Investigation of regions impacting inbreeding depression and their association with the additive genetic effect for United States and Australia Jersey dairy cattle.
Variation in environment, management practices, nutrition or selection objectives has led to a variety of different choices being made in the use of genetic material between countries. Differences in genome-level homozygosity between countries may give rise to regions that result in inbreeding depression to differ. The objective of this study was to characterize regions that have an impact on a runs of homozygosity (ROH) metric and estimate their association with the additive genetic effect of milk (MY), fat (FY) and protein yield (PY) and calving interval (CI) using Australia (AU) and United States (US) Jersey cows. Genotyped cows with phenotypes on MY, FY and PY (n = 6751 US; n = 3974 AU) and CI (n = 5816 US; n = 3905 AU) were used in a two-stage analysis. A ROH statistic (ROH4Mb), which counts the frequency of a SNP being in a ROH of at least 4 Mb was calculated across the genome. In the first stage, residuals were obtained from a model that accounted for the portion explained by the estimated breeding value. In the second stage, these residuals were regressed on ROH4Mb using a single marker regression model and a gradient boosted machine (GBM) algorithm. The relationship between the additive and ROH4Mb of a region was characterized based on the (co)variance of 500 kb estimated genomic breeding values derived from a Bayesian LASSO analysis. Phenotypes to determine ROH4Mb and additive effects were residuals from the two-stage approach and yield deviations, respectively. Associations between yield traits and ROH4Mb were found for regions on BTA13, BTA23 and BTA25 for the US population and BTA3, BTA7, BTA17 for the AU population. Only one association (BTA7) was found for CI and ROH4Mb for the US population. Multiple potential epistatic interactions were characterized based on the GBM analysis. Lastly, the covariance sign between ROH4Mb and additive SNP effect of a region was heterogeneous across the genome. We identified multiple genomic regions associated with ROH4Mb in US and AU Jersey females. The covariance of regions impacting ROH4Mb and the additive genetic effect were positive and negative, which provides evidence that the homozygosity effect is location dependent.


Comparative analysis of the phenolic contents and antioxidant activities of different parts of two pomegranate (Punica granatum L.) Cultivars: 'Tunisia' and 'Qingpi'.
Pomegranate (Punica granatum L.), with its abundant phenolic substances and strong antioxidant activity, holds significant research and utilization potential across various organs. However, there have been few studies on the phenolic content and antioxidant activity of different parts of pomegranate, especially the placenta. This study investigated the phenolic content and antioxidant activity of fruits, flowers, and leaves of two pomegranate varieties, 'Tunisia' and 'Qingpi', throughout their growth and development. Results indicated significant variations in phenolic content among different organs, with petals exhibiting the highest total polyphenol content (TPC, 49.40 mg GAE/g FW) and total anthocyanin content (TMAC, 1938.54 nmol/g FW). Placenta contained the highest levels of total flavonoids (TFC, 173.58 mg RE/g FW) and punicalagin (109.30 mg/g FW). The peel had the highest content of total flavanols (TFAC, 19.42 mg CE/g FW). Over the course of pomegranate development, total polyphenols, total flavonoids, total flavanols, punicalagin, and antioxidant activity declined in different organs. Antioxidant activity followed the order: fruit > flower > leaf, with the placenta exhibiting the highest antioxidant activity among fruits. Antioxidant activity showed a significant positive correlation with total polyphenols (R2 = 0.77-1.00), total flavonoids (R2 = 0.71-0.99, except tegmens), and punicalagin (R2 = 0.71-1.00). This study provides a comparative analysis of the phenolic content and antioxidant activity in different organs of pomegranate, highlighting the placenta as the primary source of punicalagin. This study provides a theoretical basis for the development and utilization of pomegranate phenolic compounds.


Biodegradable Antimicrobial Agent/Analgesic/Bone Morphogenetic Protein-Loaded Nanofibrous Fixators for Bone Fracture Repair.
Postoperative infection and pain management are of great concern to orthopedic surgeons. Although there are several protocols available to deal with these aspects, they are fraught with complications, such as cartilage damage, cardiovascular and neurological intoxication, and systemic adverse responses. Therefore, it is necessary to develop safe and effective perioperative protocols. In the current study, antimicrobial agents/analgesics/growth factor-embedded biodegradable hybrid fixators (polycaprolactone fixator + poly[lactide-co-glycolide] sheath-core structured nanofibers) for bone fracture repair were designed. The biodegradable hybrid fixators were fabricated using solution-extrusion three-dimensional printing and electrospinning. In vitro, the characteristics of the hybrid fixators were examined. Additionally, the release of the incorporated vancomycin, ceftazidime, lidocaine, and bone morphogenetic protein-2 (BMP-2) was evaluated. The in vivo efficacy including drug-eluting properties, fracture repair, and pain management of the biomolecule-loaded nanofibrous fixators was investigated in rabbit rib-fracture models. The nanofibrous fixators released vancomycin, ceftazidime, and lidocaine in a sustained manner under both in vitro and in vivo conditions and protected BMP-2 from burst release. The implantation of these hybrid fixators around the fractured rib significantly improved animal activities and bone union, indicating that the inclusion of analgesic in the fixator effectively reduced postsurgical pain and thereby helped in recovery. The novel biomolecule-loaded nanofibrous hybrid fixators resulted in excellent therapeutic outcomes. These fixators may be effective in the repair of rib fractures in clinical settings and may help mitigate surgical complications, such as infection, nonunion, and intolerable postoperative pain.


Characterization of male goat odors: 6-trans nonenal.
Solvent extraction and nitrogen degassing were employed to collect volatile odors from the lipid complex yielded by swabbing the sebaceous gland areas of the scalps of sexually active bucks from four breeds of goats. Gland tissue samples from freshly slaughtered bucks and does also were obtained for lipid analysis. Identified as the major compound responsible for one of the characteristic odors of the buck was 6-trans nonenal . Isolation of the compound as its 2,4-dinitrophenyl hydrazone was achieved by column and thin-layer chromatography. Tentative identification was based on comparison with known compounds by argentation thin-layer chromatography, retardation factors for the 2,4-dinitrophenyl hydrazone derivatives, and gas-liquid chromatography retention times of regenerated compounds. The presence of other nonenals suggests that the compound may be formed by oxidation of the gland lipids. The odor of the male goat in rut often is implicated as a source of the " goaty " flavor problem in fresh goat milk. When added to goat milk, 6-trans nonenal yielded a significant melon- musky flavor response from the flavor panel; the " goaty " flavor response was more significant for added 4-ethyl octanoic acid, 4-methyl octanoic acid, and 4-ethyl oct-2-enoic acid.


[Obesity persistent scleredema: study of 49 cases].
Buschke sclerodema is a very rare disease. Our objective was to show that persistent scleredema is frequent in certain group of patients at risk. We studied 49 patients, diagnosed between 1995 and 1999 in dermatology, pneumology and endocrinology departments in Martinique. Diagnosis was performed on classical clinical and histopathological aspects of sclerodema. Data studied were age, sex, mode of occurrence, clinical and histopathological aspects and associated diseases. The 49 patients presented with cutaneous infiltration of the upper part of the trunk, with thick dermis and large collagen bundles on histopathological examination. Forty-two had mucoid substance deposition, stained with Alcian Blue (this criteria was considered as inconstant by most authors in the literature). Sex ratio H/F was 0.06 (93 p. 100 females). Mediam age at onset was 50 years ranging from 20 to 79 years. The occurrence was insidious in 97 p. 100 of cases. All patients had neck and nuchae involvement. The disease involved the back in 93 p. 100, upper limbs in 50 p. 100 and lower limbs and face in 43 p. 100 of patients. Fifty-six percent of patients had limitation of shoulder movements, 16 p. 100 limitation of mouth opening, 20 p. 100 limitation of eyelid opening, 36 p. 100 had myalgia, 73 p. 100 had pruritus and 66 p. 100 had dyspnea. Obesity was present in 95 p. 100, diabetes in 79.5 p. 100, elevated blood pressure in 81.5 p. 100 and monoclonal dysglobulinemia in 46 p. 100 of patients. Twenty-five patients had a polysomnography showing severe obstructive sleep apnea syndrome. The large number of patients in our study can be explained by the search for sclerodema in patients with obesity, diabetes and high blood pressure. The disease is usually unknown by patients and physicians unless a systematic examination is performed. Association with obstructive sleep apnea syndrome was not previously reported and a larger study is ongoing.


Subungual melanoma in situ: two independent streaks in one nail bed.
We report an unusual case of two nail-bed streaks under one nail, revealing melanoma in situ affecting the nail bed and plate, but not the nail fold. This unusual mode of presentation together with the absence of any nail-fold involvement has not been reported previously. We highlight the need for early histological assessment of nail-bed lesions and discuss subungual melanoma.


Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF).
The cytokine macrophage migration inhibitory factor (MIF) has been identified to be secreted by the pituitary gland and the monocyte/macrophage and to play an important role in endotoxic shock. Despite the recent molecular cloning of a human T-cell MIF, characterization of the biochemical and biological properties of this protein has remained incomplete because substantial quantities of purified, recombinant, or native MIF have not been available. We describe the cloning of mouse MIF from anterior pituitary cells (AtT-20) and the purification of native MIF from mouse liver by sequential ion exchange and reverse-phase chromatography. For comparison purposes, human MIF was cloned from the Jurkat T-cell line and also characterized. Mouse and human MIF were highly homologous (90% identity over 115 amino acids). Recombinant mouse and human MIF were expressed in Escherichia coli and purified in milligram quantities by a simple two-step procedure. The molecular weight of native mouse MIF (12.5 kDa monomer) was identical with that of recombinant mouse MIF as assessed by gel electrophoresis and mass spectroscopy. No significant post-translational modifications were detected despite the presence of two potential N-linked glycosylation sites. Recombinant MIF inhibited monocyte migration in a dose-dependent fashion, and both recombinant and native MIF-exhibited comparable biological activities. MIF induced the secretion of tumor necrosis factor-alpha and stimulated nitric oxide production by macrophages primed with interferon-gamma. Circular dichroism spectroscopy revealed that bioactive mouse and human MIF exhibit a highly ordered, three-dimensional structure with a significant percentage of beta-sheet and alpha-helix conformation. Guanidine hydrochloride-induced unfolding experiments demonstrated that MIF is of low to moderate thermodynamic stability. These studies establish the biochemical identity of native and recombinant MIF and provide a first insight into the three-dimensional structural properties of this critical inflammatory mediator.


The relationship between resource abundance and insect herbivory on islands.
We examined the relationship between resource abundance and the feeding activity of phytophagous insects on three common island plants. The aim was to investigate the correlation between phytophagous insects' abundance and availability of food and island geography. We collected 30,835 leaves from three tree species groups (Mallotus japonicus, Prunus species, and Quercus species) on 18 islands in southwest Korea. The number of plant resources for herbivores varied: the number of leaves per shoot was the highest in Mallotus, leaf weight and the water content per leaf was significantly lower in Quercus species. External feeding was higher for Prunus and Quercus species, whereas the internal feeding type was significantly higher for Quercus species. Geography (area and distance), elevation and food resource (elevation, number of plant species, and the forest cover rate) had a variable effect on phytophagous insects feeding activities: distance and the number of plant species were more explainable to the external feeding guild. In contrast, area and forest cover were more to the internal feeding guild.


Multiple Schottky Barrier-Limited Field-Effect Transistors on a Single Silicon Nanowire with an Intrinsic Doping Gradient.
In comparison to conventional (channel-limited) field-effect transistors (FETs), Schottky barrier-limited FETs possess some unique characteristics which make them attractive candidates for some electronic and sensing applications. Consequently, modulation of the nano Schottky barrier at a metal-semiconductor interface promises higher performance for chemical and biomolecular sensor applications when compared to conventional FETs with ohmic contacts. However, the fabrication and optimization of devices with a combination of ideal ohmic and Schottky contacts as the source and drain, respectively, present many challenges. We address this issue by utilizing Si nanowires (NWs) synthesized by a chemical vapor deposition process which yields a pronounced doping gradient along the length of the NWs. Devices with a series of metal contacts on a single Si NW are fabricated in a single lithography and metallization process. The graded doping profile of the NW is manifested in monotonic increases in the channel and junction resistances and variation of the nature of the contacts from ohmic to Schottky of increasing effective barrier height along the NW. Hence multiple single Schottky junction-limited FETs with extreme asymmetry and high reproducibility are obtained on an individual NW. A definitive correlation between increasing Schottky barrier height and enhanced gate modulation is revealed. Having access to systematically varying Schottky barrier contacts on the same NW device provides an ideal platform for identifying optimal device characteristics for sensing and electronic applications.


Peripartum Depression, Traditional Culture, and Israeli Society.
Although it is known that culture affects psychopathology, the nature of the relationship between culture and peripartum depression (PPD) is not fully understood. Here we report on 2 cases of Israeli women who are affiliated with traditional cultural groups that emphasize reproduction but developed PPD after childbirth. The first woman is an ultra-Orthodox Israeli Jew and the second is an Israeli Arab. The 2 cases illustrate the effect of cultural beliefs and rituals on the conceptualization, treatment, and trajectory of PPD. The cases suggest a complex relationship between traditional cultures and PPD, including the possibility that cultural factors may have both adaptive and maladaptive consequences. Future qualitative and quantitative studies are needed to further clarify this relationship.


Legionella feeleii serotype 2 pneumonia in a man with chronic lymphocytic leukemia: a challenging diagnosis.
Legionella feeleii has rarely been reported as causing pneumonia in patients with hematologic malignancies. We present a case of Legionella feeleii serotype 2 pneumonia with empyema in a man with chronic lymphocytic leukemia and describe the methods of identifying this organism using both standard methods and newer diagnostic techniques.


Two-dimensional electroacoustic model of transducer array based on 1-3 piezocomposite materials.
An analytical model is presented to achieve simultaneous prediction of the elementary electroacoustic response and directivity pattern of a one-dimensional (1-D) piezocomposite array. The theoretical approach was based on guided wave theory in a multilayered structure in which the 1-3 piezocomposite material is considered as a homogeneous piezoelectric plate. A matrix method was applied to simulate the displacement fields generated at the surface of the array when one element was excited with an electrical pulse. A test device was manufactured, then characterized through measurements of displacement performed with an interferometric laser probe when the array vibrated in air and in water. The experimental results are presented and compared with theory.


Dental clinical evaluation: a review of the research.
Preclinical and clinical evaluation in dental education needs systematic study. Research on the main variables affecting reliable and valid clinical evaluation is reviewed to identify research findings applicable to clinical evaluation settings. The research reviewed shows that performance criteria should be objectively stated, that measurement scales should contain few points, and that evaluator training may improve reliability. Suggestions for the design of future evaluation studies are provided in an effort to expand the scope and usefulness of this type of research.


An implanted paramagnetic metallofullerene probe within a metal-organic framework.
Paramagnetic endohedral metallofullerene can be used as a molecular probe because of its sensitive electron spin characters, one of which is to sense its surroundings. Metal-organic framework (MOF) materials have significant applications in selective adsorption owing to their porous structures. Herein, we report a Sc3C2@C80 spin probe implanted in MOF-177 to detect the unusual host-guest interaction between the guest molecules of metallofullerene and the host pores of the MOF. Paramagnetic Sc3C2@C80 molecules were incorporated into the pores of MOF-177 via absorption method, and there was strong π-π interaction between oleophilic metallofullerene and aromatic framework. The electron paramagnetic resonance (EPR) signals of Sc3C2@C80 in MOF-177 exhibit anisotropic properties caused by the restricted motion of implanted Sc3C2@C80. This unusual host-guest interaction between Sc3C2@C80 and MOF-177 is gradually strengthened with decreasing temperature as revealed by the EPR signals. In addition, the gas desorption from the MOF-177 pores under subatmospheric pressure can weaken the host-guest interaction and lead to slightly enhanced Sc3C2@C80 EPR signals. Furthermore, the changes in the host-guest interaction between Sc3C2@C80 and MOF-177 at different temperatures and pressures exhibit reversibility, as shown by cycling EPR measurements. These results will inspire material design and applications of fullerene and MOF complexes.


Transcriptome analysis reveals salivary gland-specific neuropeptide signaling genes in the predatory stink bug, Picromerus lewisi.
Predatory stink bugs derive from phytophagous stink bugs and evolved enhanced predation skills. Neuropeptides are a diverse class of ancient signaling molecules that regulate physiological processes and behavior in animals, including stink bugs. Neuropeptide evolution might be important for the development of predation because neuropeptides can be converted to venoms that impact prey. However, information on neuropeptide signaling genes in predatory stink bugs is lacking. In the present study, neuropeptide signaling genes of Picromerus lewisi, an important predatory stink bug and an effective biological agent, were comprehensively identified by transcriptome analysis, with a total of 59 neuropeptide precursor genes and 58 potential neuropeptide receptor genes found. In addition, several neuropeptides and their receptors enriched in salivary glands of P. lewisi were identified. The present study and subsequent functional research contribute to an in-depth understanding of the biology and behavior of the predatory bugs and can provide basic information for the development of better pest management strategies, possibly including neuropeptide receptors as insecticide targets and salivary gland derived venom toxins as novel killing moleculars.


Progress and clinical potential of antibody-targeted therapy for arthritic damage.
The advent of biologic drugs like infliximab, Etanercept, rituximab and tocilizumab has greatly improved the treatment of rheumatoid arthritis, however, increased risk of infection and high cost still remain unmet needs. A new generation of targeted therapeutics is being developed to target payload drug specifically to arthritic tissue; to concentrate the drug in the disease area and limit the off target systemic exposure. This might also reduce total effective dose. This article summarizes the properties and progress of targeted therapies that have been published on PubMed, and addresses their clinical potential. Expert commentary: Incredible progress with targeted therapies has already been made in the short time since the principle was first proven in animal models in 2007 when targeting payload drug to overexpressed oncofetal domain of fibronectin in inflamed arthritic joints.


Muscarinic receptors as targets for anti-inflammatory therapy.
ACh, the main neurotransmitter in the neuronal cholinergic system, is synthesized by pre-ganglionic fibers of the sympathetic and parasympathetic autonomic nervous system and by post-ganglionic parasympathetic fibers. There is increasing experimental evidence that ACh is widely expressed in prokaryotic and eukaryotic non-neuronal cells. The neuronal and non-neuronal cholinergic systems comprise ACh, choline acetyltransferase and cholinesterase, enzymes that synthesize and catabolize ACh, and the nicotinic and muscarinic ACh receptors (nAChRs and mAChRs, respectively), which are the targets for ACh action. This review analyzes the participation of the cholinergic system, particularly through mAChRs, in inflammation, and discusses the role of the different mAChR antagonists that have been used to treat skin inflammatory disorders, asthma and COPD, as well as intestinal inflammation and systemic inflammatory diseases, to assess the potential application of these compounds as therapeutic tools.


Comparing nonpharmaceutical interventions for containing emerging epidemics.
Strategies for containing an emerging infectious disease outbreak must be nonpharmaceutical when drugs or vaccines for the pathogen do not yet exist or are unavailable. The success of these nonpharmaceutical strategies will depend on not only the effectiveness of isolation measures but also the epidemiological characteristics of the infection. However, there is currently no systematic framework to assess the relationship between different containment strategies and the natural history and epidemiological dynamics of the pathogen. Here, we compare the effectiveness of quarantine and symptom monitoring, implemented via contact tracing, in controlling epidemics using an agent-based branching model. We examine the relationship between epidemic containment and the disease dynamics of symptoms and infectiousness for seven case-study diseases with diverse natural histories, including Ebola, influenza A, and severe acute respiratory syndrome (SARS). We show that the comparative effectiveness of symptom monitoring and quarantine depends critically on the natural history of the infectious disease, its inherent transmissibility, and the intervention feasibility in the particular healthcare setting. The benefit of quarantine over symptom monitoring is generally maximized for fast-course diseases, but we show the conditions under which symptom monitoring alone can control certain outbreaks. This quantitative framework can guide policymakers on how best to use nonpharmaceutical interventions and prioritize research during an outbreak of an emerging pathogen.


Infrared and DFT investigations of the XC[triple bond]ReX3 and HC[triple bond]ReX3 complexes: Jahn-Teller distortion and the methylidyne C-X(H) stretching absorptions.
The XC[triple bond]ReX3 complexes (X = F, Cl) are produced by CX(4) reaction with laser-ablated Re atoms, following oxidative C-X insertion and alpha-halogen migration in favor of the carbon-metal triple bond and are identified through the observation of characteristic absorptions in the argon matrix infrared spectra and comparison with vibrational frequencies calculated by density functional theory. The methylidyne C-F and C-Cl stretching absorptions are observed near 1584 and 1328 cm-1, and the C-H stretching modes for HC[triple bond]ReX3 at 3104 and 3097 cm(-1), respectively, which are substantially higher than the precursor stretching modes and in agreement with the general trend that higher s-orbital character in carbon hybridization leads to a higher stretching frequency. The Jahn-Teller effect in the doublet-state XC[triple bond]ReX3 and HC[triple bond]ReX3 complexes gives rise to distorted structures with Cs symmetry and two equivalent longer Re-X bonds and one slightly shorter Re-X bond.


Receptor-mediated transport of lactoferrin into the cerebrospinal fluid via plasma in young calves.
Milk, especially colostrum, contains different kinds of macromolecules abundantly, such as immunoglobulin G (IgG), lactoferrin (Lf), transferrin (Tf), and growth factors. These are essential for the development and maintenance of health, which greatly depends on the absorption and transportation of macromolecules to the target organs. To evaluate the macromolecular transport, and concentrations in plasma and cerebrospinal fluid (CSF), colostrum was fed to newborn calves followed by milk and milk replacer, and maintained up to the 4th week under farm conditions. Plasma and CSF were collected at different times, and were analyzed for Lf, Tf, IgG and iron concentrations. Lf, Tf and IgG concentrations were steeply increased in plasma and CSF after colostrum feeding, and fluctuating patterns were observed during the experiments. Furthermore, intraduodenal administration of bovine Lf alone in young calf experiments revealed that the Lf concentration reached a peak at 4 hr, and was 7 and 4 times higher than preadministration in plasma and CSF, respectively. To explore the transport mechanism of Lf into CSF in young calves, epithelial membranes of the choroid plexus were prepared and a binding assay for Lf receptors (Lf-R) was carried out with 125I-Lf. The saturation kinetics revealed that the Bmax of epithelial membranes was 26.15 nmol/mg protein with a Kd of 0.11 microM, which also showed that Lf-R is saturable and specific. Scatchard plot transformation showed the presence of a single type of Lf-R in the choroid plexus. These results suggest that Lf is transported into the CSF through receptor mediated transcytosis in young calves, and that Lf may play an important role(s) in brain function.


The SCAR-3 study: 5-year adhesion-related readmission risk following lower abdominal surgical procedures.
The Surgical and Clinical Adhesions Research (SCAR) and SCAR-2 studies demonstrated that the burden of adhesions following lower abdominal surgery is considerable and appears to remain unchanged despite advances in strategies to prevent adhesions. In this study, we assessed the adhesion-related readmission risk directly associated with common lower abdominal surgical procedures, taking into account the effect of previous surgery, demography and concomitant disease. Data from the Scottish National Health Service medical record linkage database were used to assess the risk of an adhesion-related readmission following open lower abdominal surgery during April 1996-March 1997. Patients undergoing lower abdominal surgery (excluding appendicectomy) had a 5% risk of readmission directly related to adhesions in the 5 years following surgery. Appendicectomy was associated with a lower rate of readmission (0.9%), but contributed over 7% of the total lower abdominal surgery patient readmission burden. Panproctocolectomy (15.4%), total colectomy (8.8%) and ileostomy surgery (10.6%) were associated with the highest risk of an adhesion-related readmission. Overall, the risk of readmission was doubled in patients who had undergone abdominal or pelvic surgery within 5 years of the incident operation. A higher risk of readmission was also recorded in patients aged < 60 years compared with those aged > or = 60 yrs. The effect of gender was assessed. However, as the surgical codes used were found to be skewed towards women, these data have not been reported. Readmission risk was slightly higher in patients with concomitant peritonitis compared with patients without peritonitis. In contrast, Crohn's disease had no effect on risk. Patients with colorectal cancer had a lower risk of adhesion formation. However, this may have been due to the type of surgery performed in this patient group. The identification of high-risk patient subgroups may assist in effectively targeting adhesion-prevention strategies and the proffering of preoperative advice on adhesion risk.


Decreased insulin action in skeletal muscle from patients with McArdle's disease.
Insulin action is decreased by high muscle glycogen concentrations in skeletal muscle. Patients with McArdle's disease have chronic high muscle glycogen levels and might therefore be at risk of developing insulin resistance. In this study, six patients with McArdle's disease and six matched control subjects were subjected to an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp. The muscle glycogen concentration was 103 +/- 45% higher in McArdle patients than in controls. Four of six McArdle patients, but none of the controls, had impaired glucose tolerance. The insulin-stimulated glucose utilization and the insulin-stimulated increase in glycogen synthase activity during the clamp were significantly lower in the patients than in controls (51.3 +/- 6.0 vs. 72.6 +/- 13.1 micromol x min(-1) x kg lean body mass(-1), P < 0.05, and 53 +/- 15 vs. 79 +/- 9%, P < 0.05, n = 6, respectively). The difference in insulin-stimulated glycogen synthase activity between the pairs was significantly correlated (r = 0.96, P < 0.002) with the difference in muscle glycogen level. The insulin-stimulated increase in Akt phosphorylation was smaller in the McArdle patients than in controls (45 +/- 13 vs. 76 +/- 13%, P < 0.05, respectively), whereas basal and insulin-stimulated glycogen synthase kinase 3alpha and protein phosphatase-1 activities were similar in the two groups. Furthermore, the ability of insulin to decrease and increase fat and carbohydrate oxidation, respectively, was blunted in the patients. In conclusion, these data show that patients with McArdle's glycogen storage disease are insulin resistant in terms of glucose uptake, glycogen synthase activation, and alterations in fuel oxidation. The data further suggest that skeletal muscle glycogen levels play an important role in the regulation of insulin-stimulated glycogen synthase activity.


Nutrient digestibility and prediction of metabolizable energy in total mixed rations for ruminants.
The aim of the present study was to determine equations that predict ME in total mixed rations (TMR) based on routine methods. The ME content of 30 TMR for dairy cows was determined based on digestible crude nutrients obtained with wether sheep. Concentrations in the TMR (in g/kg DM) varied between 118 and 234 for crude protein, 26 and 48 for crude lipid, 131 and 250 for crude fibre, 281 and 488 for NDF, and 173 and 304 for ADF. Gas production ranged from 40.7 to 54.1 ml/200 mg DM, and enzymatically degraded organic matter from 652 to 800 g/kg DM. Digestibility [%] ranged from 68.6 to 84.0 for organic matter, from 55.6 to 84.3 for crude lipid, from 55.0 to 77.8 for crude fibre, from 57.6 to 77.0 for NDF and from 53.1 to 79.6 for ADF. ME ranged from 9.6 to 11.9 MJ/kg DM, and NEL from 5.7 to 7.4 MJ/kg DM. ME content was highly correlated with the concentration of both crude fibre and enzymatically degradable organic matter as well as with organic matter digestibility. A multiple regression equation based on crude fibre and crude lipid predicted ME with a reasonable goodness of fit (r2 = 0.81; s(y.x) = 2.4%). The inclusion of other nutrients, of neutral and acid detergent fibre, neither of gas production did improve the goodness of fit. The best prediction was achieved with inclusion of enzymatically degraded organic matter (r2 = 0.90; s(y.x) = 1.7%).


Anterior lamellar marginal z-plasty with transverse tarsotomy for management of trichiasis with cicatricial entropion--a new surgical approach.
Trichiasis is the main risk factor for corneal opacification. The primary treatment of trichiasis is surgical. Successful surgery is likely to halt the progression of corneal opacity. The aim of the study is to report the efficacy of the anterior lamellar marginal z-plasty combined with transverse tarsotomy in the management of severe trichiasis andcicatricial entropion of upper eyelid. A prospective study was carried out from January 2009 to June 2012, on 54 eyelids (44 patients) who underwent anterior lamellar marginal z-plasty with transverse tarsotomy for correction of trichiasis and cicatricial entropion involving upper eyelid with a minimum of 6 months' follow-up. Results were classified according to the presence and location of residual trichiasis and symptoms were assessed according to a three-level subjective scale (better, worse or no change). Failure was defined as recurrent trichiasis with one or more lashes touching any part of cornea in primary position. Secondary outcomes were visual acuity and corneal opacification. At the end of six month period, none of patients had any trichiatic eye lash touching the cornea in primary position (100% success). Forty-eight (88.9%) of the operated eyelids were free of trichiasis, while residual trichiasis was noticed only in 6 (11.1%) operated lids. At the end of six months, there was a significant reduction of lash burden from median of 12 trichiatic lashes from the base line to the median of 2. All the patients reported significant reduction in symptoms of irritation. Significant improvement in visual acuity (p < 0.000) and reduction in the density of corneal opacity (p < 0.000) was notified from the base line. Anterior lamellar marginal z-plasty combined with transverse tarsotomy seems to have promising surgical outcome for the correction oftrichiasis and cicatricial entropion secondary to cicatricial trachoma.


Parental reports of vaccine information statement usage in Utah.
Since the implementation in 1986, there is little research focused on vaccine information statements (VISs) use for vaccine education and parental perception. To explore parental reports of dissemination and use of VISs. Data for this pilot, cross-sectional, descriptive study were collected through an online survey in both English and Spanish. Responses from 130 parents in one school district were analyzed. Most participants (67.7%) reported getting vaccine information from a pediatric health care provider. A majority (71.5%) said that VISs were included in the vaccination process. Approximately one third of participants (37.7%) reported reading some or all the VIS before their child was vaccinated, and more than half (59.3%) read some or all the VIS after their child was vaccinated. While promising that many parents reported receiving a VIS, more than one quarter of parents reported they did not. Inadequate time to read and understand VIS information before an immunization may lead to limited parental understanding. Although some participants reported struggling to understand VISs, more than half said that VISs were helpful and would read another in the future. Without appropriate use of vaccine education material, providers miss the opportunity to educate parents on the risks and benefits of vaccinating their children. Providers must be aware of literacy levels and vaccine attitudes and create appropriate opportunities for parents to read and learn about vaccines. VISs are valuable educational tools for patients and parents. Improvements are needed to improve both VIS clarity and dissemination.


Central role of thermal collective strain in the relaxation of structure in a supercooled liquid.
The spatial distribution of structural relaxation in a supercooled liquid is studied using molecular dynamics simulations of a two-dimensional binary mixture. It is shown that the spatial heterogeneity of the relaxation along with the time scale of the relaxation is determined, not by the frequency with which particles move a distance pi/2kBragg, but by the frequency with which particles can achieve persistent displacements. We show that these persistent displacements are achieved through the coupled action of local reorganizations and unrecoverable thermal strains.


Cystic hematoma formation following use of a biodegradable arrow for meniscal repair.
This is a case report of a cystic hematoma formation following the use of a biodegradable arrow for repair of a medial meniscus tear. A literature search found no previous report of this complication. Open hematoma debridement and arrow removal were effective in the treatment of this complication following all-inside meniscal repair with a biodegradable arrow.


Psychiatric symptoms and psychological profile of patients with near fatal asthma: absence of positive findings.
We examined the presence of psychiatric symptoms and personality characteristics in patients with asthma and near fatal asthma (NFA). An NFA attack is defined by the presence of one or more of the following symptoms: respiratory arrest, alteration in consciousness, need for mechanical ventilation, Pa CO2 > 50 mm Hg. To assess the relevance of a specific psychiatric profile or the difference in personality characteristics existing in patients that survived an NFA attack and asthmatic patients. The authors interviewed a sample of 17 asthmatic patients who experienced one or more NFA attacks. A control group of 17 control patients with asthma who never experienced NFA attacks was enrolled. After a baseline assessment, the patients underwent an interview concerning their personal and familiar psychiatric history and a psychodiagnostic investigation using Hamilton scales for anxiety and depression, Zung scales for anxiety and depression, and Minnesota Multiphasic Personality Inventory. The study was performed in a 6-month period. No significant differences in the results of psychodiagnostic tests between NFA patients and the control group were reported. Psychiatric history was similar in the two groups. Our results suggest that psychiatric symptoms and personality characteristics are not related to the presence of asthma with or without NFA.


The dual-acting H3 receptor antagonist and AChE inhibitor UW-MD-71 dose-dependently enhances memory retrieval and reverses dizocilpine-induced memory impairment in rats.
Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual-acting H3R antagonist and AChEI is effective in improving retrieval processes in the one-trial inhibitory avoidance task and provide evidence to such compounds to treat cognitive disorders.


The formation of an N-hydroxymethyl intermediate in the N-demethylation of N-methylcarbazole in vivo and in vitro.
1. The metabolism of N-methylcarbazole has been studied in several mammalian species, both in vivo and in vitro. 2. An important metabolite after incubation of N-methylcarbazole with liver microsomes in vitro was identified as N-hydroxymethylcarbazole. 3. This metabolite was also found as a conjugate (probably the O-glucuronide) in the urine of some species. 4. N-Hydroxymethylcarbazole decomposed spontaneously in solution at pH 7-4 to formaldehyde and carbazole; this breakdown was enhanced by incubation with liver microsomes from several species, especially the guinea-pig. 5. The role of N-methyl hydroxylation, compared with N-oxidation, in the mechanism of N-dealkylation of non-basic N-methyl compounds is discussed.


Evaluation of the optical performance for aspheric intraocular lenses in relation with tilt and decenter errors.
To evaluate and compare the effect of misalignment and tilt on the optical performance of different aspheric intraocular lens (IOL) designs. Three aspheric IOLs with a different quantity of spherical aberration (SA) have been designed and the effect of IOL misalignment and tilt on the imaging quality of an eye model has been numerically assessed using a commercial optical design software. The prototypes have been manufactured by lathe turning and tested in vitro using the same optical bench (PMTF, Lambda-X) that complies with International Organization for Standardization standard 11979-2 requirements. Image quality was evaluated from the modulation transfer functions (MTFs), through-focus modulation transfer functions (TF-MTFs), root mean square (RMS) values of defocus, astigmatism and coma, and images of the United States Air Force (USAF) target were taken. A comparison with the optical performance of spherical IOLs has also been performed. Intraocular lens misalignment and tilt increased wavefront aberrations; the effect of misalignment on root mean square (RMS) astigmatism and coma was positively correlated with the spherical aberration of the IOL. Aberration-free IOLs showed the highest MTF for all misalignment values and for IOLs with negative SA correction the MTF decays below 0.43 when they are decentered 0.50 mm. Aspherical IOLs are more sensitive than spherical IOLs to misalignment or tilt, depending on their SA correction. The optical degradation caused by IOL misalignment had a greater effect on IOL designs with a higher amount of negative spherical aberration. In contrast, the effect of tilt on the optical performance was less sensitive to the IOL design.


Hot-Electron Intraband Luminescence from GaAs Nanospheres Mediated by Magnetic Dipole Resonances.
Significantly enhanced electric field in plasmonic hot spots can dramatically increase the linear and nonlinear absorption of light, leading to a high-temperature electron gas which radiates, through mainly intraband transition, a broadband luminescence quite similar to blackbody radiation. Here, we demonstrate that such hot-electron intraband luminescence (HEIL) can also be achieved by exploiting the significantly enhanced electric field at the magnetic dipole resonances of gallium arsenide (GaAs) nanospheres (NSs). We show that monocrystalline GaAs NSs with distinct electric and magnetic dipole (ED and MD) resonances can be obtained by using femtosecond laser ablation and annealing. Significantly enhanced second harmonic generation and broadband HEIL are observed when the MD resonances of such GaAs NSs are resonantly excited. The lifetime of the HEIL is found to be as short as ∼82 ps, indicating a significant enhancement in radiative intraband transition rate. We reveal that the slope extracted from the dependence of the HEIL intensity on the irradiance is linearly proportional to the energy of the emitted photon. The existence of distinct ED and MD resonances in combination with a direct bandgap makes GaAs NSs an attractive candidate for constructing novel all-dielectric metamaterials and active photonic devices.


[Four cases of an extramedullary plasmacytoma of the head and neck].
From 1987 to 1988, four patients with solitary, extramedullary plasmacytomas of the head and neck were seen at the Gunma Cancer Center Hospital. With reference to such plasmacytomas, we have reviewed the medical literature regarding these tumors and mainly present the results of radiation therapy with respect to these patients. One patient, who had a local recurrence after surgical treatment, underwent radiation therapy (36Gy in four weeks) that resulted in good local control of the disease. Two patients developed multiple painful bone lesions during their long follow-up periods without manifesting any abnormal laboratory findings, suggesting multiple myeloma. It was found that radiation therapy (less than 30 Gy) was useful for the palliation of painful lesions.


Further studies on psoriasis-associated HLA-Dw/DR7 using PLT cells primed against a familial psoriasis-linked HLA haplotype.
The products of the HLA-D region and their correlation to psoriasis vulgaris was studied using the primed lymphocyte typing (PLT) assay. In families with one healthy and one psoriatic parent and one psoriatic child primary MLC (mixed lymphocyte culture) stimulation was carried out between responder cells from the healthy parent and stimulator cells from the psoriatic child. In this way 21 PLT reagents directed against putative psoriasis-associated lymphocyte activating determinants were produced. Three reagents that gave clear bimodal stimulation patterns against lymphocytes of 51 psoriasis patients were further tested against 78 controls. Specificity of these reagents was studied using homozygous typing cells (HTC's) as stimulators. Compiled data show that cells from DR7 positive psoriatic patients give higher restimulation of these PLT reagents than do cells from healthy DR7 positive controls. In addition, a higher frequency of psoriasis patients compared to controls gave significant restimulation. Therefore we concluded that these PLT reagents recognized at least partly different DR7 associated determinants in the psoriasis patients and in controls. The reason is either that psoriasis patients carry a different lymphocyte activating DR associated specificity or, alternatively, that restimulation was caused by products of a distinct psoriasis associated locus in linkage disequilibrium with D/DR7 or of a determinant recognized together with D/DR7 as a restriction element. These data further support the notion that psoriasis is a disease with primary HLA associations to both class I and class II MHC genes.


A comparison of the protein-coding genomes of two green sulphur bacteria, Chlorobium tepidum TLS and Pelodictyon phaeoclathratiforme BU-1.
Chlorobium tepidum and Pelodictyon phaeoclathratiforme are organisms within the green sulphur bacteria family, Chlorobiaceae, occupying very different habitats. It has recently been proposed that the genera Chlorobium and Pelodictyon are synonymous. To investigate generic boundaries for the two species, protein families were predicted computationally based on sequence similarity across the genome-wide protein sets of Chlorobium tepidum TLS and Pelodictyon phaeoclathratiforme BU-1. The distribution of the resulting protein families across the two species was summarized. The largest number of families exhibited 1:1 putative orthology between the two species (1468 families). Of families unique to one of the species, the largest number was unique to P. phaeoclathratiforme (113 families), of which the largest family contained pentapeptide repeat proteins (16 proteins). Families unique to P. phaeoclathratiforme also included a family of gas vesicle synthesis proteins (four proteins). Although only seven families were identified as containing paralogous proteins in both species (with two or more proteins in each species), this group included families of major biochemical importance. One such family, with three members in each species, contained magnesium chelatase, an enzyme involved in the chlorophyll biosynthetic pathway. The unique protein family groups in both C. tepidum and P. phaeoclathratiforme mirror the occupancy of different environments, while key shared family groups provide evidence for a common origin for the species, as previously suggested in the literature. The current study only uses sequence similarity-based protein families for the two species. This, alone, does not permit a firm conclusion to be drawn on the taxonomic question, of whether the two species belong in one genus or two.


Fluorescent C-linked C8-aryl-guanine probe for distinguishing syn from anti structures in duplex DNA.
The synthesis and optical properties of the carbon (C)-linked C(8)-(2"-benzo[b]thienyl)-2'-deoxyguanosine ((Bth)dG), which acts as a fluorescent reporter of syn versus anti glycosidic conformations in duplex DNA, are described. In the syn-conformation, the probe stabilizes a G:G mismatch, emits at ∼385 nm (excitation ∼285 nm), and shows an induced circular dichroism (ICD) signal at ∼320 nm. Molecular dynamics (MD) simulations predict a wedge (W)-conformation for the mismatched duplex with the C(8)-benzo[b]thienyl moiety residing in the minor groove. In contrast, the probe destabilizes the duplex when base paired with its normal pyrimidine partner C. With flanking purine bases, a major groove B-type duplex is favored with (Bth)dG present in the anti-conformation emitting at ∼413 nm (excitation ∼326 nm) and no ICD signal. However, with flanking pyrimidine bases, (Bth)dG adopts the syn-conformation when base paired with C, and MD simulations predict a base-displaced stacked (S)-conformation, with the opposing C flipped out of the helix. The different duplex (B-, S-, and W-) conformers formed upon incorporation of (Bth)dG are known to play a critical role in the biological activity of N-linked C8-dG adducts formed by arylamine carcinogens. Bulky environment-sensitive fluorescent C(8)-dG adducts that mimic the duplex structures formed by carcinogens may be useful in luminescence-based DNA polymerase assays.


A new approach to preparation of antisense oligonucleotide samples with microextraction by packed sorbent.
Our research focused on applying microextraction by packed sorbent to extracting antisense oligonucleotides from serum samples. The tested sorbents included poly(styrene-co-divinylbenzene), octyl, octadecyl, and unmodified silica gel. As nonpolar sorbents were used for highly-polar molecules, this required ion-pair mode. Comprehensive optimization of extraction conditions was performed for 20-mer phosphorothioate oligonucleotide. Several parametres - the number of "draw-eject" cycles during the conditioning and load step, the amine type and concentration, and the volume of elution mixture - and the influence they had on recovery were studied for nonpolar sorbents, which made it possible to obtain high (ca. 90%) recovery values. The most influential parameter turned out to be the volume of elution mixture. Similar optimization was performed for silica sorbents; however, despite optimization of various parameters, the recovery values stayed relatively low. The optimized procedures for nonpolar sorbents were applied in extraction of six different oligonucleotides of various length and with different structure modifications. The highest recoveries were obtained for octyl and octadecyl sorbents, ranging between 80-99%. The developed microextraction method was used to extract phosphorothioate and 2'-O-(2-methoxyethyl) oligonucleotides and their two synthetic metabolites from enriched human plasma, with recoveries around 70-80%.


Comprehensive non-surgical treatment decreased the need for spine surgery in patients with spondylolisthesis: Three-year results.
Non-surgical treatment is the primary approach to degenerative conditions of the lumbar spine and may involve multiple modalities. There is little literature to guide an evidence-based approach to care. To determine the effectiveness of CNT (comprehensive non-surgical treatment) in patients with degenerative spondylolisthesis (DS) and spondylolytic spondylolisthesis (SS), and to identify predictor variables for success of CNT in avoiding surgery. All patients who underwent CNT for spondylolisthesis (n: 203) were included. CNT consisted of patient education, pain control with transforaminal epidural steroid injections (TFEs) and/or medications, and exercise programs. Surgical and non-surgical patients were similar in age, smoking status, comorbidity scores, facet joint widening, and translation of spondylolisthesis. After CNT, only 21.6% of patients with DS and 31.3% of patients with SS chose to have surgery in 3-years follow-up. The non-surgical group reported significantly better pain relief (73.6% vs 55%) after TFEs for a longer period (152.8 vs 45.6 days) and lower opioid use than the surgical group (28.2% vs 55.3%). CNT is effective in spondylolisthesis and more successful in DS than SS. CNT may decrease the need for surgery, particularly in patients who report pain relief greater than 70% for average five months after TFEs.


Neurofibroma in the mastoid segment of the facial canal.
Neural tissue-derived facial nerve tumours usually present as neurinomas. We describe the extremely rare occurrence of a histologically verified neurofibroma primarily arising in the mastoid segment of the facial canal in a patient not fulfilling diagnostic criteria for neurofibromatosis. The tumour showed evidence of perineural growth into the jugular foramen, as suggested by cross-sectional imaging and intraoperative findings.


Sera from patients with Crohn's disease break bacterial lipopolysaccharide tolerance of human intestinal epithelial cells via MD-2 activity.
Myeloid differentiation (MD)-2 is linked to the cell surface as a Toll-like receptor (TLR) 4-bound protein though may also function as a soluble receptor to enable the lipopolysaccharide (LPS)-driven response. We recently demonstrated the importance of MD-2 either as a cell-associated or as a soluble receptor in the control of intestinal epithelial cell response toward LPS. High levels of circulating MD-2 were recently proposed as a risk factor for infectious/ inflammatory diseases as septic shock. We hypothesized that MD-2 might be present in sera from patients with inflammatory bowel disease and have pathogenic consequences. We analysed MD-2 activity in sera from patients with inflammatory bowel disease or from healthy subjects. We measured MD-2 activity as the capacity to mediate LPS-driven stimulation of intestinal epithelial cells (HT29). We found that sera from patients with inflammatory bowel disease, particularly Crohn's disease, endowed HT29 cells with a markedly higher LPS-dependent stimulating capacity as compared to sera from healthy subjects. The effect of sera was specific for LPS activation and was reduced in the presence of anti-MD-2, and anti-TLR4 antibodies. We conclude that sera from patients with inflammatory bowel disease might contain increased MD-2. This might result in higher local availability of the protein leading to a loss of tolerance toward gut microbiota.


Diarylbibenzofuranone-Based Dynamic Covalent Polymer Gels Prepared via Radical Polymerization and Subsequent Polymer Reaction.
Diarylbibenzofuranone (DABBF) is a dynamic covalent bonding unit, which is in equilibrium with the corresponding radicals at room temperature, and polymers with DABBF linkages show notable properties such as self-healing. The preparation routes have been strictly limited, however, and no polymer with the linkages has been synthesized via radical polymerization because of the strong antioxidant activity of DABBF. Here we present a new method to prepare DABBF-containing polymers via radical polymerization of the precursor, arylbenzofuranone (ABF), and subsequent polymer reaction, dimerization of ABF units in the linear polymers. Polymer gels cross-linked by DABBF linkages were obtained against the relatively strong antioxidant activity of ABF and showed dynamic network reorganization at room temperature.


Pharmacokinetic Interactions Between Quinine and Lopinavir/Ritonavir in Healthy Thai Adults.
This study aimed to investigate the pharmacokinetic interactions between quinine and lopinavir boosted with ritonavir (LPV/r) in healthy Thai adults (8 males and 12 females). Period 1 (day 1): subjects received a single oral dose of 600 mg quinine sulfate. Period 2: subjects received LPV/r (400/100 mg) twice daily. Period 3: subjects received a single quinine sulfate dose plus LPV/r twice a day. Intensive blood sampling was performed during each phase. Quinine AUC0-48h (area under the plasma concentration-time curve from time 0 to 48 hours), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and Cmax (maximum concentration over the time-span specified), were 56%, 57%, and 47% lower, respectively, in the presence of LPV/r. 3-Hydroxyquinine AUC0-48h, AUC0-∞, and Cmax were significantly lower and the metabolite-to-parent ratio was significantly reduced. Lopinavir and ritonavir exposures were not significantly reduced with quinine coadministration, but Cmax of both drugs were significantly lower. The geometric mean ratio (GMR) and 90% CI of AUC0-48h, AUC0-∞, and Cmax for quinine, 3-hydroxyquinine, lopinavir, and ritonavir lay outside the bioequivalent range of 0.8-1.25. Drug treatments during all periods were generally well tolerated. The reduction in systemic exposure of quinine and 3-hydroxyquinine with concomitant LPV/r use raises concerns of suboptimal exposure. Studies in HIV/malaria coinfection patients are needed to determine the clinical impact to decide if any change to the quinine dose is warranted.


Chromatin associations in Arabidopsis interphase nuclei.
The arrangement of chromatin within interphase nuclei seems to be caused by topological constraints and related to gene expression depending on tissue and developmental stage. In yeast and animals it was found that homologous and heterologous chromatin association are required to realize faithful expression and DNA repair. To test whether such associations are present in plants we analyzed Arabidopsis thaliana interphase nuclei by FISH using probes from different chromosomes. We found that chromatin fiber movement and variable associations, although in general relatively seldom, may occur between euchromatin segments along chromosomes, sometimes even over large distances. The combination of euchromatin segments bearing high or low co-expressing genes did not reveal different association frequencies probably due to adjacent genes of deviating expression patterns. Based on previous data and on FISH analyses presented here, we conclude that the global interphase chromatin organization in A. thaliana is relatively stable, due to the location of its 10 centromeres at the nuclear periphery and of the telomeres mainly at the centrally localized nucleolus. Nevertheless, chromatin movement enables a flexible spatial genome arrangement in plant nuclei.


Physiological and immune-biological characterization of a long-term murine model of blunt chest trauma.
Blunt chest trauma causes pulmonary and systemic inflammation. It is still a matter of debate whether the long-term course of this inflammatory response is associated with persistent impairment of lung function. We hypothesized that an increase of inflammatory biomarkers may still be present at later time points after blunt chest trauma, eventually, despite normalized lung mechanics and gas exchange. Anesthetized spontaneously breathing male C57BL/6J mice underwent a blast wave-induced blunt chest trauma or sham procedure. Twelve and 24 h later, blood gases and lung mechanics were measured, together with blood, bronchoalveolar lavage (BAL), and tissue cytokine concentrations (multiplex cytokine kit); heme oxygenase 1 (HO-1), activated caspase-3, Bcl-xL, and Bax expression (Western blotting); nuclear factor-κB activation (electrophoretic mobility shift assay); nitrotyrosine formation; and purinergic (P2XR4 and P2XR7) receptor expression (immunohistochemistry). Histological damage was assessed by hematoxylin and eosin and periodic acid-Schiff staining. High-resolution respirometry allowed assessing mitochondrial respiration in diaphragm biopsies. Chest trauma significantly increased tissue and BAL cytokine levels, associated with a significant increase in HO-1, purinergic receptor expression, and tissue nitrotyrosine formation. In contrast, lung mechanics, gas exchange, and histological damage did not show any significant difference between sham and trauma groups. Activation of the immune response remains present at later time points after murine blunt chest trauma. Discordance of the increased local inflammatory response and preserved pulmonary function may be explained by a dissociation of the immune response and lung function, such as previously suggested after experimental sepsis.


Selected factors determining the failure to undertake physical activity in patients with multiple sclerosis in Poland.
The main aim of the study was to identify selected factors that determine patients with multiple sclerosis (MS') failure to take home therapeutic exercises (HTE) and other physical activity (OPA). The study was conducted using a self-completed online survey that was aimed at adult people diagnosed with MS, registered on the portal TacyJakJa.pl. In total, 335 persons were involved. Almost half of all people who completed the survey (49.9%), reported that no one encouraged them to use HTE, and only 16.1% were encouraged by their doctor. As many as 51% of the respondents reported also that no one encouraged them to undertake OPA, and only 18.5% were encouraged by their doctor. As the most important reason for not using HTE, the respondents chose fear that exercises may worsen their condition (47.3%). However, the most important reason for not using the OPA was high fatigue (61.9%). The number of people exercising at home increased with age (P = 0.013). Those surveyed with relapsing-remitting MS significantly more often (P = 0.002) took up OPA (60.7%) than the respondents with a secondary progressive MS (10.0%) and a primary progressive (4.4%). Physicians relatively rarely encourage patients with MS to undertake HTE and OPA. The patients do not perform HTE primarily because of fears of health deterioration or fatigue. Undertaking HTE is influenced by age but undertaking other forms of physical activity by the type of MS. Actions should be taken to popularize HTE and OPA, especially HTE among young patients.


Promoting positive perceptions of and motivation for research among undergraduate medical students to stimulate future research involvement: a grounded theory study.
Research is of great value to make advancements within the medical field and, ultimately, offer the best possible patient care. Physician-scientists are key in contributing to the development of medicine, as they can bridge the gap between research and practice. However, medicine currently faces a physician-scientist shortage. A possible solution to cultivate physician-scientists is to engage medical students in research in early phases of medical school. Evidence-based strategies to stimulate positive perceptions of and motivation for research among students could help to enhance research engagement. Consequently, understanding of students' perceptions of and motivation for research is needed. Therefore, this study aimed to identify conditions under which students develop positive perceptions of and motivation for research by answering the following sub-questions: 1) how do first-year medical students perceive research? and 2) which factors contribute to motivation or demotivation for conducting research? We conducted a qualitative study with individual interviews using a grounded theory approach, involving 13 purposively sampled first-year medical students at Leiden University Medical Center. Our results suggest that first-year students are already able to identify many aspects of research. Students elaborated on the relevance of research for professional practice and personal development. Furthermore, our results suggest a relationship between perceptions of and motivation for research. Some perceptions were identical to motivating or demotivating factors to conduct research, like the relevance of research for practice and performing statistics respectively. Other motivating factors were, among others, acknowledgment, autonomy, and inspiring role models. Demotivating factors were, among others, lack of autonomy and relevance, and inadequate collaboration. Our results contribute to the idea that perceptions of research are related to motivation for research, which offers possibilities for interventions to promote motivation for research by making use of student perceptions of research. Consequently, practical implications to stimulate research engagement in early phases of medical school are provided. Moreover, the results contribute to existing motivational theories like Theory of Planned Behavior and Self-Determination Theory within this specific domain.


A defect in synapsis causes male sterility in a T-DNA-tagged Arabidopsis thaliana mutant.
Fluorescence microscopy was used to study meiosis in microsporocytes from wild-type Arabidopsis thaliana and a T-DNA-tagged meiotic mutant. Techniques for visualizing chromosomes and beta-tubulin in other plant species were evaluated and modified in order to develop a method for analyzing meiosis in A. thaliana anthers. Like most dicots, A. thaliana microsporocytes undergo simultaneous cytokinesis in which both meiotic divisions are completed prior to cytokinesis. However, two unique events were observed in wild-type A. thaliana that have not been reported in other angiosperms: (1) polarization of the microsporocyte cytoskeleton during prophase I prior to nuclear envelope breakdown, and (2) extensive depolymerization of microtubules just prior to metaphase II. The first observation could have implications regarding a previously uncharacterized mechanism for determining the axis of the metaphase I spindle during microsporogenesis. The second observation is peculiar since microtubules are known to be involved in chromosome alignment in other species; possible explanations will be discussed. A T-DNA-tagged meiotic mutant of A. thaliana (syn1), which had previously been shown to produce abnormal microspores with variable DNA content, was also cytologically characterized. The first observable defect occurs in microsporocytes at telophase I, where some chromosomes are scattered throughout the cytoplasm, usually attached to stray microtubules. Subsequent development stages are affected, leading to complete male sterility. Based on similarities to synaptic mutants that have been described in other species, it is suggested that this mutant is defective in synaptonemal complex formation and/or cohesion between sister chromatids.


Comparison of technetium Tc 99m hexamethylpropyleneamine oxime single-photon emission tomograph with stump pressure during the balloon occlusion test of the internal carotid artery.
Measuring blood pressure (stump pressure) in the distal internal carotid artery during occlusion of the internal carotid artery is reportedly a reliable safety index with which to predict ischemia following permanent occlusion of the internal carotid artery. We compared the stump pressure during occlusion of the internal carotid artery with single-photon emission CT (SPECT) using technetium Tc 99m hexamethylpropyleneamine oxime (HMPAO). Twenty-seven patients underwent the balloon occlusion test. After occlusion of the internal carotid artery was performed by a balloon catheter, technetium Tc 99m HMPAO was injected, and then the balloon remained inflated for 15 minutes. The stump pressure was continuously monitored for those 15 minutes. After the balloon catheter was deflated and removed, SPECT was performed. Sixty-four symmetric pairs of regions of interest were set on both sides of the cerebral hemisphere. The radioactivity count ratio (L/n ratio) of the occluded side to the contralateral normal side was calculated. We defined hypoperfusion as an area with an L/n ratio <0.8. The minimum mean stump pressure (minMSP) during the balloon occlusion test and the pressure ratio of the minMSP to the mean systemic pressure were compared with the hypoperfusion area on SPECT. The number of regions of interest with hypoperfusion was significantly (P < .001) greater in patients with a minMSP <40 mm Hg (mean [+/-SD] = 31.5 +/- 13.7) than in patients with a minMSP > or =40 mm Hg (5.1 +/- 4.0). The number of regions of interest with hypoperfusion was also significantly (P < .001) greater in patients with a pressure ratio <0.5 (26.7 +/- 15.8) than in patients with a pressure ratio > or =0.5 (4.5 +/- 3.5). The minMSP during the balloon test occlusion reflects the extent of the hypoperfused area measured by SPECT using technetium Tc 99m HMPAO.


Recent advances in annular pathobiology provide insights into rim-lesion mediated intervertebral disc degeneration and potential new approaches to annular repair strategies.
The objective of this study was to assess the impact of a landmark annular lesion model on our understanding of the etiopathogenesis of IVD degeneration and to appraise current IVD repairative strategies. A number of studies have utilised the Osti sheep model since its development in 1990. The experimental questions posed at that time are covered in this review, as are significant recent advances in annular repair strategies. The ovine model has provided important spatial and temporal insights into the longitudinal development of annular lesions and how they impact on other discal and paradiscal components such as the NP, cartilaginous end plates, zygapophyseal joints and vertebral bone and blood vessels. Important recent advances have been made in biomatrix design for IVD repair and in the oriented and dynamic culture of annular fibrochondrocytes into planar, spatially relevant, annular type structures. The development of hyaluronan hydrogels capable of rapid in situ gelation offer the possibility of supplementation of matrices with cells and other biomimetics and represent a significant advance in biopolymer design. New generation biological glues and self-curing acrylic formulations which may be augmented with slow delivery biomimetics in microcarriers may also find application in the non-surgical repair of annular defects. Despite major advances, significant technical challenges still have to be overcome before the biological repair of this intractable connective tissue becomes a realistic alternative to conventional surgical intervention for the treatment of chronic degenerate IVDs.


Unlocking the potential of organoids in cancer treatment and translational research: An application of cytologic techniques.
Patient-derived organoid models hold promise for advancing clinical cancer research, including diagnosis and personalized and precision medicine approaches, and cytology, in particular, plays a pivotal role in this process. These three-dimensional multicellular structures are heterogeneous, potentially maintain the cancer phenotype, and conserve the genomic, transcriptomic, and epigenomic patterns of the parental tumors. To ensure that only tumor tissue is used for organoid development, cytologic validation is necessary before initiating the process of organoid generation. Here, we explore the technology of tumor organoids and discuss the fundamental application of cytology as a simple and cost-effective approach toward organoid development. We also underscore the potential application of organoid development in drug efficacy studies for lung cancer and head and neck tumors. Additionally, we stress the importance of using fine-needle aspiration to generate tumoroids.


The genus Cephaloleia (Coleoptera:Chrysomelidae) in Central America and the West Indies.
The species of Cephaloleia Chevrolat known to occur in Central America and the West Indies are revised and a key to the 88 species is presented. Most species are illustrated. Twenty new species of Cephaloleia are described: amblys, cylindrica, eumorpha, erugatus, facetus, formosus, lepida, scitulus, and weisei from Panamá; delectabilis and presignis from México; brunnea and rubra from Trinidad; immaculata, triangularis, and viltata from Costa Rica; splendida and uhmanni from Costa Rica and Panamá; cyanea from Costa Rica, Colombia, and Venezuela; and varabilis from Panamá and Colombia. Three new synonyms are given: abscissa Uhmann (= dilaticollis Baly), beckeri Weise (= gratiosa Baly), and quadrimaculata Uhmann (= fenestrata Weise). Lectotypes are designated for eleven species: belti Baly, consanguinea Baly, elegantula Baly, fulvicollis Weise, instabilis Baly, nigropicta Baly, postuma Weise, quadrilineata Baly, separata Baly, stenosoma Baly, and vicina Baly. Two species are transferred from Demotispa to Cephaloleia: coeruleata Sanderson and costaricensis Uhmann. Cephaloleia coeruleata (Sanderson) is renamed C. sandersoni.


AI4FoodDB: a database for personalized e-Health nutrition and lifestyle through wearable devices and artificial intelligence.
The increasing prevalence of diet-related diseases calls for an improvement in nutritional advice. Personalized nutrition aims to solve this problem by adapting dietary and lifestyle guidelines to the unique circumstances of each individual. With the latest advances in technology and data science, researchers can now automatically collect and analyze large amounts of data from a variety of sources, including wearable and smart devices. By combining these diverse data, more comprehensive insights of the human body and its diseases can be achieved. However, there are still major challenges to overcome, including the need for more robust data and standardization of methodologies for better subject monitoring and assessment. Here, we present the AI4Food database (AI4FoodDB), which gathers data from a nutritional weight loss intervention monitoring 100 overweight and obese participants during 1 month. Data acquisition involved manual traditional approaches, novel digital methods and the collection of biological samples, obtaining: (i) biological samples at the beginning and the end of the intervention, (ii) anthropometric measurements every 2 weeks, (iii) lifestyle and nutritional questionnaires at two different time points and (iv) continuous digital measurements for 2 weeks. To the best of our knowledge, AI4FoodDB is the first public database that centralizes food images, wearable sensors, validated questionnaires and biological samples from the same intervention. AI4FoodDB thus has immense potential for fostering the advancement of automatic and novel artificial intelligence techniques in the field of personalized care. Moreover, the collected information will yield valuable insights into the relationships between different variables and health outcomes, allowing researchers to generate and test new hypotheses, identify novel biomarkers and digital endpoints, and explore how different lifestyle, biological and digital factors impact health. The aim of this article is to describe the datasets included in AI4FoodDB and to outline the potential that they hold for precision health research. Database URL https://github.com/AI4Food/AI4FoodDB.


Basement membrane recovery process in rat soleus muscle after exercise-induced muscle injury.
Purpose: Collagen IV is a component of the basement membrane (BM) that provides mechanical support for muscle fibers. In addition, transcription factor 4 (TCF4) is highly expressed in muscle connective tissue fibroblasts and regulates muscle regeneration. However, the expression of collagen IV and TCF4 (+) cells in response to exercise-induced muscle injury is not well known. Here, we investigated the expression and localization of collagen IV and TCF4 (+) cells during the recovery process after muscle injury induced by different exercise loads.Materials and Methods: Muscle injury was observed in the soleus muscle of young Wistar rats after 12 or 18 sets-downhill running (DR) on a treadmill. After running, the rats were permitted to recover for a period of 0.5 days, 2 days, or 7 days.Results: Ectopic localization of collagen IV in injured muscle fibers was observed after DR, and the number increased at 0.5 days after 18 sets DR and at 2 days after 12 or 18 sets DR as compared to the number observed at baseline. BM disruption was observed after DR. TCF4 (+) cells appeared in the inside and around injured muscle fibers at 0.5 day of recovery. After 18 sets DR, TCF4 (+) cells were more abundant for a longer period than that observed after 12 sets DR.Conclusions: DR induces BM disruption accompanied by muscle fiber damage. It is possible that BM destruction may be accompanied by muscle damage and that TCF4 (+) cells contribute to muscle fiber and BM recovery.


Molecular mechanisms and applications of tea polyphenols: A narrative review.
Tea is a worldwide popular drink with high nutritional and medicinal values as it is rich in nutrients, such as polyphenols, amino acids, vitamins, glycosides, and so on. Among them, tea polyphenols (TPs) are the current research hotspot. TPs are known to have multiple biological activities such as anti-oxidation, anti-tumor, anti-inflammation, anti-bacteria, lowering lipid, and liver protection. By reviewing a large number of literatures, we explained the mechanism of TPs exerting biological activity and a wide range of applications. We also discussed the deficiencies and development potential of TPs, in order to provide theoretical reference and scientific basis for the subsequent development and utilization of TPs. PRACTICAL APPLICATIONS: We summarized the bioactivity mechanisms of TPs in anti-tumor, anti-oxidation, antibacterial, anti-inflammatory, lipid-lowering, and liver protection, focused on its application fields in food and medicine, and discussed the deficiency and development potential of current research on TPs, so as to provide a certain convenient way for scholars studying TPs. It is expected to contribute to the subsequent discovery of biological activity and the broadening of the field of TPs.


Is There Still a Role for Glycoprotein IIb/IIIa Antagonists in Acute Coronary Syndromes?
The role played by glycoprotein (GP) IIb/IIIa inhibitors has continuously evolved from the initial introduction in mid 90 s until the most recent guidelines for treating acute coronary syndromes, and competed with a wider use of ADP inhibitors and novel anticoagulant drugs, to the extent that they stepped down from class I to class II recommendation in the routine setting of acute coronary syndromes. As a consequence, GP IIb/IIIa use was greatly narrowed. The purpose of this review is to define the roles that GP IIb/IIIa inhibitors may still have in acute ischemic settings by explaining why in high risk patients they might be preferable and/or whether they might be added to ADP inhibitors also emphasizing the underlying mechanistic actions. It is concluded that there might be a more extensive use of GP IIb/IIIa inhibitors in patients presenting with acute coronary syndromes, strictly based on the definition for a high risk procedure: complexity, angiographic characteristics and patient's risk profile, regardless whether STEMI or NSTEMI. The positive elements one should appreciate in GP IIb/IIIa inhibitors are: efficacy, rapid onset and reversibility of action, absence of pharmacogenomic variability, pharmacoeconomic considerations and the possibility of intracoronary administration.


Direct fermentation of amorphous cellulose to ethanol by engineered Saccharomyces cerevisiae coexpressing Trichoderma viride EG3 and BGL1.
Direct ethanol fermentation from amorphous cellulose was achieved using an engineered industrial Saccharomyces cerevisiae strain. Two cellulase genes endoglucanase (eg3) and β-glucosidase (bgl1) were obtained from Trichoderma viride and integrated into the genome of S. cerevisiae. These two cellulases could be constitutively coexpressed and secreted by the recombinant strain S. cerevisiae-eb. The enzyme activities were analyzed in the culture supernatants, with the highest endoglucanase activity of 2.34 units/ml and β-glucosidase activity of 0.95 units/ml. The effects of pH, temperature and metal ions on enzyme activities were analyzed. The coexpression strain S. cerevisiae-eb could grow in carboxymethyl cellulose (CMC) and utilize it as the single carbon source. The 20 g/L CMC as a model substrate of amorphous cellulose was used in fermentation. The ethanol production reached 4.63 g/L in 24 h, with the conversion ratio of 64.2% compared with the theoretical concentration. This study demonstrated that the engineered industrial strain S. cerevisiae-eb could convert amorphous cellulose to ethanol simultaneously and achieve consolidated bioprocessing (CBP) directly.


Immune senescence in non-small cell lung cancer management: therapeutic relevance, biomarkers, and mitigating approaches.
Lung cancer and mainly non-small cell lung cancer (NSCLC) still remain a prevalent malignancy worldwide despite sustained screening approaches. Furthermore, a significant proportion of the cases are diagnosed at advanced stages when conservative therapy is often unsuccessful. Cell senescence is an endogenous antitumor weapon but when it is upregulated exerts opposite activities favoring tumor metastasizing and poor response to therapy. However, little is known about this dangerous relationship between cell senescence and NSCLC outcome or on potential approaches to mitigate its unfavorable consequences. We discuss cell senescence focusing on immune senescence, its cell and humoral effectors (namely immune senescence associated secretory phenotype-iSASP), its impact on NSCLC outcome, and its biomarkers. Senotherapeutics as mitigating approaches are also considered based on the availability of experimental data pertinent to NSCLC. Characterization of NSCLC subsets in which immune senescence is a risk factor for poor prognosis and poor therapeutic response might be very helpful in supporting the addition of senotherapeutics to conventional cancer therapy. This approach has the potential to improve disease outcome but more studies in this area are necessary.


A "story" of a woman with cystic fibrosis.
Munchausen syndrome is a pattern of abnormal behavior in which patients repeatedly present with symptoms that have no organic basis and are intentionally simulated or produced in order to assume the sick role and gain admission to the hospital. A 25-year-old white woman presented to our adult cystic fibrosis (CF) program and gave a detailed history consistent with a diagnosis of CF, a complicated disease with multiorgan involvement that is difficult to feign. However, discrepancies in her history were noted and objective measures of disease were inconsistent, including evidence of a fabricated sweat chloride result. We describe the classic characteristics of Munchausen syndrome that our patient exhibited, and report this unusual presentation of Munchausen syndrome to be consistent with the recommendation of reporting such cases to other physicians. Such knowledge is likely to result in less harm to the patient through unnecessary testing and treatment.


Amiodarone-induced thrombosis: a case series and brief review of the literature.
Amiodarone is used extensively in clinical practice for the treatment of arrhythmias but is associated with a number of well-known side effects. We present 3 cases of extensive thrombosis occurring secondary to intravenous amiodarone. In cases like these, amiodarone must be stopped immediately and patients started on appropriate anticoagulation therapy. Providing education to nursing and pharmacy staff regarding the administration of IV amiodarone and the necessity of defining institutional guidelines are central to decreasing the risk of complications from using this widely available antiarrhythmic agent.


Insufficient Angiogenesis: Cause of Abnormally Thin Endometrium in Subfertile Patients?
This study investigated subfertile patients with abnormally thin endometrium after infertility treatment. As they had adequate serum concentrations of hormones, an endometrial factor for subfertility was suspected. To elucidate the cause of subfertility, endometrial biopsies were taken in each patient in the late proliferative and mid-secretory phases of one menstrual cycle. Endometrial biopsies from women with normal menstrual cycles and confirmed fertility who were undergoing hysterectomy for benign uterine disease were used as positive controls. The tissue samples were investigated for steroid hormone receptor expression and for the proliferation marker Ki-67. Immunohistochemistry was performed with antibodies against the marker molecules for endometrial receptivity - β 3 integrin, VEGF, LIF, and CD56 (large granular lymphocytes, LGLs). The steroid hormone receptors for estrogen (E2) and progesterone (P) were expressed normally (at the first biopsy) and were down-regulated (at the second biopsy) within the cycle. Strikingly, all of the marker molecules investigated showed negative or weak and inadequate expression in the mid-secretory phase. Numbers of LGLs remained as low as in the proliferative phase. In contrast, fertile patients were found to express these marker molecules distinctly in the mid-secretory phase. It may be hypothesized that a severe deficiency of these angiogenesis-related marker molecules leads to defective development of the endometrium, which remains thin. Deficient angiogenetic development may thus provide an explanation for the endometrial factor that causes infertility. Further investigations will need to focus on identifying the regulating factors that act between steroid receptor activation and the expression of these marker molecules.


RNA-protein interactions promote asymmetric sorting of the ASH1 mRNA ribonucleoprotein complex.
In Saccharomyces cerevisiae, ASH1 mRNA is localized to the tip of daughter cells during anaphase of the cell cycle. ASH1 mRNA localization is dependent on four cis-acting localization elements as well as Myo4p, She2p, and She3p. Myo4p, She2p, and She3p are hypothesized to form a heterotrimeric protein complex that directly transports ASH1 mRNA to daughter cells. She2p is an RNA-binding protein that directly interacts with ASH1 cis-acting localization elements and associates with She3p. Here we report the identification of seven She2p mutants-N36S, R43A, R44A, R52A, R52K, R63A, and R63K-that result in the delocalization of ASH1 mRNA. These mutants are defective for RNA-binding activity but retain the ability to interact with She3p, indicating that a functional She2p RNA-binding domain is not a prerequisite for association with She3p. Furthermore, the nuclear/cytoplasmic distribution for the N36S and R63K She2p mutants is not altered, indicating that nuclear/cytoplasmic trafficking of She2p is independent of RNA-binding activity. Using the N36S and R63K She2p mutants, we observed that in the absence of She2p RNA-binding activity, neither Myo4p nor She3p is asymmetrically sorted to daughter cells. However, in the absence of She2p, Myo4p and She3p can be asymmetrically segregated to daughter cells by artificially tethering mRNA to She3p, implying that the transport and/or anchoring of the Myo4p/She3p complex is dependent on the presence of associated mRNA.


Modulation of immune response by Vernonia cinerea L. inhibits the proinflammatory cytokine profile, iNOS, and COX-2 expression in LPS-stimulated macrophages.
The effect of methanolic extract of Vernonia cinerea L. on the immune system was studied using BALB/c mice. Intraperitoneal (i.p.) administration of five doses of the extract (20 mg/kg body weight) was found to enhance the total white blood cell (WBC) count (13,700 ± 463 cells/mm(3)) on 6th day, bone marrow cellularity (27.9 ± 2.1 × 10(6) cells/femur) and number of α-esterase positive cells (1184 ± 56.29/4000 cells). Treatment with V. cinerea along with the antigen, sheep red blood cells (SRBC), produced an enhancement in the circulating antibody titre and the number of plaque forming cells (PFC) in the spleen. Maximum number of PFC (304.16 ± 12.4) was obtained on the 6th day. It also enhanced the proliferation of splenocytes, thymocytes and bone marrow cells both in the presence and absence of specific mitogens in vitro and in vivo. Administration of V. cinerea significantly reduced the lipopolysaccharide (LPS) induced elevated levels of nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1 (IL-1β), and IL-6 in mice. Treatment of V. cinerea methanolic extract also showed an enhancement in the phagocytic activity of peritoneal macrophages. Moreover The extract downregulated the inducible NO synthase and cyclooxygenase-2 (COX-2) mRNA expression in LPS-stimulated macrophages. These results indicate the immunomodulatory activity of V. cinerea.


[Cytological evaluation of urothelial damage in extracorporeal shock-wave lithotripsy].
The study proposed a technique for early detection of the damaging effect of shock waves on the urinary tract tissues, for monitoring the state of urothelial cells in the early post-procedure period and choosing an adequate method for preventing and managing possible complications. The study analyzed the urine samples of 300 patients aged 20 to 50 years, who for the first time underwent ESWL for kidney stones. The urine sediment smears were fixed in the May-Grunwald stain and stained with azure eosin solution according to Pappenheim. Besides evaluating general cytologic characteristics, a morphometric examination of urine sediment was performed. To define quantitative parameters, the total number of epithelial cells (ep) was determined with further calculation of the mean number of epithelial cells in the field of view (ep= ep/10). Correlation between the number of abnormal epithelial cells (cp) and the total number of epithelial cells (ep) was analyzed. The resulted "destruction index" (DI) was the "pool" of all cytopathological changes in epithelial cells DI = cp/ep. Immediately after ESWL, DI markedly increased with significant difference (<0.05) in numeric values. Two hours after the procedure, the DI reduced compared to the previous value. And only at day 4 DI was close to the norm, although remaining somewhat elevated. Extracorporeal shock waves lithotripsy produces the acute urothelial damage resulting in cytopathological changes of varying severity. The above-mentioned technique provides objective and highly significant clinical and diagnostic information on the state of the urothelium after the exposure to shock waves.


Obesity Paradox in Peripheral Arterial Disease: Results of a Propensity Match Analysis from the National Inpatient Sample.
Introduction The role of obesity in cardiovascular mortality is controversial. The obesity paradox has been widely attributed to smoking in the underweight. Large-scale studies analyzing the outcomes of peripheral arterial disease (PAD) in patients with a higher body mass index (BMI) while accounting for confounders such as smoking are lacking. Method The 2016 National Inpatient Sample (NIS) was used to identify all admissions with a primary discharge diagnosis of PAD. A secondary diagnosis of obesity or elevated BMI was used to segregate the admissions into two groups. Propensity scores were calculated to match and control both groups for age, smoking, and diabetes, amongst other confounders. A multivariate logistic and linear regression analysis was performed to calculate the odds ratio for in-hospital mortality, amputation, need for intervention (angioplasty or bypass), acute kidney injury, hospital charges, and length of stay. Non-obesity-related PAD admissions were selected as the reference groups. Results Among 248,288 PAD-related admissions, 41,618 had a secondary diagnosis of obesity. After calculating propensity scores for 1-1 matching, 41,589 admissions in the PAD and obesity group were compared to a similar number of admissions in the reference population. Patients with a concomitant diagnosis of obesity had lower odds of amputation (OR=0.90, 95% CI=0.84-0.95, p<0.001), need for intervention (OR=0.66, 95% CI=0.62-0.69, p<0.0001), and in-hospital mortality (OR=0.81, 95% CI=0.74-0.87, p<0.0001). On the contrary, the odds of having acute kidney injury were higher with elevated BMI (OR=1.30, 95% CI=1.26-1.34, p<0.0001). Conclusion Despite increasing the risk of hypertension, diabetes, and hypertriglyceridemia, the obesity paradox continues to exist with a better short-term prognosis in patients with PAD. Future studies looking into the pathophysiology behind this phenomenon are needed.


[High-dose chemotherapy and autologous stem cell transplantation in multiple myeloma patients--single center experience].
Multiple myeloma (MM) is one of the hematologic malignancies in which the impact of dose intensity has been demonstrated. In 2005 it was the most common disease for which autologous stem cell transplantation (ASCT) was performed. However, ASCT is not curative, and most patients relapse within a median of 3 years, the introduction of high-dose therapy resulted in prolonged survival. Novel agents such as thalidomide, bortezomib, or lenalidomide have been introduced to improve high-dose therapy outcome. From April 1998 to December 2008, 65 patients with MM underwent in our Department high-dose chemotherapy supported by autologous transplantation of peripheral blood stem cells (APBSCT). Transplantation of progenitor cells was conducted as consolidation of first line treatment in the majority of patients. Double transplantation was performed in 20 patients (31%). Conditioning regimen consisted of high-dose melphalan (200 mg/m2), in the second procedure the dose of melphalan was reduced to 140 mg/m2. Transplant related mortality was not observed. The duration of hematological recovery after first and second transplantation did not differ significantly. At the time of the analysis (June 2009) 51/65 (78.5%) patients are alive, 14/65 (21.5%) died due to disease progression. Median overall survival (OS) and progression free survival ( PFS) obtained were 86 (range 24-128) and 33 (range 4-110) months respectively. This retrospective analysis confirms the efficacy and safety of APBST in multiple myeloma patients.


Treatment of type 1 diabetes with anti-T-cell agents: from T-cell depletion to T-cell regulation.
Studies in animal models of type 1 diabetes had suggested that the disease was due to an immune-mediated destruction of insulin-producing cells. As this understanding was developed, clinical trials that were directed against T cells were begun, because these lymphocytes were thought to be the primary mediators of disease. Initial studies used broad-spectrum agents and showed general efficacy in either preventing the loss of insulin secretion or reducing the need for exogenous insulin. Although encouraging, the enthusiasm for this approach waned due to the lack of long-term effects and toxicities. These studies were followed by trials with more specific agents, but the issue of toxicity remained. Newer agents, such as anti-CD3 antibody, are also targeted against T cells but the toxicity and efficacy of modified anti-CD3 antibody, for example, appears to be improved over previously tested agents. In addition, our understanding of the immunologic effects of anti-T-cell agents has evolved. Data now suggest that efficacy and duration of the effects of anti-T-cell drugs can be enhanced when the agents provoke immune modulation rather than depletion of effector cells.


On Becoming a Humanities Curriculum: the Center for Medical Humanities and Ethics at the University of Texas Health Science Center at San Antonio.
The authors describe the development and implementation of a new longitudinal and integrated humanities curriculum in the School of Medicine at the University of Texas Health Science Center at San Antonio. Included are a history of ethics and humanities education in the medical school leading to the creation of the Center for Medical Humanities and Ethics in July 2002; an articulation of the Center's basic principles; a curricular blueprint outlining the core objectives and methodologies, such as a narrative approach of this required, four-year humanities curriculum for undergraduate medical students; and an overview of course materials and activities.