial clinical utility in children with equivocal findings of appendicitis, and its use complements the clinical management. The use of EUS can improve patient care and reduce hospital resource utilization.


Antibody-targeted cell fusion.
Membrane fusion has many potential applications in biotechnology. Here we show that antibody-targeted cell fusion can be achieved by engineering a fusogenic viral membrane glycoprotein complex. Three different single-chain antibodies were displayed at the extracellular C terminus of the measles hemagglutinin (H) protein, and combinations of point mutations were introduced to ablate its ability to trigger fusion through the native viral receptors CD46 and SLAM. When coexpressed with the measles fusion (F) protein, using plasmid cotransfection or bicistronic adenoviral vectors, the retargeted H proteins could mediate antibody-targeted cell fusion of receptor-negative or receptor-positive index cells with receptor-positive target cells. Adenoviral expression vectors mediating human epidermal growth factor receptor (EGFR)-targeted cell fusion were potently cytotoxic against EGFR-positive tumor cell lines and showed superior antitumor potency against EGFR-positive tumor xenografts as compared with control adenoviruses expressing native (untargeted) or CD38-targeted H proteins.


Computer-aided navigation in dental implantology: 7 years of clinical experience.
This long-term study gives a review over 7 years of research, development, and routine clinical application of computer-aided navigation technology in dental implantology. Benefits and disadvantages of up-to-date technologies are discussed. In the course of the current advancement, various hardware and software configurations are used. In the initial phase, universally applicable navigation software is adapted for implantology. Since 2001, a special software module for dental implantology is available. Preoperative planning is performed on the basis of prosthetic aspects and requirements. In clinical routine use, patient and drill positions are intraoperatively registered by means of optoelectronic tracking systems; during preclinical tests, electromagnetic trackers are also used. In 7 years (1995 to 2002), 55 patients with 327 dental implants were successfully positioned with computer-aided navigation technology. The mean number of implants per patient was 6 (minimum, 1; maximum, 11). No complications were observed; the preoperative planning could be exactly realized. The average expenditure of time for the preparation of a surgical intervention with navigation decreased from 2 to 3 days in the initial phase to one-half day in clinical routine use with software that is optimized for dental implantology. The use of computer-aided navigation technology can contribute to considerable quality improvement. Preoperative planning is exactly realized and intraoperative safety is increased, because damage to nerves or neighboring teeth can be avoided.


The ideal biological response modifier.
The current focus on interleukin-2 typifies the transition in cancer immunotherapy from nonspecific immunostimulants that are broadly supportive to highly defined cytokines with greater stress on treatment. With the introduction of lymphokine-activated killer cells, there was a parallel shift in emphasis from the use of allogeneic adoptive lymphocytes to in vitro expanded autologous cells. On the assumption that there should be a place for a more complete biological response modifier (BRM) applicable as a fundamental agent that would provide maximum support for all treatment modalities and that might facilitate the adoptive use of incompatible mononuclear cells when needed, an attempt was made to draw on the extensive experience with the large number of BRMs that have been studied to define the characteristics and therapeutic activities of an agent that would be ideally suited. It is ironic that the mitogenic lectins have tended to be overlooked in BRM classifications, but compelling evidence suggests that PHA-L4, the L4 isolectin of phytohemagglutinin, might at least partially fulfill all of the criteria of an ideal BRM.


Expression of tabersonine 16-hydroxylase and 16-hydroxytabersonine-O-methyltransferase in Catharanthus roseus hairy roots.
The monoterpene indole alkaloids vindoline and catharanthine, which are exclusively synthesized in the medicinal plant Catharanthus roseus, are the two important precursors for the production of pharmaceutically important anti-cancer medicines vinblastine and vincristine. Hairy root culture is an ideal platform for alkaloids production due to its industrial scalability, genetic and chemical stability, and availability of genetic engineering tools. However, C. roseus hairy roots do not produce vindoline due to the lack of expression of the seven-step pathway from tabersonine to vindoline [Murata & De Luca (2015) Plant Journal, 44, 581-594]. The present study describes the genetic engineering of the first two genes tabersonine 16-hydroxylase (T16H) and 16-O-methyl transferase (16OMT) in the missing vindoline pathway under the control of a glucocorticoid-inducible promoter to direct tabersonine toward vindoline biosynthesis in C. roseus hairy roots. In two transgenic hairy roots, the induced overexpression of T16H and 16OMT resulted in the accumulation of vindoline pathway metabolites 16-hydroxytabersonine and 16-methoxytabersonine. The levels of root-specific alkaloids, including lochnericine, 19-hydroxytabersonine and hörhammericine, significantly decreased in the induced hairy roots in comparison to the uninduced control lines. This suggests tabersonine was successfully channeled to the vindoline pathway away from the roots competing pathway based on the overexpression. Interestingly, another two new metabolites were detected in the induced hairy roots and proposed to be the epoxidized-16-hydroxytabersonine and lochnerinine. Thus, the introduction of vindoline pathway genes in hairy roots can cause unexpected terpenoid indole alkaloids (TIA) profile alterations. Furthermore, we observed complex transcriptional changes in TIA genes and regulators detected by RT-qPCR which highlight the tight regulation of the TIA pathway in response to T16H and 16OMT engineering in C. roseus hairy roots.


Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole.
Methylprednisolone is a widely used glucocorticoid. In this study, a possible interaction of itraconazole, a potent inhibitor of CYP3A4, with orally administered methylprednisolone was examined. In this double-blind, randomized, 2-phase crossover study, 10 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a dose of 16 mg methylprednisolone. Plasma concentrations of methylprednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined by HPLC up to 24 hours. Itraconazole increased the total area under the plasma methylprednisolone concentration-time curve 3.9-fold compared with placebo (1968 +/- 470 ng.hr/mL versus 520 +/- 125 ng.hr/mL [mean +/- SD]; P < .001). The peak plasma concentration of methylprednisolone was increased 1.9-fold (221 +/- 49 ng/mL versus 118 +/- 25 ng/mL; P < .001), and its elimination half-life was increased 2.4-fold (4.4 +/- 0.7 hours versus 1.9 +/- 0.3 hours; P < .001) by itraconazole. The mean plasma cortisol concentration during the itraconazole phase, measured 24 hours after ingestion of methylprednisolone, was only about 13% of that during the placebo phase (18 +/- 23 ng/mL versus 139 +/- 60 ng/mL; P < .001). Itraconazole considerably increases plasma concentrations and effects of oral methylprednisolone, probably by inhibiting its CYP3A4-mediated metabolism. Care should be taken if itraconazole or other potent inhibitors of CYP3A4 are used concomitantly with oral methylprednisolone, particularly during long-term use.


Biomarkers in neuroendocrine tumors.
Neuroendocrine tumors are a heterogeneous group of tumors with cells of neuroendocrine differentiation that arise from diverse anatomic sites with varying morphologic and clinical features. Since the natural history and prognosis varies widely between individual neuroendocrine tumor types, there is a critical need to identify accurate prognostic and predictive biomarkers and markers predictive of therapeutic efficacy. To date, plasma chromogranin-A levels have generally been accepted as the most useful biomarker, despite the fact that there are substantial concerns in sensitivity and discrepancies in measurement techniques. As a consequence, considerable attention has been focused upon the development of novel biomarkers that can be utilized with more clinical efficacy than chromogranin-A. In addition to amplifying the diagnostic/prognostic landscape, the need to calibrate the efficacy of biological targeted therapy has further accelerated the development of molecular biomarkers. At the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, Chou et al. (Abstract #e15151) presented data that chromogranin A levels can be monitored during treatment to predict clinical outcome. Modlin et al. (Abstract #4137), demonstrated a promising novel biomarker, serum multi-transcript molecular signature. Grande et al. (Abstract #4140), Heetfield et al. (Abstract #e15071) and Casanovas et al. (Abstract #4139) described sVEGFR2, p-mTOR and IGF1R as molecular markers with potential for use in targeted therapy trials. The authors review and summarize these abstracts in this article.


Mode of action of polyethylene glycol 6000 in potentiating the in vitro generation of antitumor cytotoxicity by MOPC-315 tumor bearer spleen cells.
Some of the possible mechanisms by which polyethylene glycol (PEG) augments the ability of MOPC-315 tumor bearer spleen cells to mediate in vitro antitumor cytotoxicity were evaluated. The level of antitumor cytotoxicity obtained in 5-day cultures of tumor bearer spleen cell suspensions correlated inversely with the percentage of Trinitrophenol (TNP)-rosettable cells (presumably metastatic tumor cells) present in the spleen. The kinetics of decrease in the percentage of TNP-rosettable cells coincided with the appearance of antitumor cytotoxicity. In addition, PEG was shown to interfere with the ability of viable tumor cells to suppress the in vitro generation of antitumor cytotoxicity in normal spleen cells cultured with mitomycin C-treated tumor cells. However, the decrease in the content of TNP-rosettable cells and the concurrent increase in the level of antitumor cytotoxicity were not due to direct cytotoxic and/or cytostatic effects of PEG on tumor cells. Spleen cells cultured in the presence of PEG had an increased rate of [3H]thymidine incorporation and proliferation compared to spleen cells cultured in the absence of PEG. However, the PEG-induced decrease in the percentage of TNP-rosettable cells either preceded or occurred at the same time that the PEG-induced increase in spleen cell number was observed. Therefore, spleen cell proliferation can at best explain only partially the PEG-induced decrease in the content of TNP-rosettable cells, and other mechanisms for the decrease must be considered.


Ultrastructural aspects of lingual papillae in squirrel monkey (Saimiri sciureus).
Saimiri sciureus is one of the smallest Cebidae native of Amazon region and also found at the biological reserve of northeast Atlantic forest. It is an omnivore animal, with diversified diet that directly influences the lingual mucosa, which includes certain types of papillae with different organization levels. The present study attempted to describe the morphological and ultrastructure aspects of the dorsal surface of the S. sciureus. Five tongues of de S. sciureus were analyzed from three males and two females who died from natural causes and were obtained from breeding colonies of CENP-Ananindeua-PA. Main macroscopic features were a general triangular shape with a craniocaudal elongation pointed apex. Tissue samples--apex, body, and root of tongue--were fixed in modified Karnovsky solution, following standard scanning protocol, mounted in stubs, coated by gold, and analyzed by Scanning Electron Macroscopy (SEM). Four types of papillae were described: filiform (along all tissue extension with 154 μm of diameter), fungiform (along all tissue extension with 272 μm of diameter), vallate [just three units in caudal (dorsal) portion with 830 μm of diameter] and foliate (one pair at caudolateral surface with ∼ 13 projections and 3000 μm in length). Data analysis indicates that the distribution and ultra structural morphology of the S. sciureus lingual papillae are some similar to other primates.


Distribution of tachykinin- and opioid-expressing neurons in the hamster solitary nucleus: an immuno- and in situ hybridization histochemical study.
In several sensory systems, tachykinin- and opioid-expressing neurons functionally interact and influence the processing of afferent information. To determine whether a similar relationship exists for the processing of general and special (gustatory) visceral afferent information, the present study mapped the distributions of these two neuronal phenotypes within the nucleus of the solitary tract (NST) of the hamster by employing a combination of immuno- and in situ hybridization histochemistry (ISHH). The hamster was chosen because it is frequently used as a model in taste studies, yet there is a relative dearth of data about peptide expression or the classical neurotransmitters in the brainstem of this animal. The immunohistochemical analyses employed 2 highly selective antisera directed towards the prototypical tachykinin and opioid peptides, i.e. substance P (SP) and methionine enkephalin (ENK), respectively. Intense staining of fibers and preterminal/terminal puncta was concentrated in the rostral pole or gustatory zone of the NST. SP-, but not ENK-like immunoreactivity was also observed in long courses of axon bundles traversing the brainstem enroute to the NST. Local application of colchicine engendered the appearance of a moderate number of SP-positive somata that were mostly clustered in the medial, central and intermediate subnuclei, as well as being scattered throughout the remainder of the NST, including the gustatory zone. A low number of isolated ENK-positive somata were also observed throughout the NST. The somal areas of the SP- and ENK-positive somata averaged 86.3 and 81.8 microns 2, respectively. The ISHH studies were performed using 2 selective oligodeoxynucleotide probes with complementary sequences to mRNAs encoding gamma-preprotachykinin (PPT) and preproenkephalin (PPE) molecules. Overall, the cellular expression of PPT mRNA within the NST corresponded both in distribution and in number to those identified by immunohistochemical analyses using anti-SP serum. In contrast, ISHH analyses monitored a significantly greater number of PPE-expressing somata in the medial, central, intermediate and ventrolateral nuclei than were ENK immunoreactive. These findings indicate that tachykinin and opioid peptide phenotypes are represented in neurons throughout the hamster NST and suggest a functional role for PPT- and PPE-related peptide forms in the modulation of afferent general visceral and gustatory information.


Recurrent juvenile ischemic stroke caused by bow hunter's stroke revealed by carotid duplex ultrasonography.
Bow hunter's stroke (BHS) is a rare cause of vertebrobasilar insufficiency due to rotational vertebral artery (VA) occlusion associated with head turning. We report a juvenile patient presenting with recurrent ischemic stroke caused by BHS, which was revealed by carotid duplex ultrasonography. Carotid duplex ultrasonography performed in the neutral position showed normal findings. However, disappearance of end-diastolic blood flow of contralateral VAs was observed with head rotation. Digital subtraction angiography confirmed occlusion at C1/2 levels in the VA contralateral to the head rotation, bilaterally. Importantly, our patient did not recognize the association of head rotation and previous episodes of stroke. We suggest that BHS should be considered in patients with cryptogenic stroke occurring in the vertebrobasilar artery territory.


Diabetes Mellitus and Heart Failure.
Epidemiologic and clinical data from the last 2 decades have shown that the prevalence of heart failure in diabetes is very high, and the prognosis for patients with heart failure is worse in those with diabetes than in those without diabetes. Experimental data suggest that various mechanisms contribute to the impairment in systolic and diastolic function in patients with diabetes, and there is an increased recognition that these patients develop heart failure independent of the presence of coronary artery disease or its associated risk factors. In addition, current clinical data demonstrated that treatment with the sodium glucose cotransporter 2 inhibitor empagliflozin reduced hospitalization for heart failure in patients with type 2 diabetes mellitus and high cardiovascular risk. This review article summarizes recent data on the prevalence, prognosis, pathophysiology, and therapeutic strategies to treat patients with diabetes and heart failure.


Operationalising caseload midwifery in the Australian public maternity system: Findings from a national cross-sectional survey of maternity managers.
Despite high-level evidence of the benefits of caseload midwifery for women and babies, little is known about specific practice arrangements, organisational barriers and facilitators, nor about workforce requirements of caseload. This paper explores how caseload models across Australia operate. A national cross-sectional, online survey of maternity managers in public maternity hospitals with birthing services was undertaken. Only services with a caseload model are included in the analysis. Of 253 eligible hospitals, 149 (63%) responded, of whom 44 (31%) had a caseload model. Operationalisation of caseload varied across the country. Most commonly, caseload midwives were required to work more than 0.5 EFT, have more than one year of experience and have the skills across the whole scope of practice. On average, midwives took a caseload of 35-40 women when full time, with reduced caseloads if caring for women at higher risk. Leave coverage was complex and often ad-hoc. Duration of home-based postnatal care varied and most commonly provided to six weeks. Women's access to caseload care was impacted by many factors with geographical location and obstetric risk being most common. Introducing, managing and operationalising caseload midwifery care is complex. Factors which may affect the expansion and availability of the model are multi-faceted and include staffing and model inclusion guidelines. Coverage of leave is a factor which appears particularly challenging and needs more focus.


Effect of the natural ATPase inhibitor on the binding of adenine nucleotides and inorganic phosphate to mitochondrial F1-ATPase.
(1) Incubation of the beef heart mitochondrial ATPase, F1 with Mg-ATP was required for the binding of the natural inhibitor, IF1, to F1 to form the inactive F1-IF1 complex. When F1 was incubated in the presence of [14C]ATP and MgCl2, about 2 mol 14C-labeled adenine nucleotides were found to bind per mol of F1; the bound 14C-labeled nucleotides consisted of [14C]ADP arising from [14C]ATP hydrolysis and [14C]ATP. The 14C- labeled nucleotide binding was not prevented by IF1. These data are in agreement with the idea that the formation of the F1-IF1 complex requires an appropriate conformation of F1. (2) The 14C-labeled adenine nucleotides bound to F1 following preincubation of F1 with Mg-[14C] ATP could be exchanged with added [3H]ADP or [3H]ATP. No exchange occurred between added [3H]ADP or [3H]ATP and the 14 C-labeled adenine nucleotides bound to the F1-IF1 complex. These data suggest that the conformation of F1 in the isolated F1-IF1 complex is further modified in such a way that the bound 14C-labeled nucleotides are no longer available for exchange. (3) 32Pi was able to bind to isolated F1 with a stoichiometry of about 1 mol of Pi per mol of F1 (Penefsky, H.S. (1977) J. Biol. Chem. 252, 2891-2899). There was no binding of 32Pi to the F1-IF1 complex. Thus, not only the nucleotides sites, but also the Pi site, are masked from interaction with external ligands in the isolated F1-IF1 complex.