Muscle wasting in insulinopenic rats results from activation of the ATP-dependent, ubiquitin-proteasome proteolytic pathway by a mechanism including gene transcription.
In normal subjects and diabetic patients, insulin suppresses whole body proteolysis suggesting that the loss of lean body mass and muscle wasting in insulinopenia is related to increased muscle protein degradation. To document how insulinopenia affects organ weights and to identify the pathway for accelerated proteolysis in muscle, streptozotocin-treated and vehicle-injected, pair-fed control rats were studied. The weights of liver, adipose tissue, and muscle were decreased while muscle protein degradation was increased 75% by insulinopenia. This proteolytic response was not eliminated by blocking lysosomal function and calcium-dependent proteases at 7 or 3 d after streptozotocin. When ATP synthesis in muscle was inhibited, the rates of proteolysis were reduced to the same level in insulinopenic and control rats suggesting that the ATP-dependent, ubiquitin-proteasome pathway is activated. Additional evidence for activation of this pathway in muscle includes: (a) an inhibitor of proteasome activity eliminated the increased protein degradation; (b) mRNAs encoding ubiquitin and proteasome subunits were increased two- to threefold; and (c) there was increased transcription of the ubiquitin gene. We conclude that the mechanism for muscle protein wasting in insulinopenia includes activation of the ubiquitin-proteasome pathway with increased expression of the ubiquitin gene.


Nuclear and cytoplasmic localization of β-catenin in the nail-matrix cells and in an onychomatricoma.
β-catenin plays an important role in hair morphogenesis. Previously, the nuclear and cytoplasmic localizations of β-catenin were identified in hair-matrix cells. To evaluate β-catenin expression in the nail matrix, we obtained human nail units. Immunohistochemistry for β-catenin was used to evaluate sections of normal nail units and of sections from a single case of onychomatricoma. In the nail unit, β-catenin was expressed in the nucleus and cytoplasm of the suprabasal nail-matrix cells. Of the other epithelial-cell types, only the cell membrane was β-catenin-positive. In the nail tissue from the onychomatricoma case, β-catenin was expressed in the nucleus and cytoplasm of the upper epithelial layers. Our result suggests that β-catenin plays an important role in nail formation. In addition, β-catenin expression in onychomatricoma supports the presence of nail-matrix cells in this condition. To our knowledge, this is the first report of β-catenin expression in the nucleus and cytoplasm of the nail matrix.


Elliptic flow of charged particles in Pb-Pb collisions at sqrt[S(NN)] = 2.76 TeV.
We report the first measurement of charged particle elliptic flow in Pb-Pb collisions at sqrt[S(NN)] =2.76 TeV with the ALICE detector at the CERN Large Hadron Collider. The measurement is performed in the central pseudorapidity region (|η|<0.8) and transverse momentum range 0.2<p t<5.0 GeV/c. The elliptic flow signal v₂, measured using the 4-particle correlation method, averaged over transverse momentum and pseudorapidity is 0.087 ± 0.002(stat) ± 0.003(syst) in the 40%-50% centrality class. The differential elliptic flow v₂ p t reaches a maximum of 0.2 near p t =3 GeV/c. Compared to RHIC Au-Au collisions at sqrt[S(NN)] 200 GeV, the elliptic flow increases by about 30%. Some hydrodynamic model predictions which include viscous corrections are in agreement with the observed increase.


Mechanical Properties and Processing Techniques of Bulk Metal-Organic Framework Glasses.
Melt quenched metal-organic framework (MOF) glasses define a new category of glass, distinct from metallic, organic, and inorganic glasses, owing to the dominant role of metal-ligand coordination bonding. The mechanical properties of glasses in general are important given their application in protective coatings and display technologies, though little is known about MOF glasses in this respect. The experimental elucidation of key properties such as their scratch resistance has been limited by the lack of processing methodologies capable of producing bulk glass samples. Here, nanoindentation was used to investigate the Young's modulus and hardness of four melt-quenched glasses formed from zeolitic imidazolate frameworks (ZIF): agZIF-4, agZIF-62, agZIF-76, and agZIF-76-mbIm. The creep resistance of the melt-quenched glasses was studied via strain-rate jump (SRJ) tests and through constant load and hold (CLH) indentation creep experiments. Values for the strain-rate sensitivity were found to be close to those for other glassy polymers and Se-rich GeSe chalcogenide glasses. Vacuum hot-pressing of agZIF-62 resulted in an inhomogeneous bulk sample containing the glass and amorphous non-melt-quenched aZIF-62. Remelting and annealing, however, resulted in the fabrication of a transparent, bubble-free bulk specimen, which allowed the first scratch testing experiments to be performed on an MOF glass.


Prevalence and prediction of prolonged pruritus after severe burns.
Years after injury, pruritus is a common and severe problem for many burn patients. However, its characteristics and consequences are often only partially described. The authors therefore performed a prospective detailed examination of burn- and individual-related factors and considered those in relation to pruritus severity. Sixty-seven consecutive burn patients were assessed during acute care, and at 3 and 12 months postburn regarding preburn psychiatric disorders, health-related quality of life, post traumatic stress disorder, and personality traits. Postburn pruritus was subsequently assessed 2 to 7 years postburn using the Questionnaire for Pruritus Assessment. Fifty-one individuals, 76% of the participants, reported burn pruritus any time after the burn. Thirty-three individuals, 49% of the participants, reported ongoing pruritus the last 2 months. Information on the characteristics of pruritus was obtained from 32 of these individuals. Most perceived pruritus as bothersome or annoying and as present every day, 16 (50%) were considered to have severe pruritus, and 11 (34 %) scratched themselves to the point of bleeding. In logistic regressions, this was independently related to TBSA full-thickness burn and health-related quality of life at 3 months, and to TBSA full thickness burn and the personality trait impulsiveness, respectively. About half of the previous burn patients experienced ongoing pruritus on an average of 4.5 years after injury, and half of them had severe pruritus. Scratching oneself to the point of bleeding is linked both to a certain personality and to pruritus. It is suspected that many patients are left without access to the best available treatment.


Suppressive effect of insulin on the synthesis of sucrase-isomaltase complex in small intestinal epithelial cells, and abnormal increase in the complex under diabetic conditions.
An abnormally high level of the sucrase-isomaltase (SI) complex in the small intestine of rats with streptozotocin-induced insulin-dependent diabetes mellitus (IDDM) was normalized in 11 h by the administration of insulin, in addition to normalization of the blood glucose level. Phlorizin, an inhibitor of renal glucose reabsorption, also caused normalization of the blood glucose level in the IDDM rats; however, the level of the SI complex was barely changed. When mucosa explants were cultured in a medium, the SI complex synthesized during the cultivation was accumulated as its precursor protein without maturation, owing to the absence of pancreatic proteases, and the amount of the precursor protein that accumulated in the explants was decreased by the addition of insulin into the medium. Further, the mRNA level of the SI complex in the explants incubated with insulin was obviously lower than that in the absence of insulin. These results indicate that insulin has a suppressive effect on the synthesis of the SI complex, presumably by decreasing the transcriptional level of the gene encoding the complex, in small-intestinal epithelial cells. Thus the synthesis of the SI complex might exceed normal levels in the epithelial cells as a direct result of the depletion of insulin under IDDM conditions.


Effect of Recycled Iron Powder as Fine Aggregate on the Mechanical, Durability, and High Temperature Behavior of Mortars.
This study evaluates the mechanical, durability, and residual compressive strength (after being exposed to 20, 120, 250, 400 and 600 °C) of mortar that uses recycled iron powder (RIP) as a fine aggregate. Within this context, mechanical strength, shrinkage, durability, and residual strength tests were performed on mortar made with seven different percentages (0%, 5%, 10%, 15%, 20%, 30% and 50%) of replacement of natural sand (NS) by RIP. It was found that the mechanical strength of mortar increased when replaced with up to 30% NS by RIP. In addition, the increase was 30% for compressive, 18% for tensile, and 47% for flexural strength at 28 days, respectively, compared to the reference mortar (mortar made with 100% NS). Shrinkage was observed for the mortar made with 100% NS, while both shrinkage and expansion occurred in the mortar made with RIP, especially for RIP higher than 5%. Furthermore, significantly lower porosity and capillary water absorption were observed for mortar made with up to 30% RIP, compared to that made with 100% NS, which decreased by 36% for porosity and 48% for water absorption. As the temperature increased, the strength decreased for all mixes, and the drop was more pronounced for the temperatures above 250 °C and 50% RIP. This study demonstrates that up to 30% RIP can be utilized as a fine aggregate in mortar due to its better mechanical and durability performances.


The decomposition of peroxynitrite does not yield nitroxyl anion and singlet oxygen.
In a recent article [Khan, A. U., Kovacic, D., Kolbanovsky, A., Desai, M., Frenkel, K. & Geacintov, N. E. (2000) Proc. Natl. Acad. Sci. USA 97, 2984-2989], the authors claimed that ONOO(-), after protonation to ONOOH, decomposes into (1)HNO and (1)O(2) according to a spin-conserved unimolecular mechanism. This claim was based partially on their observation that nitrosylhemoglobin is formed via the reaction of peroxynitrite with methemoglobin at neutral pH. However, thermochemical considerations show that the yields of (1)O(2) and (1)HNO are about 23 orders of magnitude lower than those of ( small middle dot)NO(2) and ( small middle dot)OH, which are formed via the homolysis of ONOOH. We also show that methemoglobin does not form with peroxynitrite any spectrally detectable product, but with contaminations of nitrite and H(2)O(2) present in the peroxynitrite sample. Thus, there is no need to modify the present view of the mechanism of ONOOH decomposition, according to which initial homolysis into a radical pair, [ONO( small middle dot) ( small middle dot)OH](cage), is followed by the diffusion of about 30% of the radicals out of the cage, while the rest recombines to nitric acid in the solvent cage.


Effects of intensive voice treatment (the Lee Silverman Voice Treatment [LSVT]) on ataxic dysarthria: a case study.
This study examined the effects of intensive voice treatment (the Lee Silverman Voice Treatment [LSVT]) on ataxic dysarthria in a woman with cerebellar dysfunction secondary to thiamine deficiency. Perceptual and acoustic measures were made on speech samples recorded just before the LSVT program was administered, immediately after it was administered, and at 9 months follow-up. Results indicate short- and long-term improvement in phonatory and articulatory functions, speech intelligibility, and overall communication and job-related activity following LSVT. This study's findings provide initial support for the application of LSVT to the treatment of speech disorders accompanying ataxic dysarthria. Potential neural mechanisms that may underlie the effects of loud phonation and LSVT are addressed.


Coronary stents and vascular response to implantation: literature review.
Drug-eluting stents (DESs) have minimized the limitations of bare-metal stents (BMSs) after percutaneous coronary interventions. Nevertheless, serious concerns remain about possible late complications of stenting, such as stent thrombosis (ST) and in-stent restenosis (ISR), although the introduction of second-generation DESs seems to have softened the phenomenon, compared to the first-generation ones. ST is a potentially catastrophic event, which has been markedly reduced by optimization of stent implantation, novel stent designs, and dual antiplatelet therapy. The exact mechanism to explain its occurrence is under investigation, and, realistically, multiple factors are responsible. ISR of BMSs has been previously considered as a stable condition with an early peak (at 6 months) of intimal hyperplasia, followed by a regression period beyond 1 year. On the contrary, both clinical and histologic studies of DESs have demonstrated evidence of continuous neointimal growth during long-term follow-up, named "late catch-up" phenomenon. The acknowledgment that ISR is a relatively benign clinical condition has been recently challenged by evidences which reported that patients with ISR can experience acute coronary syndromes. Intracoronary imaging is an invasive technology that allows identifying features of atherosclerotic plaque of stent implanted and of vascular healing after stenting; it is often used to complete diagnostic coronary angiography and to drive interventional procedures. Intracoronary optical coherence tomography is currently considered a state-of-the-art imaging technique; it provides, compared to intravascular ultrasound, better resolution (at least >10 times), allowing the detailed characterization of the superficial structure of the vessel wall. Imaging studies "in vivo," in agreement with histological findings, suggest that chronic inflammation and/or endothelial dysfunction may induce late de novo "neoatherosclerosis" inside both BMSs and DESs. So, neoatherosclerosis has become the prime suspect in the pathogenesis of late stent failure.


Iron pharmacokinetics after administration of ferric-hydroxide-polymaltose complex in rats.
This paper reports a study of the pharmacokinetics of ferrous sulphate and ferric-hydroxide-polymaltose complex (Hw 6400, Ferrum Hausmann) administered orally and intravenously to anaemic and non-anaemic rats of both sexes. Radiolabelled ferrous sulphate and ferric-hydroxide-polymaltose complex was used to study iron utilization after oral administration. Measurements of radioactivity in serum, packed red cells, whole blood, liver, kidney, spleen, bone and in some cases in the gastrointestinal tract were made following a range of dosages between 0.84 and 41.9 mg Fe/kg. No significant difference in bioavailability or iron utilization was found between the two iron preparations. Pharmacokinetic measurements following i.v. administration showed different distribution volumes, iron clearance and elimination constants for the two preparations. This difference in pharmacokinetic behaviour following oral administration, particularly in the case of non-anaemic rats, was confirmed by the observation that a 10- to 20 fold smaller dose of FeSO4 than of iron-polymaltose complex was required to achieve the same rise in serum iron. It is therefore not justifiable to draw conclusions about the bioavailability of chemically different iron preparations (iron salts and iron hydroxide complexes) on the basis of AUC values for serum iron increases observed in non-anaemic animals or human subjects.


Subcellular localization of the Agrobacterium tumefaciens T-DNA transport pore proteins: VirB8 is essential for the assembly of the transport pore.
Agrobacterium tumefaciens transforms plants by transferring DNA to the plant cell nucleus. The VirB membrane proteins are postulated to form a pore for the transport of the DNA across the bacterial membranes. Immunofluorescence and immunoelectron microscopy were used to study the transport pore complex. Three likely components of the transport pore, VirB8, VirB9 and VirB10, localized primarily to the inner membrane, outer membrane and periplasm respectively. A significant amount of VirB10 was also found associated with the outer membrane. When expressed alone VirB9 and VirB10 were randomly distributed along the cell membrane. Subcellular location of both proteins changed dramatically in the presence of the other VirB proteins. Both proteins localized to fewer sites and most of the gold particles representing protein molecules were found in clusters suggesting that the two proteins are in a protein complex. VirB8, on the other hand, localized to clusters even in the absence of the other VirB proteins. To investigate the role of VirB8 in the formation of VirB9 and VirB10 protein complexes, we studied the effect of deletion of virB8 on the subcellular location of VirB9 and VirB10. In a virB8 deletion mutant both proteins were distributed randomly on the cell membrane indicating that VirB8 is essential for complex assembly.


CircBCAR3 sponges miR-27a-3p and mediates ferroptosis in human B-prolymphocytic leukaemia cells via SLC7A11.
B-lymphocytic leukaemia is one of the most commonly diagnosed blood malignancies, and our knowledge of B-prolymphocytic leukaemia remained barely comprehensive. CircRNAs and miRNAs were identified of important regulatory roles in tumours. This study focused on the possibly existing interaction of circBCAR3 and miR-27a-3p, and downstream molecules thereafter in B-prolymphocytic leukaemia cells. CircBCAR3 and miR-27a-3p expression was evaluated in JVM-2 cell line and normal lymphocytes. Dual-luciferase luminescence assay was conducted for validation of circBCAR3 and miR-27a-3p interaction, as well as western blot and flow cytometry for evaluation and validation of their association with SLC7A11, reactive-oxygen species and Fe2+ regarding ferroptosis. CircBCAR3 were upregulated in JVM-2 cells and were reversely correlated with the expression of miR-27a-3p. CircBCAR3 targeted at miR-27a-3p and was consequently associated with SLC7A11 expression positively, inhibiting ferroptosis and peroxidative damage in JVM-2 cells. This study identified a circBCAR3-miR-27a-3p-SLC7A11 axis regulating ferroptosis and peroxidation of B-prolymphocytic leukaemia cells which might be a key mechanism facilitating the survival of tumour cells. However, further validation based on more diverse cell lines and animal models might be required.


Increased cochlear fluid-attenuated inversion recovery signal in patients with vestibular schwannoma.
Elevated protein levels have been reported in perilymph of patients with vestibular schwannoma. Fluid-attenuated inversion recovery (FLAIR) imaging is sensitive to high protein contents in fluids. The purpose of this study was to investigate if in patients with unilateral vestibular schwannoma, cochlear FLAIR signal intensity on the affected side is increased compared with the unaffected side and control subjects. Fifteen patients with unilateral vestibular schwannoma and 25 age-matched control subjects (without a history of hearing loss) were retrospectively evaluated. All patients and controls had routine 5-mm FLAIR and T1- and T2-weighted imaging of the brain. The signal intensity of both cochleae was evaluated by placing a small region of interest on FLAIR images. The signal intensity of the brain stem was also determined by placing a second region of interest. A ratio of cochlear signal intensity to brain stem signal intensity (CIBI ratio) was determined. A t test was used to compare the CIBI ratios. In patients, the mean CIBI ratio of the affected side was 0.89 +/- 0.18, and that of the unaffected side was 0.57 +/- 0.12. In control subjects, it was 0.51 +/- 0.07. The CIBI ratio of the affected side was significantly higher compared with the unaffected side (P < .001) and compared with control subjects (P < .001). Patients with vestibular schwannoma have increased cochlear FLAIR signal intensity on the affected side compared with the unaffected side and healthy subjects.


Release of kinesin from vesicles by hsc70 and regulation of fast axonal transport.
The nature of kinesin interactions with membrane-bound organelles and mechanisms for regulation of kinesin-based motility have both been surprisingly difficult to define. Most kinesin is recovered in supernatants with standard protocols for purification of motor proteins, but kinesin recovered on membrane-bound organelles is tightly bound. Partitioning of kinesin between vesicle and cytosolic fractions is highly sensitive to buffer composition. Addition of either N-ethylmaleimide or EDTA to homogenization buffers significantly increased the fraction of kinesin bound to organelles. Given that an antibody against kinesin light chain tandem repeats also releases kinesin from vesicles, these observations indicated that specific cytoplasmic factors may regulate kinesin release from membranes. Kinesin light tandem repeats contain DnaJ-like motifs, so the effects of hsp70 chaperones were evaluated. Hsc70 released kinesin from vesicles in an MgATP-dependent and N-ethylmaleimide-sensitive manner. Recombinant kinesin light chains inhibited kinesin release by hsc70 and stimulated the hsc70 ATPase. Hsc70 actions may provide a mechanism to regulate kinesin function by releasing kinesin from cargo in specific subcellular domains, thereby effecting delivery of axonally transported materials.


Birth outcome from a prospective, matched study of prenatal crack/cocaine use: II. Interactive and dose effects on neurobehavioral assessment.
This prospective, longitudinal project was designed to determine the effects of prenatal cocaine use on the neurodevelopmental outcomes of infants from a historically understudied rural public health population. We interviewed > 2500 women prenatally, identified 154 cocaine users, and matched 154 controls on race, parity, socioeconomic status, and location of prenatal care (that related to level of pregnancy risk). Drug testing was required at enrollment and at delivery; detailed demographic, psychosocial, and drug histories were taken at each available trimester and follow-up visit. After birth, certified evaluators, blinded to maternal history of drug use, administered the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) under controlled conditions. Evaluation time for preterm infants was adjusted for gestational age. After controlling for the effects of marijuana (users of other illicit drugs were excluded), alcohol, and tobacco use, the following results remained. There were significant drug group interactions on the BNBAS Qualifier Score of Alert Responsiveness that demonstrated lower scores among infants who were exposed to both cocaine and tobacco and among those exposed to both marijuana and tobacco. There were also significant correlations between the amount of cigarette, alcohol, marijuana, and cocaine exposure and several BNBAS scores. The reported amount of cocaine use in the third trimester was negatively related to scores of Orientation, Cost of Attention, and Alert Responsiveness (that was also related to amount of cocaine used over the entire pregnancy). When the effects of marijuana, alcohol, and tobacco were partialled out, the amount of cocaine use in the third trimester was negatively related to Regulation of State, a precursor of alertness, and the infant's ability to orient to the environment. The observed decrement in state regulation, attention, and responsiveness among cocaine-exposed neonates raises concerns about later developmental abilities as well as the effect these infants may have on caregivers (who themselves may be compromised in their parenting abilities by their drug use). Follow-up of these infants will reveal if these disadvantages continue. These early results also emphasize the importance of considering amount and time of drug exposure as well as the interactive effects of drug exposure and other risk variables.


Routine pharyngeal cultures may not be useful in pediatric victims of sexual assault.
This study was conducted to determine the usefulness of routine pharyngeal cultures in pediatric sexual assault victims. A retrospective chart review was conducted to examine incidence data. The study was conducted in a 656-bed tertiary care hospital with 60,000 ED visits and approximately 350 pediatric sexual assault examinations annually. Records of all pediatric sexual assault examinations completed between 12:01 AM January 1, 1994, and 12:01 AM January 1, 1997, were retrospectively reviewed for inclusion. Subjects were included if they were younger than 15 years and had a nonacute examination for a suspected sexual assault. The final sample included 370 females and 81 males (total n=451 children). Oral and anal cultures were obtained on all patients. In addition, female patients had vaginal cultures and male patients had penile cultures performed. Culture specimens were sent for detection of chlamydia and gonococcus organisms. Of the 451 sets of cultures examined, there were 6 patients with one or more positive culture results. The 6 patients yielded a total of 10 positive culture results: 1 anal only, 1 vaginal only, and 4 both anal and vaginal. This was a positive culture rate of 1.3% overall. The positive culture result rates by site were oral 0%, vaginal 1.6%, anal 1.1%, and penile 0%. The ages of patients with positive culture results ranged from 2 to 13 years; all of those with positive culture results were female. The incidence of positive oral culture results in this sample was zero. This finding supports a more limited approach to standard sexually transmitted disease screening in pediatric sexual assault victims. The elimination of routine oral cultures in pediatric victims without alleged oral contact decreases the examination time, decreases the number of invasive procedures associated with the examination, and decreases the cost of the examination without negatively affecting patient care.


Sampling Methods for Adventive Trissolcus japonicus (Hymenoptera: Scelionidae) in a Wild Tree Host of Halyomorpha halys (Hemiptera: Pentatomidae).
Halyomorpha halys (Stål) (Hemiptera: Pentatomidae) is an invasive pest that has established in much of the United States. Adventive populations of an effective Asian egg parasitoid of H. halys, Trissolcus japonicus (Ashmead) (Hymenoptera: Scelionidae), have been detected in several states, including Virginia, and its geographic range is expanding. Documenting changes in its distribution and abundance have thus become key research priorities. For these specific purposes, surveillance of T. japonicus over large geographic areas using sentinel H. halys egg masses may not be optimally efficient, and examination of alternative sampling tactics is warranted. In 2016, sentinel H. halys egg masses were deployed as vertical transects in the canopy of female Ailanthus altissima (Mill.) Swingle (Sapindales: Simaroubaceae) in Virginia. A brief follow-up study in 2016 using yellow sticky traps deployed in the same trees yielded captures of T. japonicus, leading to a comparison of vertical transects of sentinel eggs and yellow sticky traps in 2017. Both methods yielded T. japonicus detections only in the middle and upper tree canopies, whereas other known H. halys parasitoids were detected in the lower, middle, or upper canopies. Based on this information, a method for deploying yellow sticky traps in the middle canopy of H. halys host trees was assessed in 2017, yielding T. japonicus captures. A comparison of estimated time inputs revealed that traps were more efficient than sentinel eggs in this regard. Results are discussed in relation to the utility of each sampling method to address specific questions about the range expansion and ecology of T. japonicus.


Detection of herb-symptom associations from traditional chinese medicine clinical data.
Background. Traditional Chinese medicine (TCM) is an individualized medicine by observing the symptoms and signs (symptoms in brief) of patients. We aim to extract the meaningful herb-symptom relationships from large scale TCM clinical data. Methods. To investigate the correlations between symptoms and herbs held for patients, we use four clinical data sets collected from TCM outpatient clinical settings and calculate the similarities between patient pairs in terms of the herb constituents of their prescriptions and their manifesting symptoms by cosine measure. To address the large-scale multiple testing problems for the detection of herb-symptom associations and the dependence between herbs involving similar efficacies, we propose a network-based correlation analysis (NetCorrA) method to detect the herb-symptom associations. Results. The results show that there are strong positive correlations between symptom similarity and herb similarity, which indicates that herb-symptom correspondence is a clinical principle adhered to by most TCM physicians. Furthermore, the NetCorrA method obtains meaningful herb-symptom associations and performs better than the chi-square correlation method by filtering the false positive associations. Conclusions. Symptoms play significant roles for the prescriptions of herb treatment. The herb-symptom correspondence principle indicates that clinical phenotypic targets (i.e., symptoms) of herbs exist and would be valuable for further investigations.


Role of White Blood Cells in Blood- and Bone Marrow-Based Autologous Therapies.
There has been significant debate over the role of white blood cells (WBCs) in autologous therapies, with several groups suggesting that WBCs are purely inflammatory. Misconceptions in the practice of biologic orthopedics result in the simplified principle that platelets deliver growth factors, WBCs cause inflammation, and the singular value of bone marrow is the stem cells. The aim of this review is to address these common misconceptions which will enable better development of future orthopedic medical devices. WBC behavior is adaptive in nature and, depending on their environment, WBCs can hinder or induce healing. Successful tissue repair occurs when platelets arrive at a wound site, degranulate, and release growth factors and cytokines which, in turn, recruit WBCs to the damaged tissue. Therefore, a key role of even pure platelet-rich plasma is to recruit WBCs to a wound. Bone marrow contains a complex mixture of vascular cells, white blood cells present at much greater concentrations than in blood, and a small number of progenitor cells and stem cells. The negative results observed for WBC-containing autologous therapies in vitro have not translated to human clinical studies. With an enhanced understanding of the complex WBC biology, the next generation of biologics will be more specific, likely resulting in improved effectiveness.


Cost of Salmonella Infections in Australia, 2015.
Gastroenteritis caused from infections with Salmonella enterica (salmonellosis) causes significant morbidity in Australia. In addition to acute gastroenteritis, approximately 8.8% of people develop irritable bowel syndrome (IBS) and 8.5% of people develop reactive arthritis (ReA). We estimated the economic cost of salmonellosis and associated sequel illnesses in Australia in a typical year circa 2015. We estimated incidence, hospitalizations, other health care usage, absenteeism, and premature mortality for four age groups using a variety of complementary data sets. We calculated direct costs (health care) and indirect costs (lost productivity and premature mortality) by using Monte Carlo simulation to estimate 90% credible intervals (CrI) around our point estimates. We estimated that 90,833 cases, 4,312 hospitalizations, and 19 deaths occurred from salmonellosis in Australia circa 2015 at a direct cost of AUD 23.8 million (90% CrI, 19.3 to 28.9 million) and a total cost of AUD 124.4 million (90% CrI, 107.4 to 143.1 million). When IBS and ReA were included, the estimated direct cost was 35.7 million (90% CrI, 29.9 to 42.7 million) and the total cost was AUD 146.8 million (90% CrI, 127.8 to 167.9 million). Foodborne infections were responsible for AUD 88.9 million (90% CrI, 63.9 to 112.4 million) from acute salmonellosis and AUD 104.8 million (90% CrI, 75.5 to 132.3 million) when IBS and ReA were included. Targeted interventions to prevent illness could considerably reduce costs and societal impact from Salmonella infections and sequel illnesses in Australia.


Endothelial Cell Response to Combined Photon or Proton Irradiation with Doxorubicin.
Surgery, radiotherapy, and chemotherapy are essential treatment modalities to target cancer cells, but they frequently cause damage to the normal tissue, potentially leading to side effects. As proton beam radiotherapy (PBT) can precisely spare normal tissue, this therapeutic option is of increasing importance regarding (neo-)adjuvant and definitive anti-cancer therapies. Akin to photon-based radiotherapy, PBT is often combined with systemic treatment, such as doxorubicin (Dox). This study compares the cellular response of human microvascular endothelial cells (HMEC-1) following irradiation with photons (X) or protons (H) alone and also in combination with different sequences of Dox. The cellular survival, cell cycle, apoptosis, proliferation, viability, morphology, and migration were all investigated. Dox monotreatment had minor effects on all endpoints. Both radiation qualities alone and in combination with longer Dox schedules significantly reduced clonogenic survival and proliferation, increased the apoptotic cell fraction, induced a longer G2/M cell cycle arrest, and altered the cell morphology towards endothelial-to-mesenchymal-transition (EndoMT) processes. Radiation quality effects were seen for metabolic viability, proliferation, and motility of HMEC-1 cells. Additive effects were found for longer Dox schedules. Overall, similar effects were found for H/H-Dox and X/X-Dox. Significant alterations between the radiation qualities indicate different but not worse endothelial cell damage by H/H-Dox.


Rapid imaging and detection of circulating tumor cells using a wide-field fluorescence imaging system.
Circulating tumor cells (CTCs) provide potentially accessible in vivo sources of metastatic cancer cells. As such, considerable focus has been placed on analyzing the genetics of single-CTCs. Prior to these analyses, however, CTCs must first be detected within the blood samples of cancer patients. Current methods for detection of CTCs by fluorescence microscopy require the analysis of hundreds of images per blood sample, making this a time-consuming process that creates a bottleneck in CTC analysis. In this study, we therefore developed a wide-field fluorescence imaging system for rapid CTC detection. For these analyses, CTCs were first isolated using the microcavity array (MCA), a micro-sized filter for CTC recovery that separates cells based on differences in cell size and deformability. Notably, the proposed imaging system enabled rapid (∼10 s) visualization of all stained cells within the 6 mm × 6 mm MCA field via one-shot imaging. Furthermore, the morphology of the cells in the resulting images accurately reflected that observed by conventional microscopy. In total, isolation and detection of CTCs using the MCA combined with our novel wide-field fluorescence imaging system was achieved within 1 h. Thus, our proposed system will provide rapid CTC detection system.


Receptors for chemotaxis in Bacillus subtilis.
At least three receptors for chemotaxis toward L-amino acids in Bacillus subtilis could be found with the aid of taxis competition experiments. They are called the asparagine receptor, which detects asparagine and glutamine, the isoleucine receptor, which detects isoleucine, leucine, valine, phenylalanine, serine, threonine, cysteine, and methionine, and the alanine receptor, which detects alanine and proline. Histidine and glycine could not be assigned to one of these receptors. Cysteine and methionine were found to be general inhibitors of chemotaxis and serine was found to be a general stimulator of chemotaxis. Some structural analogues of amino acids were tested for chemotactic activity. The chemotactic activity of B. subtilis is compared with that of Escherichia coli.


Study of nitrogen heterocycles as DNA/HSA binder, topoisomerase inhibitors and toxicological safety.
Four new nitrogen-containing heterocyclic derivatives (acridine, quinoline, indole, pyridine) were synthesized and their biological properties were evaluated. The compounds showed affinity for DNA and HSA, with CAIC and CAAC displaying higher binding constants (Kb) of 9.54 × 104 and 1.06 × 106, respectively. The fluorescence quenching assay (Ksv) revealed suppression values ranging from 0.34 to 0.64 × 103 M-1 for ethidium bromide (EB) and 0.1 to 0.34 × 103 M-1 for acridine orange (AO). Molecular docking confirmed the competition of the derivatives with intercalation probes at the same binding site. At 10 μM concentrations, the derivatives inhibited topoisomerase IIα activity. In the antiproliferative assays, the compounds demonstrated activity against MCF-7 and T47-D tumor cells and nonhemolytic profile. Regarding toxicity, no acute effects were observed in the embryos. However, some compounds caused enzymatic and cardiac changes, particularly the CAIC, which increased SOD activity and altered heart rate compared to the control. These findings suggest potential antitumor action of the derivatives and indicate that substituting the acridine core with different cores does not interfere with their interaction and topoisomerase inhibition. Further investigations are required to assess possible toxicological effects, including reactive oxygen species generation.


DCRM Multispecialty Practice Recommendations for the management of diabetes, cardiorenal, and metabolic diseases.
Type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF)-along with their associated risk factors-have overlapping etiologies, and two or more of these conditions frequently occur in the same patient. Many recent cardiovascular outcome trials (CVOTs) have demonstrated the benefits of agents originally developed to control T2D, ASCVD, or CKD risk factors, and these agents have transcended their primary indications to confer benefits across a range of conditions. This evolution in CVOT evidence calls for practice recommendations that are not constrained by a single discipline to help clinicians manage patients with complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. The ultimate goal for these recommendations is to be comprehensive yet succinct and easy to follow by the nonexpert-whether a specialist or a primary care clinician. To meet this need, we formed a volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM Practice Recommendations, a multispecialty consensus on the comprehensive management of the patient with complicated metabolic disease. The task force recommendations are based on strong evidence and incorporate practical guidance that is clinically relevant and simple to implement, with the aim of improving outcomes in patients with DCRM. The recommendations are presented as 18 separate graphics covering lifestyle therapy, patient self-management education, technology for DCRM management, prediabetes, cognitive dysfunction, vaccinations, clinical tests, lipids, hypertension, anticoagulation and antiplatelet therapy, antihyperglycemic therapy, hypoglycemia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), ASCVD, HF, CKD, and comorbid HF and CKD, as well as a graphical summary of medications used for DCRM.


An Autopsy Case of Familial Neuronal Intranuclear Inclusion Disease with Dementia and Neuropathy.
Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease with marked variety in its clinical manifestations. While characteristic neuroimaging and skin biopsy findings are important clues to the diagnosis, autopsy studies are still important for confirming the exact disease features. We herein report the case of a patient who received an antemortem diagnosis of familial NIID with dementia-dominant phenotype that was later confirmed by an autopsy. Our report is the first to document a case of autopsy-confirmed NIID involving both cognitive impairment and sensorimotor neuropathy.


The interface of child mental health and juvenile diabetes mellitus.
Diabetes mellitus is a common childhood illness, and its management is often complicated by mental health challenges. Psychiatric comorbidities are common, including anxiety, depression, and eating disorders. The illness can profoundly affect the developing brain and family functioning and have lifelong consequences. The child mental health provider can provide valuable assistance to support the child and family and assessment and treatment of comorbid mental health problems and to promote positive family functioning and normal developmental progress.


A rare cause of postmenopausal hyperandrogenism.
We present an unusual case of mucinous cystadenoma presenting with severe virilisation in a postmenopausal woman. A 71-year-old woman was referred to our outpatient endocrinology clinic because of rapidly progressive androgenic alopecia, clitoromegaly and male pattern pubic hair growth for 1 year. Her medical history was unremarkable. The serum testosterone level was 3.35 µg/L (normal range, <0.4 µg/L), and the dehydroepiandrosterone sulfate level was 267 µg/L (normal range, 100-800 µg/L). MRI of the abdomen revealed a 4×4 cm cystic ovarian mass. A bilateral salpingo-oophorectomy was performed, and histopathology showed a unilocular cystic structure with a yellowish content, compatible with mucinous cystadenoma. Postoperative testosterone levels quickly normalised (<0.4 µg/L).Rapidly developing postmenopausal hyperandrogenism easily turns into a diagnostic challenge for the clinician. Hormone-secreting neoplasms of the ovary are most commonly of sex cord stromal derivation, but atypical causes must be recognised as well. Cystadenomas are among the most common benign ovarian neoplasms and are classically considered 'non-functional' tumours. Most of these tumours are asymptomatic and found incidentally on pelvic examination or with ultrasound. To date and to the best of our knowledge, there are only five cases of mucinous adenoma causing virilisation in postmenopausal women identified in the literature. This sixth case adds strength to the link between ovarian mucinous cystadenoma and severe, rapidly progressive hyperandrogenism during menopause. In this case, surgical resection is the treatment of choice.


Recombinant glucagon: a differential biological activity.
In Brazil, there is a growing demand for specialised pharmaceuticals, and the high cost of their importation results in increasing costs, reaching US$ 1.34 billion in 2012 and US$ 1.61 billion in 2013. Worldwide expenses related to drugs could reach US$ 1.3 trillion in 2018, especially due to new treatments for hepatitis C and cancer. Specialised or high-cost pharmaceutical drugs used for the treatment of viral hepatitis, multiple sclerosis, HIV and diabetes are distributed free of charge by the Brazilian government. The glucagon peptide was included in this group of high-cost biopharmaceuticals in 2008. Although its main application is the treatment of hypoglycaemia in diabetic patients, it can also be used with patients in an alcoholic coma, for those patients with biliary tract pain, and as a bronchodilator. Therefore, in order to reduce biopharmaceutical production costs, the Brazilian government passed laws focusing on the development and increase of a National Pharmaceutical Industrial Centre, including the demand for the national production of glucagon. For that reason and given the importance and high cost of recombinant glucagon, the purpose of this study was to develop methods to improve production, purification and performance of the biological activity of recombinant glucagon. Glucagon was recombined into a plasmid vector containing a Glutathione S-transferase tag, and the peptide was expressed in a heterologous Escherichia coli system. After purification procedures and molecular analyses, the biological activity of this recombinant glucagon was examined using in vivo assays and showed a highly significant (p < 0.00001) and prolonged effect on glucose levels when compared with the standard glucagon. The experimental procedure described here facilitates the high level production of recombinant glucagon with an extended biological activity.


Orthopaedic specialist registrar selection: the advantages of a candidate ranking procedure at interview.
For five years an orthopaedic specialist registrar appointments committee has been using a points system to rank candidates at interview. By so doing committee members have been able to devote the discussion period, after all candidates have been interviewed, to considering the merits of those candidates who have achieved the greatest degree of support. This system maximises the efficient use of committee discussion time without restricting the freedom of the committee to make the most appropriate appointments.


Innovations in adolescent substance abuse intervention.
Adolescent alcohol and other drug abuse is an important public health concern, and the past two decades has seen a dramatic increase in the demand for interventions to address substance use problems among teenagers. This demand has led to the development of multiple primary, secondary, and tertiary substance abuse prevention programs, some of which have little theoretical basis and most of which currently operate in the absence of data supporting their effectiveness. Very recently, there has been increased emphasis on the goal of developing and testing theoretically based and empirically supported intervention approaches for adolescent substance abuse. We describe five ongoing research programs devoted to meeting this goal. The background and rationale for each research program are discussed, and preliminary efficacy data concerning the specific interventions are presented.


Extremely Fast and Accurate Open Modification Spectral Library Searching of High-Resolution Mass Spectra Using Feature Hashing and Graphics Processing Units.
Open modification searching (OMS) is a powerful search strategy to identify peptides with any type of modification. OMS works by using a very wide precursor mass window to allow modified spectra to match against their unmodified variants, after which the modification types can be inferred from the corresponding precursor mass differences. A disadvantage of this strategy, however, is the large computational cost, because each query spectrum has to be compared against a multitude of candidate peptides. We have previously introduced the ANN-SoLo tool for fast and accurate open spectral library searching. ANN-SoLo uses approximate nearest neighbor indexing to speed up OMS by selecting only a limited number of the most relevant library spectra to compare to an unknown query spectrum. Here we demonstrate how this candidate selection procedure can be further optimized using graphics processing units. Additionally, we introduce a feature hashing scheme to convert high-resolution spectra to low-dimensional vectors. On the basis of these algorithmic advances, along with low-level code optimizations, the new version of ANN-SoLo is up to an order of magnitude faster than its initial version. This makes it possible to efficiently perform open searches on a large scale to gain a deeper understanding about the protein modification landscape. We demonstrate the computational efficiency and identification performance of ANN-SoLo based on a large data set of the draft human proteome. ANN-SoLo is implemented in Python and C++. It is freely available under the Apache 2.0 license at https://github.com/bittremieux/ANN-SoLo .


Human hypoxanthine-guanine phosphoribosyltransferase. Demonstration of structural variants in lymphoblastoid cells derived from patients with a deficiency of the enzyme.
We have explored the possibility of using cultured lymphoblasts from patients with a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a source of cells for the isolation and characterization of mutant forms of the enzyme. HPRT from lymphoblasts derived from six male patients of five unrelated HPRT-deficient families was highly purified and characterized with regard to: (a) level of immunoreactive protein, (b) absolute specific activity, (c) isoelectric point, (d) migration during nondenaturing polyacrylamide gel electrophoresis, and (e) apparent subunit molecular weight. There experiments were performed on small quantities of lymphoblasts using several micromethods involving protein blot analysis of crude extracts as well as isolation and characterization of enzyme labeled in culture with radioactive amino acids. The lymphoblast enzymes from four of the patients exhibited structural and functional abnormalities that were similar to the recently described abnormalities found with the highly purified erythrocyte enzymes from these same patients. In addition, a previously undescribed HPRT variant was isolated and characterized from lymphoblasts derived from two male siblings. This unique variant has been called HPRT Ann Arbor. We conclude that lymphoblastoid cell lines can be used as a source of cells for the detection, isolation, and characterization of structural variants of human HPRT.


Spectral bandwidths of color-opponent cells of geniculocortical pathway of macaque monkeys.
1. The spectral-response bandwidth and peak sensitivity of the responses of color-opponent retinal ganglion cells of the macaque monkey were examined in conditions of neutral adaptation. Color-opponent cells showed specific "signatures" in plots of response bandwidth versus wavelength of the peak sensitivity that allow for an acceptable estimate of the cone types whose signals mediate cell responses. 2. Averaged spectral bandwidths of color-opponent ganglion cells were compared with published data from color-selective neurons of subsequent levels of the geniculocortical pathway, including the extrastriate area termed V4. No significant differences were found between color-selective cells of the retina, dorsal lateral geniculate body, striate cortex, and V4. 3. The spectral location of the peak sensitivity of responses of the various types of color-opponent ganglion cells showed a relatively broad distribution, loosely clustering at some spectral loci. Comparison of such distribution with that of recently reported V4 cells response indicates that a remarkable scarcity of "blue/yellow" opponent responses in such reports. 4. In association with more recent electrophysiological studies of V4 cells, the results do not support current claims of a color specialization of this extrastriate area, and suggest lack of significant spectral tuning of the retinal output in, so far known, higher visual centers having color-selective cells.


Delivering radiology supplies just-in-time.
The radiology department at Dartmouth Hitchcock Medical Center (DHMC) adopted a just-in-time (JIT) inventory management system in 1992, reducing the volume of its in-house inventory of radiology supplies from a value of $400,000 to $16,000, just enough for four to five days of activity. An asset manager, the only person authorized to order supplies, was given responsibility for maintaining the department's supply of fixed and consumable assets. The first step in implementing the new system was to identify the supplies needed, standardize them and determine how often deliveries would be made. The JIT implementation team developed a request for proposal (RFP) that incorporated the standardized list of supplies. Three radiology supply vendors were invited to respond to the RFP. The team later determined that only one vendor was capable of implementing the JIT program. A three-year contract was awarded to that vendor. As that three-year contract reached completion, DHMC offered the JIT program to its eight affiliate hospitals and four outpatient clinics. The team decided to re-bid the contract for the entire network, which collectively performed 700,000 radiology exams annually. The new RFP encompassed 90 percent of the network's consumable supplies and offered customized delivery for each facility. The team identified eight criteria necessary for the evaluation of each vendor response to the RFP, rather than use price as the only consideration. The company that won the three-year contract furnished 90 percent of the radiology supplies for the DHMC network, allowing even further savings by the network, particularly for the smaller facilities and clinics. The program is continually monitored, adjusted and enhanced in order to incorporate changing departmental needs.


Isolation and characterization of a human monoclonal antibody which reacts with breast and colorectal carcinoma.
A human monoclonal antibody with specificity for breast and colorectal carcinoma has been isolated after hybridoma formation between regional lymph node lymphocytes from a patient with breast carcinoma and a mouse x human heteromyeloma (SPAZ-4). The monoclonal, MAB 15.2.3, is an IgM, kappa, which binds to an epitope found on at least four glycoproteins with approximate molecular weights of 37, 39, 43 and 56 kilodaltons (kD). These antigens are expressed intracellularly and on the surface of breast and colorectal carcinoma cells and their level of expression is increased by treatment with recombinant human leukocyte (IFN-alpha A) or immune (IFN-gamma) interferon. Analysis of formalin-fixed tumor cell lines indicates specificity for carcinomas. Similarly, immunostaining of paraffin-embedded tissue indicates both cell membrane and intracytoplasmic reactivity with breast (8 of 12), colorectal (3 of 4) and prostate (1 of 3) carcinomas. By employing a series of enzymes which specifically cleave sugar residues on proteins, it was demonstrated that the binding of MAB 15.2.3 could be increased. These observations suggest that the epitope recognized by MAB 15.2.3. is protein in nature and expressed on a series of glycoproteins. Pretreatment of Colo 205 (human colorectal carcinoma) cells with MAB 15.2.3 prior to implantation into nude mice, results in a reduction in the size and weight of tumors. With appropriate genetic engineering, resulting in the conversion of this antibody to an IgG, MAB 15.2.3. could prove of value for the diagnosis and ultimately the therapy of human breast and colorectal carcinomas.


Charge Condensation and Lattice Coupling Drives Stripe Formation in Nickelates.
Revealing the predominant driving force behind symmetry breaking in correlated materials is sometimes a formidable task due to the intertwined nature of different degrees of freedom. This is the case for La_{2-x}Sr_{x}NiO_{4+δ}, in which coupled incommensurate charge and spin stripes form at low temperatures. Here, we use resonant x-ray photon correlation spectroscopy to study the temporal stability and domain memory of the charge and spin stripes in La_{2-x}Sr_{x}NiO_{4+δ}. Although spin stripes are more spatially correlated, charge stripes maintain a better temporal stability against temperature change. More intriguingly, charge order shows robust domain memory with thermal cycling up to 250 K, far above the ordering temperature. These results demonstrate the pinning of charge stripes to the lattice and that charge condensation is the predominant factor in the formation of stripe orders in nickelates.


Saccharomyces cerevisiae infection: an unusual pathogen in the ICU.
A case of a mixed fungal yeast infection involving Saccharomyces cerevisiae - well known for its use in the bread and wine industries - and Candida albicans, is described in an intensive care unit patient. Mortality due to mixed fungal infections in the intensive care unit is high. An elderly smoker patient with chronic pulmonary obstructive disease and untreated bladder neoplasm was admitted to the hospital with diarrhea and progressed to septic shock. The above-mentioned yeasts were identified in blood cultures. This case with fatal outcome provides an opportunity to discuss one of the emergent germs found in the intensive care unit, in a case with an atypical presentation.


Satisfiability Attack-Resistant Camouflaged Two-Dimensional Heterostructure Devices.
Reverse engineering (RE) is one of the major security threats to the semiconductor industry due to the involvement of untrustworthy parties in an increasingly globalized chip manufacturing supply chain. RE efforts have already been successful in extracting device level functionalities from an integrated circuit (IC) with very limited resources. Camouflaging is an obfuscation method that can thwart such RE. Existing work on IC camouflaging primarily involves transformable interconnects and/or covert gates where variation in doping and dummy contacts hide the circuit structure or build cells that look alike but have different functionalities. Emerging solutions, such as polymorphic gates based on a giant spin Hall effect and Si nanowire field effect transistors (FETs), are also promising but add significant area overhead and are successfully decamouflaged by the satisfiability solver (SAT)-based RE techniques. Here, we harness the properties of two-dimensional (2D) transition-metal dichalcogenides (TMDs) including MoS2, MoSe2, MoTe2, WS2, and WSe2 and their optically transparent transition-metal oxides (TMOs) to demonstrate area efficient camouflaging solutions that are resilient to SAT attack and automatic test pattern generation attacks. We show that resistors with resistance values differing by 5 orders of magnitude, diodes with variable turn-on voltages and reverse saturation currents, and FETs with adjustable conduction type, threshold voltages, and switching characteristics can be optically camouflaged to look exactly similar by engineering TMO/TMD heterostructures, allowing hardware obfuscation of both digital and analog circuits. Since this 2D heterostructure devices family is intrinsically camouflaged, NAND/NOR/AND/OR gates in the circuit can be obfuscated with significantly less area overhead, allowing 100% logic obfuscation compared to only 5% for complementary metal oxide semiconductor (CMOS)-based camouflaging. Finally, we demonstrate that the largest benchmarking circuit from ISCAS'85, comprised of more than 4000 logic gates when obfuscated with the CMOS-based technique, is successfully decamouflaged by SAT attack in <40 min; whereas, it renders to be invulnerable even in more than 10 h when camouflaged with 2D heterostructure devices, thereby corroborating our hypothesis of high resilience against RE. Our approach of connecting material properties to innovative devices to secure circuits can be considered as a one of a kind demonstration, highlighting the benefits of cross-layer optimization.


The Effects of Cognitive Behavioral Group Therapy on Anxiety and Emotion Regulation in Thai Middle School Students.
This quasi-experimental study examined the effects of Cognitive Behavioral Group Therapy (CBGT) in alleviating anxiety and enhancing emotion regulation in community-sample Thai middle school students. Forty-seven community-sample students in Grades 7-9 with elevated SCARED scores participated in this pre-post treatment-control study. Twenty-three in the treatment group attended the eight-session 2-hour semi-weekly CBGT. The remaining were the control group. Before and after the intervention, the participants completed the measures of anxiety and emotion regulation. Data obtained were subsequently analyzed using repeated-measures and between-groups MANOVAs. At post-intervention, the treatment group reported a significant decrease in anxiety but a significant increase in emotion regulation. Furthermore, when compared with the control group, their anxiety score was significantly lower but their emotion regulation score was significantly higher, respectively. Findings supported the benefits of CBGT in reducing anxiety in Thai middle school students and in enhancing their emotion regulation skills. Therapeutic implications for anxiety reduction were discussed.


[A computerized system for clinical microbiology (author's transl)].
A system of microbiology reporting by computer which is simple to operate and provides accurate, rapid reporting of laboratory results with provisions for permanent data storage, retrieval and other programs, is described. The system provides on efficient and reliable day-to-day service and readily accessible data for retrospective research. A brief note on the computer element of the system is also given.


Prevalence of common and atypical melanocytic nevi in Turkish children.
The incidence of malignant melanoma is increasing rapidly in the white population of the world. Therefore, it is necessary to know the etiological factors of malignant melanoma and to take preventive measures in high-risk groups in different populations. This study aimed to estimate the prevalence of common melanocytic nevi (CMN) and atypical melanocytic nevi (AMN) and to identify some phenotypic factors (eye and hair color, skin type), gender, and age associated with CMN and AMN presence in primary school children in a Turkish population. In this study, 1491 children aged from 7-15 were examined. Brown-black discrete lesions of two millimeters or larger, with the exceptions of solar lentigo and ephelides, were counted as CMN. The CMN prevalence was 73.85%, and the AMN prevalence was 3.45%. The numbers of CMN and AMN were found to be higher in boys than in girls. While more CMN were present in the head and neck areas than in other anatomic regions, the number of AMN was higher on the ventral and dorsal trunk. Our study provides evidence for a significant relationship between specific characteristics, including skin type, age, gender and the number of CMN in our population. However, CMN is more frequent in children having a lighter skin type, and its number increases with age. The results of our study and further studies which take sun-exposure characteristics and pigmentary factors into account, may facilitate the determination of the other factors affecting nevus production and the development of further strategies for following and preventing cutaneous melanoma in our geographical area.


Phase I clinical trial of intracerebroventricular transplantation of allogeneic neural stem cells in people with progressive multiple sclerosis.
We report the analysis of 1 year of data from the first cohort of 15 patients enrolled in an open-label, first-in-human, dose-escalation phase I study (ClinicalTrials.gov: NCT03282760, EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of secondary progressive multiple sclerosis. Participants were treated with hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed. All participants displayed stability of clinical and laboratory outcomes, as well as lesion load and brain activity (MRI), compared with the study entry. Longitudinal metabolomics and lipidomics of biological fluids identified time- and dose-dependent responses with increased levels of acyl-carnitines and fatty acids in the cerebrospinal fluid (CSF). The absence of AEs and the stability of functional and structural outcomes are reassuring and represent a milestone for the safe translation of stem cells into regenerative medicines.


[Study of development of ciliary folds and Zinn's zonules in Rana temporaria L. by means of scanning electron microscopy].
The development of ciliary folds and zonul of Zinn has been studied in the eyes of the common frog Rana temporaria L. by means of scanning electron microscopy. The development of ciliary folds begins at the stage 45 by the flexure of the external layer in the ciliary zone. At the stage 46 this process involves the internal layer and the folds become two-layered. The zonules of Zinn form before the folds of internal layer of the ciliary epithelium begin to form as separate bundles of fibers. At the stage 45 they are already distinct. Later the ciliary filaments fold in 2 felt-like layers -- zonula which pass from the equatorial lens zone and attach near orbiculum ciliaris. In the place of attachment the margin of zonul repeats the relief of folds, thus attaching to their whole surface, and individual filaments go farther, to orbiculum ciliaris. All these processes take place in they eye prior to the beginning of metamorphosis.


A sequential experimental design method to evaluate a combination of school closure and vaccination policies to control an H1N1-like pandemic.
During the 2009 H1N1 pandemic, computational agent-based models (ABMs) were extensively used to evaluate interventions to control the spread of emerging pathogens. However, evaluating different possible combinations of interventions using ABMs can be computationally very expensive and time-consuming. Therefore, most policy studies have examined the impact of a single policy decision. To apply a sequential experimental design method with an ABM to analyze policy alternatives composed of a combination of school closure and vaccination policies to provide a set of promising "optimal" combinations of policies to control an H1N1-type epidemic to policy makers. We used an open-source agent-based modeling system, FRED (A Framework for Reconstructing Epidemiological Dynamic), to simulate the spread of an H1N1 epidemic in Alleghany County, Pennsylvania, with a census-based synthetic population. We used an approach called best subset selection method to evaluate 72 alternative policies consisting of a combination of options for school closure threshold, closure duration, Advisory Committee on Immunization Practices prioritization, and second-dose vaccination prioritization policies. Using the attack rate as a performance measure, best subset selection enabled us to eliminate inferior alternatives and identify a small group of alternative policies that could be further evaluated on the basis of other criteria. Our sequential design approach to evaluate a combination of alternative mitigation policies leads to a savings in computational effort by a factor of 2 when examining combinations of school closure and vaccination policies. Best subset selection demonstrates a substantial reduction in the computational burden of a large-scale ABM in evaluating several alternative policies. Our method also provides policy makers with a set of promising policy combinations for further evaluation based on implementation considerations or other criteria.


[Expression of Mta-1 and VEGF and their correlation in the endometrial cancer].
To explore the expression of metastasis-associated protein 1(Mta-1) and vascular endothelial growth factor (VEGF) and their correlation in the endometrial cancer. In 62 cases of endometrial cancer and 30 cases of normal endomedium, the expression of Mta-1 and VEGF was examined with immunohistochemistry and their correlation with pathological phenotype of the endometrial cancer was analyzed. The expression of Mta-1 and VEGF in endometrial cancer was higher than that in normal endomedium (P<0.01). The expression of Mta-1 and VEGF in endometrial cancer was related to clinical stage, pathologic type, lymph node metastasis and depth of myometrial invasion (P<0.05 or P<0.01). Positive correlation was observed between VEGF and Mta-1 expression(r=0.582, P<0.05). Expression of Mta-1 expression and VEGF is positively associated with the development and progression of endometrial cancer.


Prospective study of cancer in Japanese patients with type 2 diabetes: the Fukuoka Diabetes Registry.
Although the association between type 2 diabetes and cancer has been reported, few epidemiological studies have been conducted in Japanese patients whose leading cause of death is cancer. We prospectively studied the incidence of site-specific cancer, risk factors for developing cancer, cancer death, and survival in Japanese patients with type 2 diabetes. We followed 4923 participants (mean age, 65 years) with type 2 diabetes attending an outpatient diabetes clinic for a median of 5.3 years (follow-up rate, 99.0%). During the follow-up period, cancer occurred in 450 participants (incidence rate, 22.3/1000 person-years in men and 12.2/1000 person-years in women). In men, prostate cancer was the most common cancer (4.3/1000 person-years), colorectal cancer was the second (3.6/1000 person-years), and gastric cancer was the third (3.3/1000 person-years). In women, colorectal cancer was the most common cancer (2.6/1000 person-years), gastric cancer was the second (2.0/1000 person-years), and breast cancer was the third (1.4/1000 person-years). Smoking, male sex, low-density lipoprotein cholesterol, family history of cancer, and reduced intake of isoflavone daidzein were significant risk factors for developing cancer using multivariable Cox proportional hazards models. The leading cancer death was lung cancer in men and pancreatic cancer in women. The survival was the best for prostate cancer and the worst for pancreatic cancer (2-year cancer-specific survival 95.4%, 30.0%, respectively). Since the leading cause of death in patients with type 2 diabetes is cancer in Japan, clinicians should be aware of epidemiological data regarding cancer besides diabetic complications.


Changes in the characteristics of the bone marrow during therapy for acute non-lymphocytic leukemia: relationship to response to remission induction therapy.
The bone marrows of patients with acute non-lymphocytic leukemia being treated with 'high dose' cytosine arabinoside remission induction therapy were sampled prior to the initiation of chemotherapy, after 6 days of therapy and again 7 days after the conclusion of therapy. These studies demonstrated that the marrows of patients who would enter remission (CR patients) contained less leukemic cells prior to therapy than patients who would fail to enter remission because of persistent leukemia (resistant disease, or RD patients). A comparison of the day 6 and 7-day post-therapy marrows with the pretherapy marrow demonstrated that while the % reduction in leukemic cells was greater for CR patients than for RD patients, the absolute reduction in leukemic cell mass was the same for both groups. While there was no relationship between the percentage of cells in S phase and the pretherapy leukemic cell mass, the greater the pretherapy leukemic cell mass the greater the likelihood that the leukemic cells would be resistant to the metabolic effects of cytosine arabinoside in vitro.


The use of hyperoxia to induce chronic mild oxidative stress in RPE cells in vitro.
To establish a model of mild and chronic oxidative stress using hyperoxia for retinal pigment epithelial (RPE) cells in vitro. RPE340 cells and WI38 lung fibroblasts were grown in normal oxygen (20% O2) and hyperoxia (40% O2 or 60% O2). After cell viability was examined, the levels of reactive oxygen intermediates (ROI) by flow cytometry and heme oxygenase-1 (HO-1) mRNA by northern analysis were measured as markers of oxidative stress in both cell types. Proliferative ability and gene expression pattern of growth factors were studied to demonstrate the phenotypic changes induced by mild oxidative stress upon these cells. While decreased by 60% O2, 40% O2 did not affect viability in both cell types, ROI production and HO-1 mRNA expression were elevated in hyperoxia compared to controls, but were inhibited with the antioxidant dehydro-ascorbic acid (DHA). The proliferation of cells by hyperoxia was inhibited in both cell types. The expression of growth factors induced by hyperoxia was cell type dependent. Fibroblast growth factor-2 mRNA was unchanged in RPE cells, but was increased in fibroblasts. Transforming growth factor-beta2 was decreased in RPE cells, but unchanged in fibroblasts. Vascular endothelial growth factor was downregulated in RPE cells, while upregulated in fibroblasts. Connective tissue growth factor was decreased in RPE cells, but was unchanged in fibroblasts. The results demonstrate that hyperoxia induces mild oxidative stress which alters the phenotype of cells in a cell type specific manner.


Deep Label Distribution Learning With Label Ambiguity.
Convolutional neural networks (ConvNets) have achieved excellent recognition performance in various visual recognition tasks. A large labeled training set is one of the most important factors for its success. However, it is difficult to collect sufficient training images with precise labels in some domains, such as apparent age estimation, head pose estimation, multilabel classification, and semantic segmentation. Fortunately, there is ambiguous information among labels, which makes these tasks different from traditional classification. Based on this observation, we convert the label of each image into a discrete label distribution, and learn the label distribution by minimizing a Kullback-Leibler divergence between the predicted and ground-truth label distributions using deep ConvNets. The proposed deep label distribution learning (DLDL) method effectively utilizes the label ambiguity in both feature learning and classifier learning, which help prevent the network from overfitting even when the training set is small. Experimental results show that the proposed approach produces significantly better results than the state-of-the-art methods for age estimation and head pose estimation. At the same time, it also improves recognition performance for multi-label classification and semantic segmentation tasks.


Evaluating the impact of expanded practice dental hygienists in Oregon: an outcomes assessment.
Currently the dental hygiene practice model in Oregon includes the Expanded Practice Dental Hygienist (EPDH), which allows dental hygienists with an Expanded Practice Permit (EPP) to provide care to limited access populations without the supervision of a dentist. The number and types of services provided by EPDH practitioners is thus far undocumented. The purpose of this study is to conduct an outcomes assessment of EPDH practitioners in order to quantify the impact, defined by count of services, on the access to care crisis in Oregon. A 16 question confidential survey was developed and approved by the Pacific University institutional review board. The mail-based survey was sent to 181 EPDHs in Oregon in November 2011 (all EPDHs except pilot testers and one author). A second mailing was sent to non-respondents. Data were analyzed using descriptive statistics and chi-square analysis in SPSS. The response rate was 39% (n = 71). Approximately 41% (n = 29) of the respondents were currently using their EPP to provide care to limited access patients with an additional 21% (n = 15) planning to start their own expanded practice. The majority of practicing EPDHs provide care in residential care facilities (n = 21) and in school settings (n=13). Of the current practicing EPP holders, 76% practice ≤ 10 hours per week, and 66% make < $10,000 per year. Total services reported in an average month from all responding EPDH practitioners were: 254 adult prophylaxes, 1,003 child prophylaxes, 106 adult fluorides, 901 child fluorides and 1,994 fluoride varnishes, among many other preventive procedures. To a limited extent, the amount and type of services provided by EPDHs has now been quantified, and EPDHs are making an impact on the access to care crisis in Oregon. Continued outcomes assessment is needed to further quantify the impact of EPDHs.


Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60)-63-tris Malonic Acid [C3] in Mice and Primates.
Fullerene-based compounds are a novel class of molecules being developed for a variety of biomedical applications, with nearly 1000 publications in this area in the last 4 years alone. One such compound, the e,e,e-methanofullerene(60)-63-tris malonic acid (designated C3), is a potent catalytic superoxide dismutase mimetic which has shown neuroprotective efficacy in a number of animal models of neurologic disease, including Parkinsonian Macaca fascicularis monkeys. The aim of this study was to characterize its toxicity and pharmacokinetics in mice and monkeys. To assess pharmacokinetics in mice, we synthesized and administered 14C-C3 to mice using various routes of delivery, including orally. To assess potential toxicity in primates, serial blood studies and electrocardiograms (ECGs) were obtained from monkeys treated with C3 (3 or 7 mg/kg/day) for 2 months. The plasma half-life of C3 was 8.2 ± 0.2 h, and there was wide tissue distribution, including uptake into brain. The compound was cleared by both hepatic and renal excretion. C3 was quite stable, with minimal metabolism of the compound even after 7 days of treatment. The LD50 in mice was 80 mg/kg for a single intraperitoneal injection, and was > 30 mg/kg/day for sustained administration; therapeutic doses are 1-5 mg/kg/day. For primates, no evidence of renal, hepatic, electrolyte, or hematologic abnormalities were noted, and serial ECGs demonstrated no alteration in cardiac electrical activity. Thus, doses of C3 that have therapeutic efficacy appear to be well tolerated after 2 years (mice) or 2 months (non-human primates) of treatment.


Phrynoderma: a forgotten entity in a developed country.
Phrynoderma is a type of follicular hyperkeratosis attributed to various nutritional deficiencies, most notably vitamin A. We report a case of a 31-year-old mentally-deficient man who was a resident of a voluntary welfare nursing home. He presented with characteristic hyperkeratotic follicular papules on his trunk in a setting of low serum level of vitamin A and malnutrition. Although commonly seen in South and East Asia, it is rarely reported in Singapore. However, there is still a population at risk here--patients with malabsorption and eating disorders, and institutionalised persons. Phrynoderma should, therefore, be considered in the differential diagnosis in patients with hyperkeratotic folliculitis, especially when malnutrition is also present.


Clinically approved liposomal nanomedicines: lessons learned from the biomolecular corona.
Nowadays, liposomes are the most successful drug delivery systems with a dozen drug products available in the clinic. Grafting poly-(ethylene glycol) (PEG) onto the liposome surface prevents protein binding thus prolonging blood circulation, while synthetic modification of the terminal PEG molecule with ligands (e.g. monoclonal antibodies and peptides) should promote selective accumulation in the tumor region with respect to healthy tissues. However, despite big efforts, advances have not outgrown the development stage and just a few targeted liposomal drugs are commercially available. The latest studies have clarified that following exposure to physiological environments liposomes are covered by a biomolecular corona (BC). Main factors shaping the BC are the liposomes' physicochemical properties (i.e. size, surface charge and lipid composition), the biological fluid (e.g. plasma of healthy volunteers vs. plasma of cancer patients) and environmental factors (e.g. temperature). Combining the most recent evidence reported in the literature, herein we suggest that the liposome-BC could act as a personalized "endogenous trigger" affecting off-target interactions and controlling the indication for disease of clinically approved formulations. In this Opinion paper, we suggest that a better understanding of the liposome-BC together with improvements in mapping corona proteins will open the fascinating possibility to manipulate the BC by liposome design. This is not an easy task, but it could represent a turning point in the development of novel liposome-based targeting strategies for personalized nanomedicines.


Protein Crystallography and Site-Direct Mutagenesis Analysis of the Poly(ethylene terephthalate) Hydrolase PETase from Ideonella sakaiensis.
Unlike traditional recycling strategies, biodegradation is a sustainable solution for disposing of poly(ethylene terephthalate) (PET) waste. PETase, a newly identified enzyme from Ideonella sakaiensis, has high efficiency and specificity towards PET and is, thus, a prominent candidate for PET degradation. On the basis of biochemical analysis, we propose that a wide substrate-binding pocket is critical for its excellent ability to hydrolyze crystallized PET. Structure-guided site-directed mutagenesis revealed an improvement in PETase catalytic efficiency, providing valuable insight into how the molecular engineering of PETase can optimize its application in biocatalysis.


Obinutuzumab plus lenalidomide in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA study.
Obinutuzumab and lenalidomide (referred to as the GALEN combination) is an active immunomodulatory combination with a manageable safety profile in multiple types of lymphoma. We report efficacy and safety results for the phase 2 GALEN study in previously untreated patients with advanced follicular lymphoma (FL). Eligible patients aged ≥18 years had an Eastern Cooperative Oncology Group performance status ≤2 and high-tumor burden, grade 1 to 3a FL. Induction treatment was obinutuzumab (1000 mg IV, days 8, 15, and 22, cycle 1; day 1, cycles 2-6) plus lenalidomide (20 mg/d, days 1-21, cycle 1; days 2-22, cycles 2-6) for six 28-day cycles. Maintenance included obinutuzumab (1000 mg every 2 cycles) plus lenalidomide (10 mg, days 2-22) for ≤12 cycles (year 1) followed by obinutuzumab (1000 mg every 56 days) for 6 cycles (year 2). The primary end point was complete response rate (CRR) after induction per the 1999 International Working Group criteria. From October 2015 to February 2017, a total of 100 patients were enrolled. CRR after induction was 47%, and the overall response rate (ORR) was 92%. Post hoc analyses per the 2014 Lugano classification, including patients with missing bone marrow assessments, identified an additional 13 patients fulfilling CRR criteria, resulting in a complete metabolic response of 80% and an ORR of 94%. At a median follow-up of 3.7 years, 3-year progression-free survival and overall survival were 82% and 94%, respectively. The most common adverse event was neutropenia (48% any grade; 47% grade ≥3). Only 2% of patients presented with febrile neutropenia; others were mainly grade ≤2. No other specific grade ≥3 toxicity occurred at a frequency >3%. Overall, these results showed promising clinical efficacy for the chemotherapy-free GALEN backbone in previously untreated patients with high tumor burden FL. Except for neutropenia, the safety profile of the combination is remarkable. The study was registered at clinicaltrials.gov as #NCT01582776.


The impact of topical mupirocin on peritoneal dialysis infection rates in Singapore General Hospital.
Peritonitis and exit-site infections (ESI) are major causes of technique failure and morbidity in peritoneal dialysis (PD) patients. Topical mupirocin on the exit-site has been shown to reduce such complications and prolong life in PD. Since the year 2000, such an approach has been adopted for our new incident PD population. We now report the results of this new protocol. We also studied the effect of co-morbidity on peritonitis occurrence. A total of 740 incident PD patients were studied. Patients were divided into two groups based on year of entry into PD (Group 1 from January 1998-December 1999 without topical mupirocin and Group 2 from January 2000-March 2004 with topical mupirocin). Variables studied included gender, age, diabetic status, ischaemic heart disease, peripheral vascular disease, cerebrovascular disease and serum albumin. Topical mupirocin at the exit-site has led to a significant reduction in peritonitis rate (0.443 vs 0.339 episodes/patient-year; P<0.0005) and ESI (0.168 vs 0.156 episodes/patient-year; P<0.005) attributed primarily to the significant reduction in Staphylococcus aureus infections. There was an unexpected finding of lower Pseudomonas aeruginosa peritonitis in the mupirocin group (P<0.005). Stepwise multiple logistic regression analysis revealed that only mupirocin application and serum albumin were significant predictors of peritonitis. Our study, although limited by its retrospective nature, demonstrated that topical mupirocin was associated with a significant reduction in ESI and peritonitis with unexpected findings of lower Pseudomonas peritonitis. Serum albumin prior to the initiation of PD was a strong predictor of subsequent peritonitis. Mupirocin, with its low toxicity, ease of application and demonstrable beneficial effect in reducing ESI and peritonitis is now used on all incident PD patients.


Origins of accessory small ring marker chromosomes derived from chromosome 1.
Three patients with accessory small ring chromosomes derived from chromosome 1 are presented together with additional clinical details and cytogenetic analyses of a previously reported patient. Cytogenetic analysis was undertaken by FISH using a reverse painting probe generated from one of the patients by microdissection of the r(1) chromosome and with a BAC923C6 which maps to 1p12. Results indicated that patients with r(1) chromosomes consisting of 1q12 heterochromatin and short arm pericentric euchromatin which extends to at least the BAC923C6 were associated with a normal or mild phenotype. Patients with abnormal phenotypes possessed two types of rings. One patient had evidence for contiguous pericentric short arm euchromatin which extended from the centromere to beyond the BAC923C6. Two patients showed molecular cytogenetic results which were compatible with non-contiguous chromosome 1 euchromatin. The diversity of origin of r(1)s will hamper attempts to define phenotype/genotype relationships.


Exploring the needs and coping strategies of family caregivers taking care of dying patients at home: a field study.
Most Chinese patients chose to die at home, therefore there is a reliance on the family caregivers to be involved in their palliative care. The needs and coping strategies of family caregivers in home-based palliative care are rooted in culture. Little is known about the needs and coping strategies of family caregivers taking care of dying patients at home. A field study using semi-structured interview, participant observation, documents and records collection was employed. The study was conducted in two palliative care outpatient departments in tertiary hospitals and four communities in Beijing, China from March 2021 to July 2022. Using purposive sampling, twenty-five family caregivers were recruited. All collected data were analyzed using content analysis approach. Five themes emerged, including three care needs and two coping strategies. Family caregivers need to learn care skills and acquire care resources, including (i) decision-making about home-based palliative care, (ii) improving patient's quality of life, and (iii) signs of final hours and funeral procedures. In facing the care burden, family caregivers coped by (iv) balancing the roles of caregivers and individuals: giving priority to patient care while maintaining their own normal life. In facing the death of a loved one, family caregivers responded by (v) making room for coming death by facing death indirectly and "rescuing" patients for consolation while preparing for the coming death. Family caregivers strive to balance the roles of being caregivers and being themselves. As caregivers, they actively prepare patients for good death with no regrets. As individuals, they preserve themselves from being hurt to maintain normal life. The needs of family caregivers focus on caregiver role and are manifested in care skills and resources. Not registered.


[Genetic analysis of mutant genes and RAPD marker of mutant gene of narrow leaflet in soybean].
Mutant E182 with "narrow leaflet-4 seeded pod" was selected from descendents of EMS-treated seeds of soybean variety Lu Dou No. 4 (LD4) with "ovate leaflet-without 4 seeded pod". Genetic analyses of F2 individuals of crossing between mutant E182 and parent LD4 indicated that segregation ratio between ovate and narrow leaflet was 3:1, so was segregation ratio between "without 4 seeded pod" and "4 seeded pod". Segregation ratios of four character types in F2 population of 1,654 individuals were beyond 9:3:3:1 of two pairs of independent gene, showing linkage inheritance. Reccmbinant ratio between mutant genes of narrow leaflet and 4 seeded pod was 11.24% +/- 0.81%. On the other hand, mutant E182, parent LD4 and F2, F3 individuals of their hybrids were analyzed by means of RAPD technique. The marker OPY6-1300 linked with the mutant gene of narrow leaflet was generated, and genetic distance of the marker and mutant gene was 8 cent Morgan (cM), being 10 cM nearer than RFLP marker of narrow leaflet generated by shoemaker.


Differential mRNA expression of insulin-like growth factor system during renal injury and hypertrophy.
The cellular effects of insulin-like growth factor I (IGF-I) are modified by a family of binding proteins (IGFBPs) that act as reservoirs in serum for the growth factor and are produced locally by tissues, including the kidney. Because regulation of these proteins may influence renal repair, either directly or by their interactions with IGF-I, we studied gene expression during the recovery from renal failure induced by folic acid and during the compensatory increase in renal function following uninephrectomy (UNX). Expression of IGF-I, the IGF-I receptor (IGF-IR), and all six IGFBPs was detected using an ribonuclease protection assay. IGFBP-5 was the most abundant binding protein mRNA present in kidney, whereas IGFBP-2 and -6 were the least abundant. During regeneration following folic acid-induced acute renal failure, IGF-I, IGFBP-3, and IGFBP-5 mRNAs declined in abundance approximately two- to threefold. On the other hand, IGF-IR, IGFBP-1, and IGFBP-2 were increased (approximately 2-, 6-, and 6-fold, respectively) in the first 24 h. IGFBP-1 mRNA remained elevated for at least 3 days. Despite the known increase in cellular RNA content following UNX, little difference in specific expression of mRNAs was observed. Because IGFBP-1 has been shown to stimulate cell migration and has previously been localized to the distal nephron, the site of greatest injury in the folic acid model, these data are compatible with the notion that this protein may function either directly to affect cellular repair or act as a reservoir for IGF-I under conditions of cellular damage.


Olive leaf extract modulates glycerol-induced kidney and liver damage in rats.
The present study was conducted to examine the protective effect of olive leaf extract (OLE) against glycerol-induced oxidative stress in rats. Sixty male albino rats were used and allocated randomly into four groups, each of 15 rats. Groups (1) and (2) were administered intraperitoneally (i.p.) a single dose of 500 μL normal saline and hypertonic glycerol solution (10 mL/kg b.wt., 50% v/v, in sterile saline), respectively, followed by a 24-h period of water deprivation. Group (3) was orally given OLE (500 mg/kg b.wt.) for 22 days and glycerol as mentioned above on the 14th day of OLE administration followed by a 24-h period of water deprivation. Group (4) was administered OLE alone. Five rats from each group were sacrificed and samples were collected 1, 5, and 8 days after water deprivation. Alterations in hematobiochemical parameters, renal and hepatic oxidative stress markers, as well as histopathology of the kidney and liver, were evaluated. Glycerol treatment resulted in significant hematological and biochemical alterations as well as significant renal and hepatic oxidative stress. Administration of OLE has significantly ameliorated renal dysfunction, morphological alterations of kidney and liver, and relieved the oxidative stress. These findings show obviously the role of oxidative stress and its relevance to renal dysfunction and suggest the ameliorative impact of OLE in glycerol-induced acute kidney damage in rats, possibly due to its antioxidant properties.


Quantitative structure activity relationship studies of sulfamide derivatives as carbonic anhydrase inhibitor: as antiglaucoma agents.
Selective inhibition of ciliary process enzyme i.e. Carbonic Anhydrase-II is an excellent approach in reducing elevated intraocular pressure, thus treating glaucoma. Due to characteristic physicochemical properties of sulphonamide (Inhibition of Carbonic Anhydrase), they are clinically effective against glaucoma. But the non-specificity of sulphonamide derivatives to isozyme, leads to a range of side effects. Presently, the absence of comparative studies related to the binding of the sulphonamides as inhibitors to CA isozymes limits their use. In this paper we have represented "Three Dimensional Quantitative Structure Activity Relationship" study to characterize structural features of Sulfamide derivative [RR'NSO(2)NH(2)] as inhibitors, that are required for selective binding of carbonic anhydrase isozymes (CAI and CAII). In the analysis, stepwise multiple linear regression was performed using physiochemical parameters as independent variable and CA-I and CA-II inhibitory activity as dependent variable, respectively. The best multiparametric QSAR model obtained for CA-I inhibitory activity shows good statistical significance (r= 0.9714) and predictability (Q(2)=0.8921), involving the Electronic descriptors viz. Highest Occupied Molecular Orbital, Lowest Unoccupied Molecular Orbital and Steric descriptors viz. Principal moment of Inertia at X axis. Similarly, CA-II inhibitory activity also shows good statistical significance (r=0.9644) and predictability (Q(2)=0.8699) involving aforementioned descriptors. The predictive power of the model was successfully tested externally using a set of six compounds as test set for CA-I inhibitory activity and a set of seven compounds in case of CA-II inhibitory activity with good predictive squared correlation coefficient, r(2)(pred)=0.6016 and 0.7662, respectively. Overview of analysis favours substituents with high electronegativity and less bulk at R and R' positions of the parent nucleus, provides a basis to design new Sulfamide derivatives possessing potent and selective carbonic anhydrase-II inhibitory activity.


Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA.
Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.


Organizational factors associated with adherence to low tidal volume ventilation: a secondary analysis of the CHECKLIST-ICU database.
Survival benefit from low tidal volume (VT) ventilation (LTVV) has been demonstrated for patients with acute respiratory distress syndrome (ARDS), and patients not having ARDS could also benefit from this strategy. Organizational factors may play a role on adherence to LTVV. The present study aimed to identify organizational factors with an independent association with adherence to LTVV. Secondary analysis of the database of a multicenter two-phase study (prospective cohort followed by a cluster-randomized trial) performed in 118 Brazilian intensive care units. Patients under mechanical ventilation at day 2 were included. LTVV was defined as a VT ≤ 8 ml/kg PBW on the second day of ventilation. Data on the type and number of beds of the hospital, teaching status, nursing, respiratory therapists and physician staffing, use of structured checklist, and presence of protocols were tested. A multivariable mixed-effect model was used to assess the association between organizational factors and adherence to LTVV. The study included 5719 patients; 3340 (58%) patients received LTVV. A greater number of hospital beds (absolute difference 7.43% [95% confidence interval 0.61-14.24%]; p = 0.038), use of structured checklist during multidisciplinary rounds (5.10% [0.55-9.81%]; p = 0.030), and presence of at least one nurse per 10 patients during all shifts (17.24% [0.85-33.60%]; p = 0.045) were the only three factors that had an independent association with adherence to LTVV. Number of hospital beds, use of a structured checklist during multidisciplinary rounds, and nurse staffing are organizational factors associated with adherence to LTVV. These findings shed light on organizational factors that may improve ventilation in critically ill patients.