Ethanol-induced increased surface-localized fibrinolytic activity in cultured human endothelial cells: kinetic analysis.
Moderate alcohol consumption is associated with reduced risk for coronary heart disease and this cardioprotection may be due, in part, to increased fibrinolysis. We have previously demonstrated that low concentrations of ethanol (0.1%, v/v) induce the short-term (<1 hr) and sustained, long-term (24 hr) increase in surface-localized fibrinolytic activity; it up-regulates t-PA, u-PA, and the candidate plasminogen receptor (PmgR), annexin II, and gene transcription in cultured human umbilical vein endothelial cells (HUVECs). These studies describe the short- and long-term effects of low concentrations of ethanol on the kinetics of cell-bound 125I-labeled Glu-plasminogen (Glu-Pmg) activation by receptor (R)-bound t-PA, resulting in increased fibrinolytic activity in cultured HUVECs. Live cultured HUVECs were incubated with varying concentrations of Glu-Pmg (0.25-2 /M) and ethanol (0.025-0.1%, v/v) (in the presence of Aprotinin and alpha2-antiplasmin) and the direct activation of cell-bound 125I-labeled Glu-Pmg quantitated by measurement of 125I-labeled Mr 20 kDa plasmin light-chain, after reduction/SDS-PAGE. The effects of ethanol on '25I-labeled Glu-Pmg and t-PA ligand binding were determined by Scatchard analysis (Bmax, sites/cell). Cell-bound t-PA (endogenous/exogenous) activation of cultured HUVEC-bound 125I-labeled Glu-Pmg (short- and long-term) obeyed Michaelis-Menten kinetics, both in the absence/presence of low ethanol, as shown by Lineweaver-Burke plot analysis. In the short-term, ethanol (at 0.1%) increased the Vmax (2.5-fold), kcat (2-fold) and the apparent kcat/Km (4-fold), commensurate with a significant decrease in the apparent Km (6-fold) and increase in '25I-labeled Glu-Pmg ligand binding, Bmax (2-fold). In the long-term, ethanol increased the Vmax (2- to 3-fold), kcat (2.5-fold), apparent kcat/Km (5-fold), and Bmax (2-fold) for 125I-labeled Glu-Pmg ligand binding, without significantly affecting the apparent K . Low concentrations of ethanol induce the short- versus long-term increase in surface-localized fibrinolytic activity in cultured HUVECs via different mechanisms. Short-term effects may be mediated by ethanol-induced membrane conformational changes that simultaneously facilitate increased surface-localized HUVEC PmgR availability and fibrinolytic protein/receptor interactions, resulting in the increased affinity of t-PA for Glu-Pmg and the accelerated activation of Glu-Pmg (increased Bmax, decreased apparent Km). The long-term effects may be attributed primarily to the ethanol-induced increased availability of both newly synthesized t-PA and PmgR and, hence, the accelerated activation of Glu-Pmg (increased Bmax)


Personal recollection. Some Chicago aberrations.
This article presents my reminiscences of the work in Chicago on the correction or reduction of lens aberrations. Studies began in the early 1960s and extended over a period of almost 40 years, although it was never the primary focus of the work of the laboratory. The account is almost entirely based on my own memory, which is not a very reliable instrument. It is not intended to be a review and is more accurately describable as a personal recollection.


Fast platelet suppression by lysine acetylsalicylate in chronic stable coronary patients. Potential clinical impact over regular aspirin for coronary syndromes.
The rapid utilization of fibrinolytics following Q-wave myocardial infarction has clearly modified the evolution of this disease. However, it is still not known whether the immediate inhibition of platelet aggregation (PA) during the coronary event improves outcomes. The present study was designed to test, in patients with known coronary artery disease (chronic stable angina), whether the particular kinetic pattern of lysine acetylsalicylate (LA) compared with aspirin may affect the time to onset of inhibition of platelet aggregation. Ten patients suffering from chronic stable angina participated in this study to compare the efficacy and speed of the inhibition of PA with 320 mg of LA versus 320 mg of aspirin. All patients discontinued the use of aspirin and any other anti-inflammatory agents for 15 days prior to the beginning of the study. They were randomly assigned to LA or aspirin. Blood specimens were obtained to measure the PA at admission, and 5, 10, 20, 30, and 60 min after ingestion. Patients continued to take the assigned drug once a day for the following 4 days. On Day 5, a new blood sample was taken. After this, patients underwent a 15-day wash-out period, and then crossed over to the opposite drug. The samples were analyzed immediately using platelet-rich plasma stimulated with adenosine diphosphate (ADP) 2 mumol/l, collagen 1 microgram/ml, epinephrine 20 mumol/l, and sodium arachidonate acid 0.75 mm/l. The same level of PA inhibition after 30 and 60 min of aspirin administration can be obtained with LA 5 min following ingestion (sodium arachidonate acid: LA: 16.3 +/- 25.9 vs. aspirin 57.6 +/- 8.2; p = 0.00014; collagen: LA 18.9 +/- 20.1 vs. aspirin 47.2 +/- 10.5; p = 0.00092; ADP: LA 27.3 +/- 18.4 vs. aspirin 39.7 +/- 21.8, p = 0.18; epinephrine: LA 22.0 +/- 9.9 vs. aspirin 55.4 +/- 10.9, p = 0.00002. Platelet aggregation inhibition immediately following LA may have significant clinical implications for the treatment of coronary syndromes.


[Effect of polyene macrolide antibiotics on normal and cell wall deficient Escherichia coli W1655F+ cells].
The polyene macrolide antibiotics are active against yeast, fungi, and other eukaryotic cells, but are with a few exceptions inactive against bacteria. The resistance of bacteria against these compounds is usually explained by the absence of sterols in their cells, the target sites of polyene antibiotics. However, in our experiments with mycotrienin, nystatin, tetramycin, lucenosmycin, rimocidin, filipin, lagosin, flavofungin, flavomycoin, antibiotic 2814P, antibiotic 5001P, and candicidin it was demonstrated that bacteria may be susceptible to polyene antibiotics, too, if the wall-less stable protoplast type L-form of E. coli W1655F+ is used. The measured growth inhibition concentrations were comparable with those of typical antibacterial antibiotics. Our experiments have shown that the normal rod form and the wall-less L-form of E. coli W1655F+ contain traces of sterols in nearly the same concentration range. This means that the selective sensitivity of the L-form cannot be explained by higher sterol content of these cells in comparison to the resistant normal rod form cells. We assume that the bacterial cell wall is responsible for the resistance of the normal rod form by masking internal target sites.


Utility of the Structured Interview of Reported Symptoms (SIRS-2) in detecting feigned adult attention-deficit/hyperactivity disorder.
Introduction: The Structured Interview of Reported Symptoms (SIRS-2) utilizes various strategies in the detection of simulated psychiatric disorders. The present study aimed to examine which of these strategies proves most useful in uncovering feigned attention deficit hyperactivity disorder (ADHD) in adulthood. Method: One-hundred seventy-one individuals instructed to feign ADHD were compared to 46 genuine patients with ADHD as well as 99 neurotypical controls in their reports provided on the SIRS-2. Results: Responses provided by simulators resembled those of genuine patients with ADHD on all SIRS-2 subscales with the exception of a supplementary scale tapping Overly Specified symptom reports, where a moderate effect emerged (d = 0.88). Classification accuracy remained low, with particularly poor sensitivity (sensitivity = 19.30%). Sensitivity was higher when the decision rules postulated in the first edition SIRS were applied instead of its successor's decision model, yet this increase in sensitivity came at the price of unacceptably low specificity. Conclusion: The present results call for a disorder-specific instrument for the detection of simulated ADHD and offer starting points for the development of such a tool.


Operative and nonoperative treatment of cervical disc herniation in National Football League athletes.
Limited evidence exists to guide clinical decision making regarding cervical disc herniations in professional athletes playing for the National Football League (NFL) in the United States. To describe the presentation and treatment outcomes of cervical disc herniations in NFL athletes with a focus on safety and return to sport. Case series; Level of evidence, 4. The records of a single NFL team and its consulting physicians were reviewed from 2000 to 2011. Only athletes with magnetic resonance imaging (MRI)-proven disc herniation concordant with the reported symptoms were included. A total of 16 athletes met inclusion criteria. Linemen, linebackers, and defensive backs were the most represented positions (13/16 athletes; 81%). The most common presentation was radiculopathy after a single traumatic event (9/16 athletes; 56%). Three players had transient paresis. Three players underwent one-level anterior cervical discectomy and fusion. These 3 players had failed nonoperative therapy and had evidence of spinal cord compression with signal change on MRI, but only 1 returned to sport. Three players received epidural steroid injections, which provided transient symptomatic relief. Five players were treated nonoperatively and did not return to sport. Two of these 5 athletes had cord compression with signal change and retired rather than undergo surgery. The other 3 were cleared but were released by the team. Eight players were treated nonoperatively and returned to sport. Three of these 8 athletes had evidence of disc material abutting the cord without cord signal change but had a normal examination finding and returned to sport after resolution of their symptoms and repeat MRI that demonstrated no cord compression. Five of the 8 players had evidence of root compression and were treated symptomatically. There were no subsequent traumatic spinal cord injuries at a minimum of 1-year follow-up. Data regarding the treatment of this unique population are limited but suggest that NFL athletes can safely return to sport after the treatment of cervical disc herniations. In the treatment algorithm for this study, cord compression with signal change in the cord on MRI was a consistent operative indication. Discs abutting the cord can be treated nonoperatively but do not allow for return to sport until symptoms have improved and repeat imaging demonstrates no cord compression. Isolated nerve root compression has a more favorable prognosis. It can be treated symptomatically and return to sport allowed when symptoms permit.


Increased soluble platelet/endothelial cellular adhesion molecule-1 and osteonectin levels in patients with severe congestive heart failure. Independence of disease etiology, and antecedent aspirin therapy.
Platelet-endothelial interactions modulated by adhesion molecules, may play an important role in the pathogenesis of congestive heart failure (CHF). Soluble levels of these molecules and platelet-derived substances are reportedly elevated in patients with CHF. However, no data are available on the plasma levels of Platelet/Endothelial Cell Adhesion Molecule-1 (PECAM-1), and platelet-derived osteonectin in this growing population. Soluble levels by ELISA were prospectively determined in patients with severe CHF (n = 37) and correlated to etiology and antecedent aspirin use, and compared with 14 healthy control subjects. Left ventricular dysfunction was attributed to idiopathic dilated cardiomyopathy in 18 and coronary artery disease in 19 patients. Twenty-one patients were aspirin-free and 16 patients were using aspirin (81-500 mg daily). Elevated soluble PECAM-1 (51.31+/-2.44 ng/ml, P = 0.0001), and osteonectin (826.27+/-22.37 ng/ml, P = 0.0001) were observed in patients with CHF, as compared to healthy controls (32.56+/-1.21 ng/ml, and 478.02+/-31.32 ng/ml, respectively). Neither etiology of CHF, nor antecedent aspirin therapy significantly affects the levels of PECAM-1 or osteonectin. Despite long-term aspirin therapy and independently of the etiology of the disease, soluble PECAM-1 and osteonectin were elevated in the majority of patients with severe CHF, suggesting platelet-endothelial activation. The present data provide additional evidence that more potent anti-platelet and endothelial preservation regimens deserve further study in the heart failure population.


Is in vivo measurement of size of polyps during colonoscopy accurate?
Accurate measurement of polyp size during colonoscopy is important because of the direct correlation of size with colon cancer. Major studies of colorectal neoplasms have measured polyp size differently. It is also well documented that endoscopists underestimate polyp size frequently. The goal of this prospective study was to determine which one of the five methods of estimating polyp size during colonoscopy is most accurate. One hundred colon polyps were measured by means of visual estimation, open biopsy forceps methods, linear probe, a ruler immediately after excision, and after fixation in formalin. The size of the polyps measured outside the body immediately after excision was considered the "gold standard" against which all measurements were compared. Forty-seven polyps were 5 mm or less in diameter, 33 polyps were 5.01 mm to 10 mm, and 20 polyps were more than 10 mm in size. For all polyps the mean difference versus the actual size of the polyps was 3.4% for linear probe, 6.4% for visual estimation, and 12.3% for the forceps. Measurement of polyp size by linear probe agreed best with the actual polyp size, followed closely by visual estimation. The open biopsy forceps method was the least accurate.


Seventh nerve spasm: effect of modification of cholinergic balance.
The seventh cranial nerve spasms of the face and the eyelids, including essential blepharospasm, are usually intractable and sometimes disabling. Deanol acetamidobenzoate was compared with the anticholinergic orphenadrine for relief of these spasms. Deanol cured two of 16 (12%) subjects and improved a third. Orphenadrine was much more effective, improving the conditions of 16 of 26 (62%) subjects between 57% and 100%. A crossover double-blind experiment showed high significance over a placebo.


Mouse ganglion-cell photoreceptors are driven by the most sensitive rod pathway and by both types of cones.
Intrinsically photosensitive retinal ganglion cells (iprgcs) are depolarized by light by two mechanisms: directly, through activation of their photopigment melanopsin; and indirectly through synaptic circuits driven by rods and cones. To learn more about the rod and cone circuits driving ipRGCs, we made multielectrode array (MEA) and patch-clamp recordings in wildtype and genetically modified mice. Rod-driven ON inputs to ipRGCs proved to be as sensitive as any reaching the conventional ganglion cells. These signals presumably pass in part through the primary rod pathway, involving rod bipolar cells and AII amacrine cells coupled to ON cone bipolar cells through gap junctions. Consistent with this interpretation, the sensitive rod ON input to ipRGCs was eliminated by pharmacological or genetic disruption of gap junctions, as previously reported for conventional ganglion cells. A presumptive cone input was also detectable as a brisk, synaptically mediated ON response that persisted after disruption of rod ON pathways. This was roughly three log units less sensitive than the rod input. Spectral analysis revealed that both types of cones, the M- and S-cones, contribute to this response and that both cone types drive ON responses. This contrasts with the blue-OFF, yellow-ON chromatic opponency reported in primate ipRGCs. The cone-mediated response was surprisingly persistent during steady illumination, echoing the tonic nature of both the rod input to ipRGCs and their intrinsic, melanopsin-based phototransduction. These synaptic inputs greatly expand the dynamic range and spectral bandpass of the non-image-forming visual functions for which ipRGCs provide the principal retinal input.


Stratification of acute myocardial and endothelial cell injury, salvage index and final infarct size by systematic microRNA profiling in acute ST-elevation myocardial infarction.
Acute injury and subsequent remodelling responses to ST-segment elevation myocardial infarction (STEMI) are major determinants of clinical outcome. Current imaging and plasma biomarkers provide delayed readouts of myocardial injury and recovery. Here, we sought to systematically characterize all microRNAs (miRs) released during the acute phase of STEMI and relate miR release to magnetic resonance imaging (MRI) findings to predict acute and late responses to STEMI, from a single early blood sample. miRs were quantified in blood samples obtained from patients after primary PCI (PPCI) for STEMI. Cardiac MRI (cMRI) was performed to quantify myocardial edema, infarct size and salvage index. Regression models were constructed to predict these outcomes measures, which were then tested with a validation cohort. Transcoronary miR release was quantified from paired measurements of coronary artery and coronary sinus samples. A cell culture model was used to identify endothelial cell-derived miRs.A total of 72 patients undergoing PPCI for acute STEMI underwent miR analysis and cMRI. About >200 miRs were detectable in plasma after STEMI, from which 128 miRs were selected for quantification in all patients. Known myocardial miRs demonstrated a linear correlation with troponin release, and these increased across the transcoronary gradient. We identified novel miRs associated with microvascular injury and myocardial salvage. Regression models were constructed using a training cohort, then tested in a validation cohort, and predicted myocardial oedema, infarct size and salvage index. Analysis of miR release after STEMI identifies biomarkers that predict both acute and late outcomes after STEMI. A novel miR-based biomarker score enables the estimation of area at risk, late infarct size and salvage index from a single blood sample 6 hours after PPCI, providing a simple and rapid alternative to serial cMRI characterization of STEMI outcome.


The health-related, social, and economic consequences of parkinsonism: a controlled national study.
Parkinson's disease (PD) and atypical parkinsonism (AP) cause a significant socioeconomic burden, but there is insufficient information about the total disease burden at a national level. Thus, the goal of this study was to estimate the excess direct and indirect costs of PD and AP in a national sample. Using records from the Danish National Patient Registry (1997-2007), 13,400 PD and 647 AP patients were identified and compared with, respectively, 53,600 and 2,588 control cases randomly selected with respect to age, gender, civil status, and geographic location. Direct costs including frequencies of primary and sector contacts and procedures, and medication from primary and secondary sectors were obtained from the Danish Ministry of Health, the Danish Medicines Agency, and the National Health Security. Indirect costs, which included labor supply and social transfer payments, were based on income data derived from the Coherent Social Statistics. Patients with PD and AP had significantly higher rates of health-related contact and medication use and a higher socioeconomic cost. Furthermore, they had very low employment rates, and those in employment had a lower income level than employed control subjects. The annual mean excess health-related cost was <euro>6,500 ($8,975/£5,543) and <euro>9,771 ($13,491/£8,332) for each patient with PD and AP, respectively. In addition, the patients with PD and AP received an annual mean excess social transfer income of <euro>324 (£276/$447) and <euro>844 (£719/$1,165), respectively. The employment- and health-related consequences could be identified up to 8 years before the first diagnosis and increased with disease advancement. PD and AP have major socioeconomic consequences for patients and society. The health effects are present for up to more than 8 years before a diagnosis of PD/AP.


Mitochondrial noncoding RNA-regulatory network in cardiovascular disease.
Mitochondrial function and integrity are vital for the maintenance of cellular homeostasis, particularly in high-energy demanding cells. Cardiomyocytes have a large number of mitochondria, which provide a continuous and bulk supply of the ATP necessary for cardiac mechanical function. More than 90% of the ATP consumed by the heart is derived from the mitochondrial oxidative metabolism. Decreased energy supply as the main consequence of mitochondrial dysfunction is closely linked to cardiovascular disease (CVD). The discovery of noncoding RNA (ncRNAs) in the mitochondrial compartment has changed the traditional view of molecular pathways involved in the regulatory network of CVD. Mitochondrial ncRNAs participate in controlling cardiovascular pathogenesis by regulating glycolysis, mitochondrial energy status, and the expression of genes involved in mitochondrial metabolism. Understanding the underlying mechanisms of the association between impaired mitochondrial function resulting from fluctuation in expression levels of ncRNAs and specific disease phenotype can aid in preventing and treating CVD. This review presents an overview of the role of mitochondrial ncRNAs in the complex regulatory network of the cardiovascular pathology. We will summarize and discuss (1) mitochondrial microRNAs (mitomiRs) and long noncoding RNAs (lncRNAs) encoded either by nuclear or mitochondrial genome which are involved in the regulation of mitochondrial metabolism; (2) the role of mitomiRs and lncRNAs in the pathogenesis of several CVD such as hypertension, cardiac hypertrophy, acute myocardial infarction and heart failure; (3) the biomarker and therapeutic potential of mitochondrial ncRNAs in CVD; (4) and the challenges inherent to their translation into clinical application.


Randomised trial of endoscopic argon laser photocoagulation in bleeding peptic ulcers.
Emergency endoscopy on 332 patients with acute upper gastrointestinal bleeding showed that 178 had peptic ulcers; 28 of these were actively bleeding (spurting) and 108 showed stigmata of recent haemorrhage (vessels or spots in the ulcer base) suggesting a risk of rebleeding. These 136 patients were randomly allocated to Argon laser photocoagulation or to no additional therapy (controls) at the time of initial endoscopy. All patients received conventional management, and the controlling clinicians did not know whether or not the laser had been used in any individual patients. The laser system proved both simple and safe in use. Initial haemostasis was achieved by the laser in 10 of 15 'spurting vessels', but four of 13 'control' spurting vessels also stopped bleeding spontaneously. Overall, there were no statistically significant differences between the laser treated and control groups in terms of rebleeding, the need for surgical intervention, or death. These results require amplification in larger trials, and comparison with other studies using different protocols and other haemostatic methods.


Fishing for pleiotropic QTLs in a polygenic sea.
The application of factor analysis to human genetics has the potential to discover the coordinated control of multiple traits by common environment, common polygenes, or a single major gene. Classical factor analysis explains the covariation among the components of a random vector by approximating the vector by a linear transformation of a small number of uncorrelated factors. In the current paper we show how factor analysis dovetails with the classical variance decompositions of biometrical genetics. To explore the relationships between related quantitative variables, and avoid complicated positive definiteness constraints, we employ Cholesky and factor analytic decompositions. We derive an ECM algorithm and a competing quasi-Newton algorithm for estimating parameters by maximum likelihood and propose tactics for selecting initial parameter values. We also show how parameter asymptotic standard errors under these parameterizations propagate to asymptotic standard errors of the underlying variance components. Our genetic analysis program Mendel, which now incorporates the program Fisher, has performed well on a variety of data sets. We illustrate our methods, algorithms, and models on two data sets: a bivariate quantitative genetic example using total finger ridge count data and a multivariate linkage example using insulin resistance data.


Efficacy and toxicity of bimodal radiotherapy in WHO grade 2 meningiomas following subtotal resection with carbon ion boost: prospective phase 2 MARCIE trial.
Novel radiotherapeutic modalities using carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, delivering a higher biological dose while reducing the radiation exposure for adjacent organs. This prospective phase 2 trial investigated bimodal radiotherapy using photons with carbon-ion (C12)-boost in patients with WHO grade 2 meningiomas following subtotal resection (Simpson grade 4 or 5). A total of 33 patients were enrolled from July 2012 until July 2020. Study treatment comprised a C12-boost (18 Gy [RBE] in 6 fractions) applied to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). Primary endpoint was the 3-year progression-free survival (PFS) , and secondary endpoints included overall survival, safety and treatment toxicities. With a median follow-up of 42 months, the 3-year estimates of PFS, local PFS and overall survival were 80.3%, 86.7% and 89.8%, respectively. Radiation-induced contrast enhancement (RICE) was encountered in 45%, particularly in patients with periventricularly-located meningiomas. Patients exhibiting RICE were mostly either asymptomatic (40%) or presented immediate neurological and radiological improvement (47%) after the administration of corticosteroids or bevacizumab in case of radiation necrosis (3/33). Treatment-associated complications occurred in one patient with radiation necrosis who died due to postoperative complications after resection of radiation necrosis. The study was prematurely terminated after recruiting 33 of the planned 40 patients. Our study demonstrates a bimodal approach utilizing photons with C12-boost may achieve an superior local PFS to conventional photon RT, but must be balanced against the potential risks of toxicities.


Structural and functional heterogeneity of mammalian nephrons.
Since the anatomical descriptions of Bowman showing differences between nephrons originating in the superficial and deep cortex, the concept of heterogeneity has been extended from identification of dissimilarities between nephrons to recognition of inhomogeneity within major portions of individual nephrons. We are now aware of functional correlates for the anatomical differences between nephrons, between analogous parts of different nephrons, and between the three portions of the proximal tubule and the three or more parts of the distal tubule. The implications of all of these differences for major renal processes, such as isosmotic fluid transport, salt balance, hypertension, urinary acidification, and the concentration or urine are now being defined. It seems likely that new conceptual and technical approaches, especially electron probe microanalysis, will add appreciably to defining the role of heterogeneity in these and other processes. Despite the increasing complexity of nephron heterogeneity, it is recommended that our basic nomenclature be retained and that new findings be incorporated into the schema set forth by Karl Peter. It would be very helpful if reports of investigations on single nephrons or segments of nephrons were to include diagrams delineating the structures on which the work was performed.


Cancer in the older person.
Cancer in the older person is an increasingly common problem, due to the progressive prolongation of the life-expectancy of the Western population. This article reviews the mechanisms associating aging and cancer, age-related changes in cancer biology, assessment of the older person to estimate life-expectancy, treatment tolerance, and medical and social conditions that may interfere with cancer treatment, effectiveness of cancer prevention and cancer treatment in older individuals. A comprehensive geriatric assessment (CGA) is commonly used to predict life-expectancy and functional reserve and to unearth conditions that may jeopardize cancer prevention and treatment. In the interest of cost and time, shortened forms of CGA are being explored. Chemoprevention of cancer is a promising form of prevention that at present has no conclusive clinical indications. Early diagnosis of breast and colon cancer through screening of asymptomatic patients at risk may be beneficial for individuals with a life-expectancy of 5 years or longer. Early detection of lung cancer in ex-smokers is undergoing clinical trials, as this disease is becoming more and more common. Age should not prevent appropriate treatment of cancer in older individuals, especially in those with adequate life-expectancy and functional reserve. The National Cancer Center Network (NCCN) has issued a series of guidelines to minimize the toxicity and promote the effectiveness of cancer in older patients. Important interventions include prevention of neutropaenic infections with filgrastim and peg-filgrastim, prevention of anaemia with epoietin or darbepoietin, and prevention and early management of mucositis.


Exploration of functionalized CdTe nanoparticles for latent fingerprint detection.
The potential of using water-soluble photoluminescent nanoparticles of different sizes for latent fingerprint detection has been explored. In this pilot study, green (582 nm) and red (755 nm) CdTe nanocrystals coated with thioglycolic acid were used. Latent fingerprints on aluminum and glass surfaces were successfully labeled with these nanoparticles for time periods ranging from 30 min to 24 h. The labeling is probably due to the amidation reaction between the surface carboxylic groups of the nanoparticles with the amine groups of the biomaterials present in the fingerprint residues. The 582 nm emitting nanoparticles appeared to better label the fingerprint ridges than did the 755 nm emitting ones for both surfaces. However, the 755 nm emitting nanoparticles were able to target the sweat pores within the ridges of the fingerprints. Other than high quantum yield and photostability, the tunable emission wavelength, the narrow bandwidth, the customizable surface characteristics, and the relatively long fluorescence decay lifetime of these nanoparticles are useful and necessary features for the future development of ultra-sensitive, target-specific, background suppressed latent fingerprint detection for forensic applications.


MATERIALS SCIENCE: Weird Gold Nanowires.
When the dimensions of matter are reduced to the nanometer scale and beyond, strange properties often emerge. In their Perspective, Tosatti and Prestipino discuss the weird gold nanowire structures reported by Kondo and Takayanagi. They explain why the wires may be helical and only form certain "magic" sizes. Other metals may form similarly strange structures with unusual properties.


Charybdotoxin and apamin block EDHF in rat mesenteric artery if selectively applied to the endothelium.
In rat mesenteric artery, endothelium-derived hyperpolarizing factor (EDHF) is blocked by a combination of apamin and charybdotoxin (ChTX). The site of action of these toxins has not been established. We compared the effects of ChTX and apamin applied selectively to the endothelium and to the smooth muscle. In isometrically mounted arteries, ACh (0.01-10 micrometers), in the presence of indomethacin (2.8 microM) and Nomega-nitro-L-arginine methyl ester (L-NAME) (100 microM), concentration dependently relaxed phenylephrine (PE)-stimulated tone (EC50 50 nM; n = 10). Apamin (50 nM) and ChTX (50 nM) abolished this relaxation (n = 5). In pressurized arteries, ACh (10 microM), applied intraluminally in the presence of indomethacin (2.8 microM) and L-NAME (100 microM), dilated both PE-stimulated (0.3-0.5 microM; n = 5) and myogenic tone (n = 3). Apamin (50 nM ) and ChTX (50 nM) applied intraluminally abolished ACh-induced dilatations. Bath superperfusion of apamin and ChTX did not affect ACh-induced dilatations of either PE-stimulated (n = 5) or myogenic tone (n = 3). This is the first demonstration that ChTX and apamin act selectively on the endothelium to block EDHF-mediated relaxation.


2017 update on pain management in patients with chronic kidney disease.
The prevalence of pain has been reported to be >60-70% among patients with advanced and end-stage kidney disease. Although the underlying etiologies of pain may vary, pain per se has been linked to lower quality of life and depression. The latter is of great concern given its known association with reduced survival among patients with end-stage kidney disease. We herein discuss and update the management of pain in patients with chronic kidney disease with and without requirement for renal replacement therapy with the focus on optimizing pain control while minimizing therapy-induced complications.


Vitamin D analogs and bone.
Vitamin D analogs increase intestinal calcium absorption, and have been shown to possess antiresorptive and also bone anabolic properties in vivo. Therefore, the pharmacological profile of vitamin D analogs would be well suited for the treatment of osteoporosis. However, the calcemic side effects of this compound class, especially at higher doses, have hampered their wide use in osteoporotic patients. Nevertheless, the clear potential for bone anabolic properties together with oral availability have stimulated the interest in this substance class, and there is an active search for bone selective vitamin D compounds. After an overview of the physiological functions of vitamin D in bone, this article focuses on the effects of acute and chronic administration of pharmacological doses of vitamin D analogs on bone in animal models and humans. Furthermore, the endocrinological, cellular, and microanatomical mechanisms involved in the skeletal actions of vitamin D analogs are discussed. The final section briefly reviews the available data on possible bone selective vitamin D analogs.


Blood Epigenetic Age may Predict Cancer Incidence and Mortality.
Biological measures of aging are important for understanding the health of an aging population, with epigenetics particularly promising. Previous studies found that tumor tissue is epigenetically older than its donors are chronologically. We examined whether blood Δage (the discrepancy between epigenetic and chronological ages) can predict cancer incidence or mortality, thus assessing its potential as a cancer biomarker. In a prospective cohort, Δage and its rate of change over time were calculated in 834 blood leukocyte samples collected from 442 participants free of cancer at blood draw. About 3-5 years before cancer onset or death, Δage was associated with cancer risks in a dose-responsive manner (P = 0.02) and a one-year increase in Δage was associated with cancer incidence (HR: 1.06, 95% CI: 1.02-1.10) and mortality (HR: 1.17, 95% CI: 1.07-1.28). Participants with smaller Δage and decelerated epigenetic aging over time had the lowest risks of cancer incidence (P = 0.003) and mortality (P = 0.02). Δage was associated with cancer incidence in a 'J-shaped' manner for subjects examined pre-2003, and with cancer mortality in a time-varying manner. We conclude that blood epigenetic age may mirror epigenetic abnormalities related to cancer development, potentially serving as a minimally invasive biomarker for cancer early detection.


Unravelling the role of SNM1 in the DNA repair system of Trypanosoma brucei.
All living cells are subject to agents that promote DNA damage. A particularly lethal lesion are interstrand cross-links (ICL), a property exploited by several anti-cancer chemotherapies. In yeast and humans, an enzyme that plays a key role in repairing such damage are the PSO2/SNM1 nucleases. Here, we report that Trypanosoma brucei, the causative agent of African trypanosomiasis, possesses a bona fide member of this family (called TbSNM1) with expression of the parasite enzyme able to suppress the sensitivity yeast pso2Δ mutants display towards mechlorethamine, an ICL-inducing compound. By disrupting the Tbsnm1 gene, we demonstrate that TbSNM1 activity is non-essential to the medically relevant T. brucei life cycle stage. However, trypanosomes lacking this enzyme are more susceptible to bi- and tri-functional DNA alkylating agents with this phenotype readily complemented by ectopic expression of Tbsnm1. Genetically modified variants of the null mutant line were subsequently used to establish the anti-parasitic mechanism of action of nitrobenzylphosphoramide mustard and aziridinyl nitrobenzamide prodrugs, compounds previously shown to possess potent trypanocidal properties while exhibiting limited toxicity to mammalian cells. This established that these agents, following activation by a parasite specific type I nitroreductase, produce metabolites that promote formation of ICLs leading to inhibition of trypanosomal growth.


The (ongoing) problem of relative growth.
Differential growth, the phenomenon where parts of the body grow at different rates, is necessary to generate the complex morphologies of most multicellular organisms. Despite this central importance, how differential growth is regulated remains largely unknown. Recent discoveries, particularly in insects, have started to uncover the molecular-genetic and physiological mechanisms that coordinate growth among different tissues throughout the body and regulate relative growth. These discoveries suggest that growth is coordinated by a network of signals that emanate from growing tissues and central endocrine organs. Here we review these findings and discuss their implications for understanding the regulation of relative growth and the evolution of morphology.


Management of vascular access for extracorporeal life support: A cohort study.
Extracorporeal membrane oxygenation (ECMO) is required for patients with refractory cardiac or respiratory failure. Inadequate securement of ECMO cannulae may lead to adverse events, ranging from line kinking to catastrophic accidents, such as air entrainment into the circuit or massive bleeding. Furthermore, the micro-motion of the cannulae at the entry site might increase the risk of local infections. Since 2015, we implemented a written protocol for management of ECMO cannulae and tubing, which specifically includes the securement of each cannula with three sutureless devices. The aim of the present study was to retrospectively assess cannulae micro-motion and the rate of bleeding events at the insertion site. Secondarily we aimed to evaluate the impact of prone positioning maneuvers during ECMO on these events. We performed a single-centre retrospective analysis of prospectively collected data on nursing care of ECMO cannulae. We included adult patients treated with veno-venous (V-V) or veno-arterial (V-A) ECMO between 2015 and 2018 in our general intensive care unit. The distance between the insertion site and the end of the wire-wound part of the cannula was recorded daily. Variations of this distance (defined as "cannula micro-motion") were recorded. Forty-five ECMO consecutive adult patients (40 V-V and 5 V-A) were included. No accidental cannula dislodgement was recorded. Median daily "cannula micro-motion" was 0.0 (-0.5 to 0.2) cm, without any significant difference between ECMO configuration, cannula type, and insertion site. Twelve patients (26%) presented at least one bleeding episode at cannula insertion site, none of which required surgical intervention. In the subgroup of patients who underwent prone positioning, no difference in cannulae micro-motion was recorded. An ECMO nursing protocol for cannulae management providing sutureless devices for cannula and tubing securement allows safe line stabilization, with the potential to reduce complications related to ECMO vascular access.


A role for antimetabolites in glaucoma tube surgery: current evidence and future directions.
Glaucoma is the leading cause of irreversible blindness worldwide. The main treatment modality for glaucoma is the reduction and control of the intraocular pressure (IOP). Glaucoma filtration surgery, including trabeculectomy and/or implantation of a glaucoma drainage device (GDD), is warranted if IOP remains medically uncontrolled. However, postoperative scarring remains a critical determinant of long-term bleb survival and IOP control after drainage surgery. Antimetabolites, such as mitomycin C and 5-fluorouracil, have been used for many years to increase survival time of filtration surgeries by preventing bleb fibrosis and scarring. The aim of this study is to provide an overview of: the current usage of these antimetabolites in GDD, the recent advancements of these antimetabolites in combination with other technologies, and the role of future antimetabolites. Mitomycin C and 5-fluorouracil have been used in GDD and trabeculectomy to prevent the exaggerated cellular reaction that leads to fibrosis. The adjunctive administration of these drugs intraoperatively and postoperatively has resulted in a lower rate of the hypertensive phase, and possibly a better long-term success rate in Ahmed valve surgeries. However, the application of these antimetabolites and their multiple-dosing applications are associated with nonspecific cytotoxicity and potentially severe complications such as bleb leak and conjunctival erosion over the tube. Recent studies are thus focusing on different medications, targeting new molecular pathways, and designing new delivery vehicles to minimize current antimetabolites side-effects and increase their efficacy. Promising results of these studies have led to development of new collaborative medications and advanced drug delivery systems for better modulation of GDD surgeries' predictable outcomes. The development of small molecule therapeutics, combination therapies, and innovative drug vehicles to prevent postsurgical fibrosis and achieve better surgical outcome in glaucoma filtration surgeries is promising.


Physics of virus transmission by speaking droplets.
To make the physics of person-to-person virus transmission from emitted droplets of oral fluid while speaking easily understood, we present simple and transparent algebraic equations that capture the essential physics of the problem. Calculations with these equations provide a straightforward way of determining whether emitted droplets remain airborne or rapidly fall to the ground, after accounting for the decrease in droplet size from water evaporation. At a relative humidity of 50%, for example, droplets with initial radii larger than about 50 μm rapidly fall to the ground, while smaller, potentially virus-containing droplets shrink in size from water evaporation and remain airborne for many minutes. Estimates of airborne virion emission rates while speaking strongly support the proposal that mouth coverings can help contain the COVID-19 pandemic.


The effect of alcohol withdrawal syndrome severity on sleep, brain and cognition.
In alcohol use disorder, drinking cessation is frequently associated with an alcohol withdrawal syndrome. Early in abstinence (within the first 2 months after drinking cessation), when patients do not exhibit physical signs of alcohol withdrawal syndrome anymore (such as nausea, tremor or anxiety), studies report various brain, sleep and cognitive alterations, highly heterogeneous from one patient to another. While the acute neurotoxicity of alcohol withdrawal syndrome is well-known, its contribution to structural brain alterations, sleep disturbances and neuropsychological deficits observed early in abstinence has never been investigated and is addressed in this study. We included 54 alcohol use disorder patients early in abstinence (from 4 to 21 days of sobriety) and 50 healthy controls. When acute physical signs of alcohol withdrawal syndrome were no longer present, patients performed a detailed neuropsychological assessment, a T1-weighted MRI and a polysomnography for a subgroup of patients. According to the severity of the clinical symptoms collected during the acute withdrawal period, patients were subsequently classified as mild alcohol withdrawal syndrome (mild-AWS) patients (Cushman score ≤ 4, no benzodiazepine prescription, N = 17) or moderate alcohol withdrawal syndrome (moderate-AWS) patients (Cushman score > 4, benzodiazepine prescription, N = 37). Patients with severe withdrawal complications (delirium tremens or seizures) were not included. Mild-AWS patients presented similar grey matter volume and sleep quality as healthy controls, but lower processing speed and episodic memory performance. Compared to healthy controls, moderate-AWS patients presented non-rapid eye movement sleep alterations, widespread grey matter shrinkage and lower performance for all the cognitive domains assessed (processing speed, short-term memory, executive functions and episodic memory). Moderate-AWS patients presented a lower percentage of slow-wave sleep, grey matter atrophy in fronto-insular and thalamus/hypothalamus regions, and lower short-term memory and executive performance than mild-AWS patients. Mediation analyses revealed both direct and indirect (via fronto-insular and thalamus/hypothalamus atrophy) relationships between poor sleep quality and cognitive performance. Alcohol withdrawal syndrome severity, which reflects neurotoxic hyperglutamatergic activity, should be considered as a critical factor for the development of non-rapid eye movement sleep alterations, fronto-insular atrophy and executive impairments in recently detoxified alcohol use disorder patients. The glutamatergic activity is involved in sleep-wake circuits and may thus contribute to molecular mechanisms underlying alcohol-related brain damage, resulting in cognitive deficits. Alcohol withdrawal syndrome severity and sleep quality deserve special attention for a better understanding and treatment of brain and cognitive alterations observed early in abstinence, and ultimately for more efficient relapse prevention strategies.


Real-Time Suicide Surveillance: Comparison of International Surveillance Systems and Recommended Best Practice.
Some countries have implemented systems to monitor suicides in real-time. These systems differ because of the various ways in which suicides are identified and recorded. The main objective of this study was to conduct an international comparison of major real-time suicide mortality surveillance systems to identify joint strengths, challenges, and differences, and thereby inform best-practice criteria at local, national, and international levels. Five major real-time suicide mortality surveillance systems of various coverage levels were identified and selected for review via an internet-based scoping exercise and prior knowledge of existing systems. Key information including the system components and practices was collated from those organizations that developed and operate each system using a structured template. The information was narratively and critically synthesized to determine similarities and differences between the systems. The comparative review of the five established real-time suicide surveillance systems revealed more commonalities than differences overall. Commonalities included rapid, routine surveillance based on minimal, provisional data to facilitate timely intervention and postvention efforts. Identified differences include the timeliness of case submission and system infrastructure. The recommended criteria could promote replicable components and practices in real-time suicide surveillance while offering flexibility in adapting to regional/local circumstances and resource availability.HIGHLIGHTSEvidence-informed recommendations for current best practice in real-time suicide surveillance.Proposed comprehensive framework can be adapted based on available resources and capacity.Real-time suicide mortality data facilitates rapid data-driven decision-making in suicide prevention.


Production and characterization of monoclonal antibody against Saffron pollen profilin, Cro s 2.
Allergy to Saffron (Crocus sativus) pollen has been described in people involved in processing of saffron flower stamens. Profilins have been identified as a pan-allergen in different plant pollens and foods. This molecule is an actin-binding protein with a molecular weight of 12-16 kDa found in eukaryotic species. The aim of this study was to generate monoclonal antibody against Cro s 2 in order to characterize this major allergen of saffron pollen. BALB/c mice were immunized to obtain adequate humoral response. Splenocytes were prepared from the immunized animals, mixed with the P3-X63-Ag8.653 myeloma cells and fused by means of PEG 1500. After two weeks of culturing in HAT-containing media, the supernatant from those wells growing hybridomas were screened by ELISA using plates coated with Cro s 2. Cells from positive wells were cloned at least 3 times by limiting dilution. Specificity and cross-reactivity of the mAbs were determined by Western blot analysis and sandwich ELISA. Two stable hybridoma clones secreting mAbs against Cro s 2 were obtained and expanded. The anti-Cro s 2 mAbs were also found to cross-react with other plant profilins. Isotype of this mAb was identified as micro heavy chain and k light chain. The anti-Cro s 2 mAb could be a useful tool for characterization and standardization of many pollen and fruit-derived profilins.


Structure and regulation of voltage-gated Ca2+ channels.
Voltage-gated Ca(2+) channels mediate Ca(2+) entry into cells in response to membrane depolarization. Electrophysiological studies reveal different Ca(2+) currents designated L-, N-, P-, Q-, R-, and T-type. The high-voltage-activated Ca(2+) channels that have been characterized biochemically are complexes of a pore-forming alpha1 subunit of approximately 190-250 kDa; a transmembrane, disulfide-linked complex of alpha2 and delta subunits; an intracellular beta subunit; and in some cases a transmembrane gamma subunit. Ten alpha1 subunits, four alpha2delta complexes, four beta subunits, and two gamma subunits are known. The Cav1 family of alpha1 subunits conduct L-type Ca(2+) currents, which initiate muscle contraction, endocrine secretion, and gene transcription, and are regulated primarily by second messenger-activated protein phosphorylation pathways. The Cav2 family of alpha1 subunits conduct N-type, P/Q-type, and R-type Ca(2+) currents, which initiate rapid synaptic transmission and are regulated primarily by direct interaction with G proteins and SNARE proteins and secondarily by protein phosphorylation. The Cav3 family of alpha1 subunits conduct T-type Ca(2+) currents, which are activated and inactivated more rapidly and at more negative membrane potentials than other Ca(2+) current types. The distinct structures and patterns of regulation of these three families of Ca(2+) channels provide a flexible array of Ca(2+) entry pathways in response to changes in membrane potential and a range of possibilities for regulation of Ca(2+) entry by second messenger pathways and interacting proteins.


Age-sex trends of phobic and anxiety symptoms in adolescents.
The prevalence of phobic and anxiety symptoms was investigated in school children and students aged 11-23 years by questionnaire to find age-sex trends of these symptoms. Phobic symptoms were found more prevalent in girls except for fear of talking. Among symptoms which tended to appear in anxiety or under stress, frequency of micturition was more prevalent in boys and the remaining symptoms showed no persistent sex difference. Fear of going out of doors alone and feeling of impending death tended to decrease with age. Symptoms which peaked in adolescence (fear of blushing, fear of being looked at and most anxiety symptoms) occurred at an earlier age in girls than in boys.


[Structural state of the cardiomyocyte sarcolemma in animals of different ages].
Cardiomyocyte plasmalemma membranes of adult (12 months) and old (24-26 months) rats have been studied. Ageing is accompanied with an essential decrease of the content of the membrane protein SH-groups. We have found an increase in the fraction of strongly immobilized spin-labeled SH-groups, a decrease in that of unsaturated lipids, as well as an increase in that of lysophosphatidylcholine in old rats membranes. The pattern of the response of beta-adrenergic receptors to isoproterenol is changed with age. The mobility of spin probe 5NS in the membranes of old rats is lowered at 22.5 degrees C. However there is no statistically significant age difference in the spin-probe mobility at 37 degrees C. Possible role of lysophosphatidylcholine in the stabilization of membrane lipid "fluidity" at physiological temperatures is suggested.


The development of a brain bank.
The methods used in developing a brain bank are described. The techniques for encouraging brain donation and the precautions to be used when dealing with medical examiner cases are outlined. Simplifying the donation process by the pathologist in order to gain his cooperation is essential. The importance of keeping an open telephone link available at all hours of the day and night and the need to solicit the donating families' cooperation in seeking clinical records is emphasized. Detailed neuropathological examination of every brain is essential for diagnostic purposes. Recent techniques to improve the qualify of postmortem brain tissue for molecular genetic studies are described.


Prevention and treatment of septal deformity in infancy and childhood.
There are two basic types of septal deformity, namely anterior nasal deformity and combined septal deformity, which may occur independently or both together. They are considered to be acquired from different types of pressures on the foetus during pregnancy or parturition. The incidence of anterior nasal deformity was found to be 4% in cases of spontaneous vaginal delivery, but 13% in cases of increased pressure as persistent occipitoposterior. The combined septal deformity is part of a facial deformity, and is best tested by using simple nasal testing struts. The incidence of straight septa varied with the degree of pressure with an average of 42%. In adult surveys a little over 20% are straight. Methods of manipulation are described using special infant forceps. Indications for manipulation are: Stuffy nose, feeding problems and sticky eyes. The procedure and results of rapid maxillary expansion are presented.


Luminescence and Energy Transfer between Ce3+ and Pr3+ in BaY2Si3O10 under VUV-vis and X-ray Excitation.
A detailed investigation on photoluminescence properties and energy transfer (ET) dynamics of Ce3+, Pr3+-doped BaY2Si3O10 is provided along with the potential X-ray excited luminescence application. The luminescence properties of Pr3+ are studied in VUV-UV-vis spectral range at low temperature, and the spectral profiles of Pr3+3P0 and 1D2 emission lines are determined using time-resolved emission spectra. Upon 230 nm excitation, the electron population from Pr3+ 4f5d state to its 4f2 excited state is discussed in detail. As Pr3+ concentration rises, Pr3+3P0 and 1D2 luminescence possess different concentration-related properties. The incorporation of Ce3+ in the codoped sample produces the strong Ce3+ luminescence under 230 nm excitation, which is the combined result of Pr3+ 4f5d → Ce3+ 5d ET and Ce3+ intrinsic excitation. On the other hand, the increasingly strong ET of Ce3+ 5d → Pr3+ 4f2 results in the decrease of Ce3+ emission intensity and the gradual deviation of Ce3+ luminescence decay from the single exponential in the system. By employing the Inokuti-Hirayama model, the dipole-dipole interaction is confirmed as the predominant multipolar effect in controlling this ET process, and the value of C DA is determined to be 9.97 × 10-47 m6·s-1. Finally, the relatively low scintillation light yield of Ce3+-doped BaY2Si3O10 material impedes its application potential in the scintillator field, and the cosubstitution of Pr3+ results in the observable decline of scintillation performance.


Perceptions and experiences toward extended-release buprenorphine among persons leaving jail with opioid use disorders before and during COVID-19: an in-depth qualitative study.
Extended-release buprenorphine (XRB) offers a novel approach to sustained monthly treatment for people who use opioids in criminal justice settings (CJS). This study explores the experiences of adults receiving XRB as a jail-to-community treatment. In-depth qualitative interviews were conducted among adult participants with opioid use disorder (OUD; n = 16) who were recently released from NYC jails and maintained on XRB after switching from daily sublingual buprenorphine (SLB). Interviews elaborated on the acceptability and barriers and facilitators of XRB treatment pre- and post-release. Interviews were audio recorded, transcribed, and analyzed for content related to factors influencing XRB treatment uptake and community reentry. Important themes were grouped into systems, medication, and patient-level factors. Key systems-level factors influencing initiation of XRB in jail included an alternative to perceived stigmatization and privacy concerns associated with daily in-jail SLB administration and less concerns with buprenorphine diversion. In-jail peer networks positively influenced participant adoption of XRB. XRB satisfaction was attributed to reduced in-jail clinic and medication administration visits, perceived efficacy and blockade effects upon the use of heroin/fentanyl following release, and averting the risk of criminal activities to fund opioid use. Barriers to retention included post-injection withdrawal symptoms and cravings attributed to perceived suboptimal medication dosing, injection site pain, and lack of in-jail provider information about the medication. Participants were generally favorable to XRB initiation in jail and retention post-release. Further studies are needed to address factors influencing access to XRB in criminal justice settings, including stigma, ensuring patient privacy following initiation on XRB, and patient-, provider-, and correctional staff education pertaining to XRB. Trial Registration ClinicalTrials.gov Identified: NCT03604159.


Characteristics of functional impairment in patients with long-standing rheumatoid arthritis based on range of motion of joints: Baseline data from a multicenter prospective observational cohort study to evaluate the effectiveness of joint surgery in the treat-to-target era.
To explore the characteristics of functional impairment in patients with established rheumatoid arthritis (RA) based on the range of motion (ROM) of joints in a prospective observational study of RA patients undergoing joint surgery. We collected data on demographics, Health Assessment Questionnaire Disability Index (HAQ-DI), and the ROM of large joints including the shoulder, elbow, wrist, hip, knee, and ankle. Associations between the ROM of each joint and disability in the eight HAQ-DI categories were determined using receiver operating characteristic (ROC) and logistic regression analyses. ROM cut-off values of each joint for the absence of disability in each HAQ-DI category were determined using ROC curves. A total of 460 patients were enrolled and analyzed in this study. Based on ROC analysis, the ROM of each joint was significantly associated with disability in each category. After adjusting for disease activity, age, and sex, shoulder abduction had the highest independent impact on disability in activity [cut-off: 139 degrees (OR: 5.26)], elbow flexion-extension in dressing [121 degrees (OR: 2.22)], wrist flexion-extension in reach [86 degrees (OR: 2.71)], hip flexion-extension in walking [126 degrees (OR: 3.42)], and knee flexion-extension in walking [134 degrees (OR: 2.97)]. Limited ROM of multiple joints was significantly associated with functional impairment in patients with long-standing RA. Motion in daily activity involves multiple joints, and at least two joints were independently involved in disability.


Modified white-light Mach-Zehnder interferometer for direct group-delay measurements.
A modified white-light Mach-Zehnder interferometer based on a single beam splitter is described for direct group-delay measurements. The arms of the interferometer are folded in such a manner that a single beam splitter can be used to split the incoming beam and combine the outgoing beams. This method offers a twofold advantage: The measuring range of the interferometer is twice as large as that of the Michelson interferometer, and the systematic error that is associated with the beam splitter is minimized because of the configuration. We report the results of measurements on various optical components performed in the 555-630-nm spectral region and propose a scheme for the processing of the experimental data. We present a comparison of the data analyzed by the proposed processing scheme along with the theoretical calculations.


Fatty acid-binding protein 5 regulates diet-induced obesity via GIP secretion from enteroendocrine K cells in response to fat ingestion.
Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K cells in response to nutrient intake, especially fat. GIP is one of the contributing factors inducing fat accumulation that results in obesity. A recent study shows that fatty acid-binding protein 5 (FABP5) is expressed in murine K cells and is involved in fat-induced GIP secretion. We investigated the mechanism of fat-induced GIP secretion and the impact of FABP5-related GIP response on diet-induced obesity (DIO). Single oral administration of glucose and fat resulted in a 40% reduction of GIP response to fat but not to glucose in whole body FABP5-knockout (FABP5(-/-)) mice, with no change in K cell count or GIP content in K cells. In an ex vivo experiment using isolated upper small intestine, oleic acid induced only a slight increase in GIP release, which was markedly enhanced by coadministration of bile and oleic acid together with attenuated GIP response in the FABP5(-/-) sample. FABP5(-/-) mice exhibited a 24% reduction in body weight gain and body fat mass under a high-fat diet compared with wild-type (FABP5(+/+)) mice; the difference was not observed between GIP-GFP homozygous knock-in (GIP(gfp/gfp))-FABP5(+/+) mice and GIP(gfp/gfp)-FABP5(-/-) mice, in which GIP is genetically deleted. These results demonstrate that bile efficiently amplifies fat-induced GIP secretion and that FABP5 contributes to the development of DIO in a GIP-dependent manner.


Sporichthya brevicatena sp. nov.
A strain was isolated from soil that formed short chains of aerial mycelium dividing into motile spores on an agar medium, but not substrate mycelium. The organism had menaquinone 9(H8), LL-diaminopimelic acid in the cell wall amino acids and a DNA G + C content of 71 mol%. On the basis of the morphological and chemotaxonomic characteristics and phylogenetic analysis, this strain was classified into the genus Sporichthya. DNA-DNA hybridization revealed that the strain differed from the known species, Sporichthya polymorpha. Therefore, a new species, Sporichthya brevicatena sp. nov., is proposed. The type strain is S. brevicatena YU720-21T (= IFO 16195T).


A systematic review of the evidence regarding efficacy of obesity prevention interventions among adults.
In the past, interventions aimed at reducing obesity have mainly targeted at weight loss treatment in obese adults, with limited long-term effects. With the increasing number of people being obese and being at risk for obesity, there has been a shift in focus towards prevention of obesity. We conducted a systematic review of the peer-reviewed literature on the efficacy of obesity prevention interventions in adults in order to identify effective interventions and intervention elements. Pubmed, OVID, and Web of Science databases were searched from January 1996 to June 2006. Interventions aimed at primary prevention of weight gain among adults achieved by focusing on dietary intake, physical activity or the combination of both were included. The outcome measure had to be difference in change in body mass index or body weight between the intervention and the control groups. Nine studies were included, five long-term studies (at least 1 year) and four short-term (3 months to 1 year). Seven studies evaluated an intervention that focused on a combination of diet and physical activity to prevent weight gain, one on diet only and one on physical activity only. One dietary intervention (long-term), and three combined dietary and physical activity interventions (one long-term and two short-term) produced significantly positive results at end of follow-up. The two long-term, effective interventions consisted of intensive and long-term intervention implementation, including groups sessions designed to promote behavioural changes. The current evidence of efficacy of obesity prevention interventions is based on a very small number of studies. Some studies showed a positive impact on body mass index or weight status, but there was too much heterogeneity in terms of study design, theoretical underpinning and target population to draw firm conclusions about which intervention approaches are more effective than others. More research is urgently needed to extend the body of evidence.


Long-term results in a case of meningioma treated by embolization alone--case report.
A 73-year-old female, unable to walk without a cane, was hospitalized for evaluation of left sensorimotor disturbance. Computed tomographic (CT) scans revealed a large parasagittal mass, which was markedly and homogeneously enhanced by contrast material. Bilateral external carotid angiograms showed that the middle meningeal arteries supplied the tumor. Both CT and angiographic findings suggested a right frontal parasagittal meningioma. Catheter embolization with Ivalon (polyvinyl alcohol foam) particles was carried out prior to the planned surgery for the purpose of decreasing intraoperative hemorrhage from the tumor. However, her clinical symptoms began to improve 9 days after the embolization procedure, and surgery was decided against because of her advanced age and symptomatic improvement. Ten months after embolization, she was able to walk unassisted and CT scans showed a 60% reduction of the pre-embolization tumor size. Four years after embolization, she remained nearly asymptomatic despite some regrowth of the tumor.


Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy.
Targeted whole-exome sequencing (WES) is a powerful diagnostic tool for a broad spectrum of heterogeneous neurological disorders. Here, we aim to examine the impact on diagnosis, treatment and cost with early use of targeted WES in early-onset epilepsy. WES was performed on 180 patients with early-onset epilepsy (≤5 years) of unknown cause. Patients were classified as Retrospective (epilepsy diagnosis >6 months) or Prospective (epilepsy diagnosis <6 months). WES was performed on an Ion Proton™ and variant reporting was restricted to the sequences of 620 known epilepsy genes. Diagnostic yield and time to diagnosis were calculated. An analysis of cost and impact on treatment was also performed. A molecular diagnoses (pathogenic/likely pathogenic variants) was achieved in 59/180 patients (33%). Clinical management changed following WES findings in 23 of 59 diagnosed patients (39%) or 13% of all patients. A possible diagnosis was identified in 21 additional patients (12%) for whom supporting evidence is pending. Time from epilepsy onset to a genetic diagnosis was faster when WES was performed early in the diagnostic process (mean: 145 days Prospective vs. 2,882 days Retrospective). Costs of prior negative tests averaged $8,344 per patient in the Retrospective group, suggesting savings of $5,110 per patient using WES. These results highlight the diagnostic yield, clinical utility and potential cost-effectiveness of using targeted WES early in the diagnostic workup of patients with unexplained early-onset epilepsy. The costs and clinical benefits are likely to continue to improve. Advances in precision medicine and further studies regarding impact on long-term clinical outcome will be important.


AMG 193 Effective in Multiple Tumor Types.
In a phase I trial of the MTA-cooperative PRMT5 inhibitor AMG 193, five of 39 patients with advanced MTAP-deleted solid tumors who had scans following initial treatment experienced partial responses. The responses occurred in five tumor types-esophageal, pancreatic, renal cell, gallbladder, and ovarian Sertoli-Leydig cell cancer.


Early development of the cerebral vesicles in man.
Two human embryos which were immediately before and soon after the appearance of the cerebral vesicle were cut into complete serial sections in almost the same direction and studied comparatively. The findings on these two sets of serial sections indicate that the rostral continuations of subthalamus and ventral thalamus along the ventral thalamic sulcus continuing from the sulcus limitans of the midbrain are destined to give rise to the formation of the cerebral vesicle. The rostral continuation of the subthalamus becomes the floor of the interventricular foramen, and that of the ventral thalamus the pallium. The rostral end of the continuation of the subthalamic matrix is not only the site of the beginning of evagination of the cerebral vesicle, but also the site of elevation of the ganglionic hill or striatum. As the evagination of the cerebral vesicle proceeds exceedingly dorsocaudolaterally from the rostral end of the continuation of the ventral thalamus, the elevation of the striatum occurs also in the same direction, getting in touch with the folding of the hemispheric stalk of Kuhlenbeck to enclose the interventricular foramen. Tt is noticed that, at the beginning of evagination, the grade of depression of the nasal pit was always parallel with that of evagniation of the cerebral vesicle.


Characterization of TNF receptor subtype expression and signaling on pulmonary endothelial cells in mice.
TNF plays a crucial role in the pathogenesis of acute lung injury. However, the expression profile of its two receptors, p55 and p75, on pulmonary endothelium and their influence on TNF signaling during lung microvascular inflammation remain uncertain. Using flow cytometry, we characterized the expression profile of TNF receptors on the surface of freshly harvested pulmonary endothelial cells (PECs) from mice and found expression of both receptors with dominance of p55. To investigate the impact of stimulating individual TNF receptors, we treated wild-type and TNF receptor knockout mice with intravenous TNF and determined surface expression of adhesion molecules (E-selectin, VCAM-1, ICAM-1) on PECs by flow cytometry. TNF-induced upregulation of all adhesion molecules was substantially attenuated by absence of p55, whereas lack of p75 had a similar but smaller effect that varied between adhesion molecules. Selective blockade of individual TNF receptors by specific antibodies in wild-type primary PEC culture confirmed that the in vivo findings were due to direct effects of TNF receptor inhibition on endothelium and not other cells (e.g., circulating leukocytes). Finally, we found that PEC surface expression of p55 dramatically decreased in the early stages of endotoxemia following intravenous LPS, while no change in p75 expression was detected. These data demonstrate a crucial in vivo role of p55 and an auxiliary role of p75 in TNF-mediated adhesion molecule upregulation on PECs. It is possible that the importance of the individual receptors varies at different stages of pulmonary microvascular inflammation following changes in their relative expression.


Modelling Keloids Dynamics: A Brief Review and New Mathematical Perspectives.
Keloids are fibroproliferative disorders described by excessive growth of fibrotic tissue, which also invades adjacent areas (beyond the original wound borders). Since these disorders are specific to humans (no other animal species naturally develop keloid-like tissue), experimental in vivo/in vitro research has not led to significant advances in this field. One possible approach could be to combine in vitro human models with calibrated in silico mathematical approaches (i.e., models and simulations) to generate new testable biological hypotheses related to biological mechanisms and improved treatments. Because these combined approaches do not really exist for keloid disorders, in this brief review we start by summarising the biology of these disorders, then present various types of mathematical and computational approaches used for related disorders (i.e., wound healing and solid tumours), followed by a discussion of the very few mathematical and computational models published so far to study various inflammatory and mechanical aspects of keloids. We conclude this review by discussing some open problems and mathematical opportunities offered in the context of keloid disorders by such combined in vitro/in silico approaches, and the need for multi-disciplinary research to enable clinical progress.


Implicating calpain in tau-mediated toxicity in vivo.
Alzheimer's disease and other related neurodegenerative disorders known as tauopathies are characterized by the accumulation of abnormally phosphorylated and aggregated forms of the microtubule-associated protein tau. Several laboratories have identified a 17 kD proteolytic fragment of tau in degenerating neurons and in numerous cell culture models that is generated by calpain cleavage and speculated to contribute to tau toxicity. In the current study, we employed a Drosophila tauopathy model to investigate the importance of calpain-mediated tau proteolysis in contributing to tau neurotoxicity in an animal model of human neurodegenerative disease. We found that mutations that disrupted endogenous calpainA or calpainB activity in transgenic flies suppressed tau toxicity. Expression of a calpain-resistant form of tau in Drosophila revealed that mutating the putative calpain cleavage sites that produce the 17 kD fragment was sufficient to abrogate tau toxicity in vivo. Furthermore, we found significant toxicity in the fly retina associated with expression of only the 17 kD tau fragment. Collectively, our data implicate calpain-mediated proteolysis of tau as an important pathway mediating tau neurotoxicity in vivo.


The anatomy and function of the gluteus minimus muscle.
In order to investigate the functional anatomy of gluteus minimus we dissected 16 hips in fresh cadavers. The muscle originates from the external aspect of the ilium, between the anterior and inferior gluteal lines, and also at the sciatic notch from the inside of the pelvis where it protects the superior gluteal nerve and artery. It inserts anterosuperiorly into the capsule of the hip and continues to its main insertion on the greater trochanter. Based on these anatomical findings, a model was developed using plastic bones. A study of its mechanics showed that gluteus minimus acts as a flexor, an abductor and an internal or external rotator, depending on the position of the femur and which part of the muscle is active. It follows that one of its functions is to stabilise the head of the femur in the acetabulum by tightening the capsule and applying pressure on the head. Careful preservation or reattachment of the tendon of gluteus minimus during surgery on the hip is strongly recommended.


Cross-cultural adaptation and psychometric evaluation of the early childhood oral health impact scale (ECOHIS) in chilean population.
The Early Childhood Oral Health Impact Scale (ECOHIS) measures the impact of dental diseases on Oral Health-Related Quality of Life both in children and their families. The aim of this study was to develop a Chilean Spanish version of the ECOHIS that is conceptually equivalent to the original and to assess its acceptability, reliability and validity in the preschool population of Chile. The Chilean version of the ECOHIS was obtained through a process including forward and back-translation, expert panel, and cognitive debriefing interviews. To assess metric properties, a cross-sectional study was carried out in Carahue, Southern Chile (April-October 2016). Children younger than six years old without systemic diseases, disabilities or chronic medication from eleven public preschools were included. Parents were invited to complete the Chilean version of the ECOHIS, PedsQL™4.0 Generic Core and PedsQL Oral Health scales, and to answer global questions about their children's general and oral health. A subsample was administrated ECOHIS a second time 14-21 days after. A clinical examination was performed to assess dental caries, malocclusion, and traumatic dental injuries. Reliability was evaluated using measures of internal consistency (Cronbach's alpha) and reproducibility (Intraclass correlation coefficient - ICC). Construct validity was assessed by testing hypotheses based on available evidence about known groups and relationships between different instruments. The content comparison of the back-translation with the original ECOHIS showed that all items except one were conceptually and linguistically equivalent. The cognitive debriefing showed a suitable understanding of the Chilean version by the parents. In the total sample (n = 302), the ECOHIS total score median was 1 (IQR 6), floor effect was 41.6%, and ceiling effect 0%. Cronbach's alpha was 0.89 and the ICC was 0.84. The correlation between ECOHIS and PedsQL™4.0 Generic Core was weak (r = 0.21), while it was strong-moderate (r = 0.64) with the PedsQL Oral Health scale. In the known groups comparison, the ECOHIS total score was statistically higher in children with poor than excellent/very good oral health (median 11.6 vs 0, p < 0.01), and in the high severity than in the caries-free group (median 8 vs 0.5, p < 0.01). No differences were found according to malocclusion and traumatic dental injuries groups. These results supported the feasibility, reliability and validity of the Chilean version of ECOHIS questionnaire for preschool children through proxy.


The phenotype of aging in the dog: how aging impacts the health and well-being of dogs and their caregivers.
Aging is the single most important cause of disease, disability, and death in adult dogs. Contrary to the common view of aging as a mysterious and inevitable natural event, it is more usefully understood as a set of complex but comprehensible biological processes that are highly conserved across species. Although the phenotypic expression of these processes is variable, there are consistent patterns both within and between species. The purpose of this feature is to describe the patterns currently recognized in the physical and behavioral manifestations of aging in the dog and how these impact the health and welfare of companion dogs and their human caregivers. Important gaps in our knowledge of the canine aging phenotype will be identified, and current research efforts to better characterize aging in the dog will be discussed. This will help set the context for future efforts to develop clinical assessments and treatments to mitigate the negative impact of aging on dogs and humans.


Changes in bronchoalveolar lavage fluid proteins in sarcoidosis: a proteomics approach.
In sarcoidosis, an inflammatory lung disease, the protein profile of bronchoalveolar lavage fluid (BALF) is altered. To study the BALF protein pattern changes in sarcoidosis, samples from six patients and four healthy individuals were analysed by two-dimensional polyacrylamide gel electrophoresis. A comparison of the protein-spot patterns showed a significantly higher number of protein spots in the pH range 5.5-6.7 in patients compared to controls (472 versus 384). Furthermore, the number of protein spots in the patients were significantly decreased in the acidic pH range 4.5-5.5 (399 versus 518). Measurement of the optical density in the gels showed varying expression levels for several protein spots. Seventeen of the altered protein spots were identified, of which seven have previously not been reported for BALF. Many of these are nonplasma proteins involved in the inflammatory and oxidant-antioxidant processes. In conclusion, the bronchoalveolar lavage fluid protein content is altered in sarcoidosis patients, especially for proteins that are not derived from plasma. The described proteomics approach will in the future be used to asses overall changes in the protein content associated with sarcoidosis and may offer the possibility of identifying disease-specific proteins.


Mechanism of liver glycogen repletion in vivo by nuclear magnetic resonance spectroscopy.
In order to quantitate the pathways by which liver glycogen is repleted, we administered [1-13C]glucose by gavage into awake 24-h fasted rats and examined the labeling pattern of 13C in hepatic glycogen. Two doses of [1-13C]glucose, 1 and 6 mg/g body wt, were given to examine whether differences in the plasma glucose concentration altered the metabolic pathways via which liver glycogen was replenished. After 1 and 3 h (high-dose group) and after 1 and 2 h (low-dose group), the animals were anesthetized and the liver was quickly freeze-clamped. Liver glycogen was extracted and the purified glycogen hydrolyzed to glucose with amyloglucosidase. The distribution of the 13C-label was subsequently determined by 13C-nuclear magnetic resonance spectroscopy. The percent 13C enrichment of the glucosyl units in glycogen was: 15.1 +/- 0.8%(C-1), 1.5 +/- 0.1%(C-2), 1.2 +/- 0.1%(C-3), 1.1 +/- 0.1%(C-4), 1.6 +/- 0.1%(C-5), and 2.2 +/- 0.1%(C-6) for the high-dose study (n = 4, at 3 h); 16.5 +/- 0.5%(C-1), 2.0 +/- 0.1%(C-2), 1.3 +/- 0.1%(C-3), 1.1 +/- 0.1%(C-4), 2.2 +/- 0.1%(C-5), and 2.4 +/- 0.1%(C-6) in the low-dose study (n = 4, at 2 h). The average 13C-enrichment of C-1 glucose in the portal vein was found to be 43 +/- 1 and 40 +/- 2% in the high- and low-dose groups, respectively. Therefore, the amount of glycogen that was synthesized from the direct pathway (i.e., glucose----glucose-6-phosphate----glucose-1-phosphate----UDP-glucose---- glycogen) was calculated to be 31 and 36% in the high- and low-dose groups, respectively. The 13C-enrichments of portal vein lactate and alanine were 14 and 14%, respectively, in the high-dose group and 11 and 8%, respectively, in the low-dose group. From these enrichments, the minimum contribution of these gluconeogenic precursors to glycogen repletion can be calculated to be 7 and 20% in the high- and low-dose groups, respectively. The maximum contribution of glucose recycling at the triose isomerase step to glycogen synthesis (i.e., glucose----triose-phosphates----glycogen) was estimated to be 3 and 1% in the high- and low-dose groups, respectively. In conclusion, our results demonstrate that (a) only one-third of liver glycogen repletion occurs via the direct conversion of glucose to glycogen, and that (b) only a very small amount of glycogen synthesis can be accounted for by the conversion of glucose to triose phosphates and back to glycogen; this suggests that futile cycling between fructose-6-phosphate and fructose-1,6-diphosphate under these conditions is minimal. Our results also show that (c) alanine and lactate account for a minimum of between 7 and 20% of the glycogen synthesized, and that (d) the three pathways through which the labeled flux is measured account for a total of only 50% of the total glycogen synthesized. These results suggest that either there is a sizeable amount of glycogen synthesis via pathway(s) that were not examined in the present experiment or that there is a much greater dilution of labeled alanine/lactate in the oxaloacetate pool than previously appreciated, or some combination of these two explanations.


Exposure of three generations of the estuarine sheepshead minnow (Cyprinodon variegatus) to the androgen, 17beta-trenbolone: effects on survival, development, and reproduction.
Estimating long-term effects of endocrine-disrupting chemicals on a species is important to assessing the overall risk to the populations. The present study reports the results of a 42-week exposure of estuarine sheepshead minnows (Cyprinodon variegatus) to the androgen, 17beta-trenbolone (Tb) conducted to determine if partial-(F0) or single-generation (F1) fish exposures identify multigenerational (F0-F3) effects of androgens on fish. Adult F0 fish were exposed to 0.007, 0.027, 0.13, 0.87,and 4.1 microg Tb/L, the F1 generation to < or =0.87 microg Tb/L, the F2 fish to < or =0.13 microg Tb/L, and the F3 fish to < or =0.027 microg Tb/L. The highest concentrations with reproducing populations at the end of the F0, F1, and F2 generations were 4.1, 0.87, and 0.027 microg Tb/L, respectively. Reproduction in the F0, F1, and F2 generations was significantly reduced at 0.87, 0.027, and 0.027 microg Tb/L, respectively. Fish were significantly masculinized in the F1 generation exposed to 0.13 microg Tb/L or greater. Female plasma vitellogenin was significantly reduced in F0 fish exposed to > or =0.87 microg Tb/L. Gonadosomatic indices of the F0 and F1 generations were significantly increased at 0.87 and 0.13 microg Tb/L in the F0 and F1 generation, respectively, and were accompanied by ovarian histological changes. Reproduction was the most consistently sensitive measure of androgen effects and, after a life-cycle exposure, the daily reproductive rate predicted concentrations affecting successive generations. The present study provides evidence that a multiple generation exposure of fish to some endocrine-disrupting chemicals can result in developmental and reproductive changes that have a much greater impact on the success of a species than was indicated from shorter term exposures.


Analysis of whole genome biomarker expression in blood and brain.
The consistency of peripheral gene expression data and the overlap with brain expression has not been evaluated in biomarker discovery, nor has it been reported in multiple tissues from the same subjects on a genome wide transcript level. The effects of processing whole blood, transformation, and passaged cell lines on gene expression profiling was studied in healthy subjects using Affymetrix arrays. Ficoll extracted peripheral blood mononuclear cells (PBMCs), Epstein-Barr virus (EBV) transformed lymphocytes, passaged lymphoblastic cell lines (LCLs), and whole blood from Tempus tubes were compared. There were 6,813 transcripts differentially expressed between different methods of blood preparation. Principal component analysis resolved two partitions involving pre- and post-transformation EBV effects. Combining results from Affymetrix arrays, postmortem subjects' brain and PBMC profiles showed co-expression levels of summarized transcripts for 4,103 of 17,859 (22.9%) RefSeq transcripts. In a control experiment, rat hemi-brain and blood showed similar expression levels for 19% of RefSeq transcripts. After filtering transcripts that were not significantly different in abundance between human cerebellum and PBMCs from the Affymetrix exon array the correlation in mean transcript abundance was high as expected (r = 0.98). Differences in the alternative splicing index in brain and blood were found for about 90% of all transcripts examined. This study demonstrates over 4,100 brain transcripts co-expressed in blood samples can be further examined by in vitro and in vivo experimental studies of blood and cell lines from patients with psychiatric disorders.


DNA polymorphic haplotypes on the short arm of chromosome 11 and the inheritance of type I diabetes mellitus.
The linked polymorphic loci 5' to the insulin gene and 3' to the c-Harvey-ras-1 (c-Ha-ras) gene, both localised to the short arm of chromosome 11, have been studied in 14 type I diabetic pedigrees. The use of a cloned gene probe corresponding to the polymorphic locus adjacent to the insulin gene, in combination with the restriction endonuclease PvuII, has permitted an improvement in the resolution of sizes of insert at this locus. An MspI restriction fragment length polymorphism at the c-Ha-ras proto-oncogene locus (4 cM upstream from the insulin gene) was used to identify parental insulin gene related alleles unambiguously, and subsequently a pedigree analysis was performed to determine whether subclasses of inserts at this locus track with insulin dependent diabetes. Segregation analysis demonstrated no linkage between the polymorphic loci 5' to the insulin gene, nor 3' to the c-Ha-ras, and type I diabetes. However, a similar analysis confirmed an association between the HLA locus chromosome 6 and insulin dependent diabetes.


Lithium and hematopoietic toxicity. I. Recovery in vivo of murine hematopoietic stem cells (CFU-S and CFU-Mix) after single-dose administration of cyclophosphamide.
Studies are described that demonstrate the ability of lithium (Li) to enhance the recovery of the total peripheral blood neutrophil and pluripotential stem cell (CFU-S and CFU-Mix) populations per femur from mice administered cyclophosphamide (CTX)(200 mg/kg body weight). Beginning 2 h after CTX administration and on the following two days, mice received ultra-pure Li2CO3 (35 micrograms/kg body weight) intraperitoneally. Control groups consisted of mice receiving either CTX or phosphate-buffered saline only; 24 h later and, on days 2-5, 7, 9, 12, 14, 16, 21, and 28, three mice from each group were serially sacrificed. Peripheral blood was obtained and examined for their hematocrit, white blood cell (WBC), and differential values. Bone marrow was harvested and assayed in vivo for CFU-S and in vitro for CFU-Mix. In addition, cell-cycle status of regenerating marrow was evaluated in vitro by use of the hydroxyurea suicide technique. Mice receiving CTX plus Li developed a significant elevation in the WBC which was demonstrated by an increase in the total neutrophil population when compared with CTX-administered controls. This enhanced hematopoietic activity was further demonstrated by an accelerated recovery of CFU-S and CFU-Mix compared with CTX controls. Cell kinetic studies demonstrated that a greater percentage of these stem cells obtained from Li-treated animals were in active cell cycle. These results demonstrate and confirm the capability of Li to accelerate hematopoietic recovery following the use of agents known to suppress hematopoiesis.


A comparison study of effects of Echinacea extract and levamisole on phenytoin-induced cleft palate in mice.
There are many reports that the teratogenic effects of phenytoin, especially cleft palate can be decreased by stimulation of maternal immune system. Also, there is some evidence that Echinacea extract and levamisole are immunomodulator drugs. So, in this study, we compared the prophylactic effects of levamisole and Echinacea extract on teratogenic effects of phenytoin. This study was performed on 32 pregnant mice that were divided into four groups. The first group (control group) received normal saline intraperitoneally and the other groups (test groups) received phenytoin (65 mg/kg intraperitoneally) at 10th day of gestation. Levamisole and extract of Echinacea purpurea were administrated at dose of 10 and 360 mg/kg intraperitoneally, respectively, in along with and 12h later after phenytoin injection, in two groups. Fetuses were carried out in 19th day of gestation and after determination of weight and length; they were stained by Alizarin red-Alcian blue method. Cleft palate incidence was 16, 5.3, and 3.2% in fetuses of mice that received only phenytoin, phenytoin with levamisole, and phenytoin with Echinacea extract, respectively. Mean weight and length of fetuses of animals that received levamisole and Echinacea extract were significantly greater than those received only phenytoin. It is concluded that Echinacea can stimulate immune system more than levamisole and has better prophylactic effect on incidence of phenytoin-induced cleft palate, but it is not significant.


[Long-range interactions between macromolecules, introduced into smectic liquid crystals].
Equations for the potentials of interactions between macromolecules of different shapes incorporated into smectic liquid crystals are presented. In addition to accurate equations, simple formula for estimation are given.


Predictors of ongoing implantation in IVF in a good prognosis group of patients.
The aim of this study was to investigate whether, in a large randomized trial, it is possible to identify specific maternal and/or embryo variables that could independently correlate with ongoing implantation in IVF/ICSI. In a Scandinavian study, 661 women were randomized to elective single embryo transfer or double embryo transfer. Women aged <36 years undergoing their first or second IVF cycle and with at least two good quality embryos were eligible. Only one cycle per subject was included. In the present study, cycles with 0 or 100% ongoing implantation (n = 520) were analysed regarding maternal and embryo variables. In this selected study group, the ongoing implantation rate was 195/734 (26.6%). In the univariate analysis, first IVF cycle, conventional IVF as fertilization method and 4-cell embryos showed a statistically higher ongoing implantation rate than did second IVF cycle, ICSI and non-4-cell embryos. In the multivariate analysis the same variables correlated independently to ongoing implantation. In addition, ovarian sensitivity correlated independently to ongoing implantation. This information should be used when selecting the number of embryos for transfer with the overall aim to reduce the rate of multiple births while maintaining a satisfactory birth rate.


Reproductive performance and pre-weaning mortality: Preliminary analysis of 27,221 purebred female dogs and 204,537 puppies in France.
The objective of this study was to describe efficiency of reproduction of purebred dogs in field breeding conditions, from mating to weaning in France. Data were collected between 2010 and 2014 in 5,667 French breeding kennels via a reproduction management software (Breeding Management System, Royal Canin, Aimargues, France). Effect of breed size (Mini: adult body weight <10 kg; Medium: 10-25 kg; Maxi: 25-40 kg; Giant: >40 kg), age of dam and male on pregnancy rate, abortion rate and litter size were evaluated by multivariable models. Data on 45,913 heats (all with mating), from 27,221 bitches from 248 breeds, were analysed. At mating, mean age (±SD) was 3.1 ± 1.8 years for bitches and 3.3 ± 2.0 for males. Males originated from the same kennel as the females in 88.5% of the matings. Based on breeder's evaluation of the pregnancy status, pregnancy rate (number of pregnant females based on breeders declaration/number of heats) was 87.8% and abortion rate was 6.8%. Finally, 81.9% of the mated females gave birth to a litter. On 37,946 litters (204,537 puppies), mean litter size was 5.4 ± 2.8 puppies (range 1-24), which was influenced by breed size and dam age (p < .0001). Stillbirth rate was 7.4% and puppy mortality rate (stillbirth + mortality until 2 months of age) was 13.4%. Prolificacy and puppy mortality rates were affected by breed size and within a breed size, by breed. Despite probable approximations (as data originate from breeders declaration), this large-scale analysis provides reference values on reproductive performance in dogs.


Molecular composition and pathology of entheses on the medial and lateral epicondyles of the humerus: a structural basis for epicondylitis.
To improve the understanding of epicondylitis by describing the normal structure and composition of the entheses associated with the medial and lateral epicondyles and their histopathology in elderly cadavers. Medial and lateral epicondyles were obtained from 12 cadavers. Six middle aged cadavers (mean 47 years) were used to assess the molecular composition of "normal" entheses from people within an age range vulnerable to epicondylitis. Cryosections of epicondylar entheses were immunolabelled with monoclonal antibodies against molecules associated with fibrocartilage and related tissues. A further six elderly cadavers (mean 84 years) were used for histology to assess features of entheses related to increasing age. Tendon entheses on both epicondyles fused with those of the collateral ligaments and formed a more extensive structure than hitherto appreciated. Fibrocartilage (which labelled for type II collagen and aggrecan) was a constant feature of all entheses. Entheses from elderly subjects showed extensive microscopic damage, hitherto regarded as a hallmark of epicondylitis. Fibrocartilage is a normal feature and not always a sign of enthesopathy. Furthermore, pathological changes documented in patients with epicondylitis may also be seen in elderly people. The fusion of the common extensor and flexor tendon entheses with those of the collateral ligaments suggests that the latter may be implicated as well. This may explain why pain and tenderness in epicondylitis may extend locally beyond the tendon enthesis and why some patients are refractory to local treatments.


New insights into the pathogenesis of tuberculosis revealed by Mycobacterium marinum: the zebrafish model from the systems biology perspective.
Tuberculosis remains a worldwide health concern, largely due to the emergence of multi-drug-resistant (MDR) and extensive-drug-resistant (XDR) Mycobacterium tuberculosis co-infection with HIV. The exact mechanism of Mycobacterium virulence, pathogenesis, and persistence is not fully understood. The hallmark of tuberculosis, granulomas are promoted by Mycobacterium virulence factors, and they have long been considered a structural advantage to the host. However, this traditional view has been challenged recently, largely due to the evidence originating from the M. marinum-zebrafish model. As a genetically tractable model, zebrafish provide unprecedented opportunities to address the pathogenesis of tuberculosis from a systems biology perspective. The latest data from this model are summarized in this review, special attention is given to the shared pathway and network between zebrafish and humans. This research serves to deepen our understanding of this complex process and to promote the discovery of better countermeasures against tuberculosis.