Bone marrow MyD88 signaling modulates neutrophil function and ischemic myocardial injury.
Myeloid differentiation factor 88 (MyD88), an adaptor critical for innate immune function, plays a role in neutrophil recruitment and myocardial injury after transient ischemia. However, how MyD88 signaling modulates neutrophil function and myocardial injury remains unclear. In an in vivo model of neutrophil migration and a chimeric model of MyD88 deletion, we demonstrated that Gr-1-positive (Gr-1(+)) neutrophil migration was significantly decreased by 68% in MyD88-deficient (Myd88(-/-)) mice and by 33% in knockout→wild-type (KO→WT; donor→recipient) chimeric mice, which lacked MyD88 in bone marrow cells but maintained normal MyD88 expression in the heart. This marked attenuation in neutrophil migration was associated with decreased peritoneal neutrophil CXCR2 expression and lower peritoneal KC, a neutrophil chemoattractant, in MyD88(-/-) mice. Moreover, in vitro, KC induces significantly more downregulation of CXCR2 expression in MyD88(-/-) than WT neutrophils. In an in vivo model of myocardial ischemia-reperfusion (I/R) injury, KO→WT chimeric mice had significantly smaller infarct sizes compared with the WT→WT mice. While there was a marked increase in proinflammatory cytokine/chemokine expression in the myocardium following I/R, there was no significant difference between WT→WT and KO→WT mice. In contrast, Gr-1(+) neutrophil recruitment in the myocardium was markedly attenuated in MyD88(-/-) mice. Deletion of Toll-interleukin-1 receptor (TIR)-domain-containing adaptor protein-inducing interferon-β-mediated transcription factor (Trif), another innate immune adaptor, had no effect on the KC-mediated CXCR2 downregulation or on myocardial neutrophil recruitment after I/R. Taken together, these findings suggest that MyD88 signaling is essential for maintaining neutrophil migratory function and chemokine receptor expression. MyD88 signaling in bone marrow-derived circulating cells may play a specific and critical role in the development of myocardial I/R-induced injury.


Specialize or risk disappearance - empirical evidence of anisomerism based on comparative and developmental studies of gnathostome head and limb musculature.
William K. Gregory was one of the most influential authors defending the existence of an evolutionary trend in vertebrates from a higher degree of polyisomerism (more polyisomeric or 'serial' anatomical structures arranged along any body axis) to cases of anisomerism (specialization or loss of at least some original polyisomeric structures). Anisomerism was the subject of much interest during the 19th and the beginning of the 20th centuries, particularly due to the influence of the Romantic German School and the notion of 'primitive archetype' and because it was conceptually linked to other crucial biological issues (e.g. complexity, scala naturae, progress, modularity or phenotypic integration). However, discussions on anisomerism and related issues (e.g. Williston's law) have been almost exclusively based on hard tissues. Here we provide the first detailed empirical test, and discussion, of anisomerism based on quantitative data obtained from phylogenetic and comparative analyses of the head and forelimb muscles of gnathostomes. Our results strongly support the existence of such a trend in both forelimb and head musculature. For instance, the last common ancestor (LCA) of extant tetrapods likely had 38 polyisomeric muscles (PMs) out of a total of 70 forelimb muscles (i.e. 54%), whereas in the LCAs of extant amniotes and of mammals these numbers were 38/73 (52%) and 21/67 (31%), and in humans are 11/59 (19%). Interestingly, the number of PMs that became specialized during the forelimb evolutionary transition from the LCA of extant tetrapods to humans (13) is very similar to the number of PMs that became lost (14), indicating that both specialization and loss contributed equally to the trend towards anisomerism. By contrast, during the evolution of the head musculature from the LCA of gnathostomes to humans a total of 27 PMs were lost whereas only one muscle became specialized. Importantly, the evolutionary trend towards anisomerism is not related to a general trend leading to the presence of fewer muscles in derived taxa, because for instance humans have more head muscles in total, but many less head polyisomeric muscles than early gnathostomes and extant fish such as sharks, and than early tetrapods and amphibians such as salamanders. This is because new muscles have also been acquired during gnathostome evolution (e.g. facial muscles of mammals). Interestingly, many new PMs have also been acquired during head evolution (but subsequently lost during the transitions towards humans), whereas only a few new PMs were acquired during forelimb evolution. Our comparisons and review of the literature indicate that there is also a trend towards anisomerism during development, thus providing a further example of a parallel between ontogeny and phylogeny, e.g. some forelimb PMs (e.g. contrahentes, intermetacarpales) become specialized or lost (re-absorbed) during human ontogeny and some head PMs (e.g. constrictores branchiales) become lost during salamander ontogeny. This review will inform future discussions on modularity, complexity, body plans, phenotypic integration and macroevolution, which should ideally include soft tissues and the use of new tools (e.g. anatomical networks) in order to provide a broader and more integrative understanding of these relevant subjects.


Characterization of genetic diversity and linkage disequilibrium of ZmLOX4 and ZmLOX5 loci in maize.
Maize (Zea mays L.) lipoxygenases (ZmLOXs) are well recognized as important players in plant defense against pathogens, especially in cross kingdom lipid communication with pathogenic fungi. This study is among the first to investigate genetic diversity at important gene paralogs ZmLOX4 and ZmLOX5. Sequencing of these genes in 400 diverse maize lines showed little genetic diversity and low linkage disequilibrium in the two genes. Importantly, we identified one inbred line in which ZmLOX5 has a disrupted open reading frame, a line missing ZmLOX5, and five lines with a duplication of ZmLOX5. Tajima's D test suggests that both ZmLOX4 and ZmLOX5 have been under neutral selection. Further investigation of haplotype data revealed that within the ZmLOX family members only ZmLOX12, a monocot specific ZmLOX, showed strong linkage disequilibrium that extends further than expected in maize. Linkage disequilibrium patterns at these loci of interest are crucial for future candidate gene association mapping studies. ZmLOX4 and ZmLOX5 mutations and copy number variants are under further investigation for crop improvement.


[Advances in copepod resting egg ecology in estuarine and coastal waters].
Copepods are the key group in aquatic ecosystems, and play an important role in energy flow, the cycle of materials and information transfer. This paper summarized the distribution and composition of the copepods that spawn resting eggs in the estuarine and coastal marine areas. It also reviewed the survival time, hatching rates, abundance of resting eggs in the sediments, and the potential recruitment into the plankton population as correlated with environmental factors. The prospects of copepod resting egg ecology were also proposed in order to provide new ideas for future research.


Change in nasopharyngeal carriage of Streptococcus pneumoniae resulting from antibiotic therapy for acute otitis media in children.
Acute otitis media is the leading reason for antibiotic prescriptions in childhood. The increase in antibiotic resistance of Streptococcus pneumoniae is generally attributed to the extensive use of antibiotics and the selective pressure on the bacterial strains of the nasopharyngeal flora. To evaluate the change in nasopharyngeal carriage of S. pneumoniae during antibiotic therapy prescribed for acute otitis media. Between October, 1993, and March, 1994, we conducted a clinical trial comparing cefpodoxime-proxetil and amoxicillin-clavulanate in acute otitis media. From 364 children, 4 months to 4.5 years old, a nasopharyngeal sample was obtained before and after treatment. Antibiotic susceptibility was established by determining minimal inhibitory concentrations by the agar dilution method. Serotype and randomly amplified polymorphic DNA analysis were used to compare pre- and posttreatment S. pneumoniae strains. The risk for a child to carry penicillin-resistant S. pneumoniae (MIC > or = 0.125 mg/l) did not increase after antibiotic treatment: 84 of 364 (23.1%) before, 70 of 364 (19.2%) after. There was a significant decrease of penicillin-susceptible S. pneumoniae carriage, 117 of 364 (32.1%) before treatment compared with 24 of 364 (6.6%) (P = 0.0001) after treatment. However, among the children carrying S. pneumoniae at the end of the treatment there was an increase in the percentage of penicillin-resistant pneumococci: 84 of 201 (41.8%) before treatment and 70 of 94 (74.5%) after treatment. Among the 94 children carrying S. pneumoniae at the end of the treatment, 22 did not harbor pneumococcus before, 16 carried another genotypically different serotype and 56 harbored the same serotype. Among these 56 children 2 patients harbored strains that had increased MICs for the tested beta-lactam antibiotics. The randomly amplified polymorphic DNA analysis showed that in one case, the strains were genetically different. These data illustrate that antibiotic therapy did not increase the rate at which children carried penicillin-resistant S. pneumoniae, but there was an increase in the rate of resistance among the children carrying pneumococci at the end of the treatment, mainly as a result of reduction of susceptible strains.


Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura.
Congenital thrombotic thrombocytopenic purpura (TTP) is associated with ADAMTS13 mutations. The major site of ADAMTS13 synthesis is the liver. Expression in other tissues, and in TTP, has not been shown. In this study, ADAMTS13 protein expression was investigated in normal kidney and in renal tissue from two TTP patients, with a compound heterozygous mutation (P353L and P457L) and a homozygous mutation (4143insA). Real-time polymerase chain reaction demonstrated ADAMTS13 mRNA in normal kidney. ADAMTS13 was detected in the glomeruli and tubuli of normal and TTP kidney using anti-ADAMTS13 antibodies. In the glomeruli, expression was localised to podocytes (as demonstrated by counterstaining with two podocyte markers) and endothelium. Similar distribution was detected in the TTP kidneys. Electron microscopy detected ADAMTS13 in podocytes, endothelium and glomerular basement membrane. Cultured human podocytes expressed ADAMTS13 mRNA and protein, and podocyte lysate exhibited von Willebrand factor-cleaving activity. Mutation expression studies of the P353L and P457L mutations showed partially impaired secretion and lower activity of the secreted mutants. Impaired secretion has previously been shown for the 4143insA mutation. Podocyte-derived ADAMTS13 may offer local protection in the high-shear microcirculation of the glomerulus. The mutations in the two TTP patients studied enabled protein expression in the podocytes but affected protease secretion.


Endoscopic endonasal approach for clival chordomas.
Cranial base chordomas are difficult lesions to treat. The endoscopic endonasal approach (EEA) takes advantage of the natural sinus corridor and may provide a less invasive approach for these midline tumors. Patients undergoing EEA for chordomas were selected from a database of more than 800 consecutive patients undergoing EEA at the University of Pittsburgh Medical Center and were retrospectively evaluated. Additionally, a systematic review of the literature of endoscopic endonasally resected chordomas was performed and compared with our personal experience. Twenty patients (8 females and 12 males) underwent 26 endoscopic EEAs for cranial base chordomas. Eight chordomas (40%) were recurrent. Treatment of the 12 newly diagnosed chordomas included 8 total resections (66.7%), 2 near total resections (16.7%), and 2 subtotal resections (16.7%). Treatment of the 8 recurrent chordomas included 1 gross total resection (12.5%), 2 near total resections (25.0%), and 5 subtotal resections (62.5%). Two patients (10%) had recurrences, and 5 patients (25%) progressed during the mean follow-up period of 13 months (range, 1-45 months). Five patients (25%) underwent re-resection, 1 patient was lost to follow-up, and 1 patient died secondary to progression of disease. There was 1 intraoperative vascular complication with no sequelae. The cerebrospinal fluid leak rate was 25%, and there were no cases of bacterial meningitis. The incidence of a new permanent neurological complication was 5%. A systematic review of the literature yielded a total of 26 cases of chordomas resected via a completely endoscopic endonasal technique. Endoscopic endonasal resection of cranial base chordomas is safe once adequate experience is gained with the technique. This approach provides the potential for, at the least, similar resections compared with traditional cranial base approaches while potentially limiting morbidity.


[Acute caffeine intoxication after intake of 'herbal energy capsules'].
Two males, 15 and 17 years old respectively, presented at the Emergency Department complaining of cramping abdominal pain, nausea and vomiting after ingestion of energy capsules. Physical examination revealed sinus tachycardia and slight abdominal pain. Laboratory examination showed substantial hypokalaemia and mild hyperglycaemia. Questioning revealed that they had taken 5 and 3 'herbal energy capsules' respectively and that these capsules supposedly contained 200 mg of caffeine each. Toxicological analysis showed a greatly increased serum caffeine concentration in both patients. The peak concentrations calculated were in the highly toxic range and could have led to severe acute complications such as convulsions. Pharmaceutical analysis demonstrated that these 'Supercap Xtreme'-capsules contained 700 mg caffeine or more. All symptoms presented were compatible with caffeine intoxication. The content of these capsules is not reliable and could lead to life-threatening intoxication.


Coming to power: women's fake orgasms and best orgasm experiences illuminate the failures of (hetero)sex and the pleasures of connection.
While some literature has explored women's sexual satisfaction and, to a lesser degree, women's faking orgasm experiences, little research has examined the context and conditions around women's best and most memorable orgasms. This paper utilised thematic analysis of qualitative data from a community sample of 20 women in the USA (mean age = 34 years, SD = 13.35 years) from a wide range of racial, socioeconomic, and sexual identity backgrounds to illuminate their experiences with fake or pretend orgasms, and with their best orgasms. While faking orgasm narratives reflected themes of wanting to reinforce a partner's sexual skills, strategically ending sexual interactions, and suppressing feelings of abnormality and shame, best orgasm experiences showcased the power of interpersonal connection, the joys of masturbation and other non-penile-vaginal intercourse behaviours, and the significance of 'transformative embodiment'. Implications for the relative failures of (hetero)sex, particularly in the context of gendered power imbalances, along with the importance of deconstructing the sexually 'functional' or 'dysfunctional' woman are explored.


Somatic antigens of Streptococcus group E. II. Separation and a partial physicochemical characterization.
Antigenic extracts of Streptococcus group E (SGE) were subjected to fractional ethanol precipitation, block (preparative) electrophoresis, and gel filtration for the purpose of separating the type antigen from the group antigen. Ethanol precipitation was ineffective in separating the substances. Block electrophoresis yielded serologically pure group antigen and a mixture of type and group antigen. Serologically pure type antigen was obtained by gel filtration. In some cases, pure group antigen was also recovered; in others, it was contaminated with type antigen. Gel filtration column effluents of antigenic extracts of SGE serotypes, I, II, III, IV, V and "untypable" isolates, collected from the region in which type antigen was eluted, were studied by paper chromatography and infrared spectrophotometry in an effort to develop a nonserological means of detecting type antigen. Hydrolysates of type antigens or suspect type antigens of serotypes I through V contained l-rhamnose, d-glucose, and several unidentified substances. d-Galactose also was present in hydrolysates of serotypes III and V. Untypable isolates and negative controls contained traces of d-glucose only. The data suggested that serotypes I through V contained a type antigen and that the untypable isolates were devoid of type antigen. Infrared absorbance spectra seemed to support the paper chromatography data.


Topical application of the phospholipid growth factor lysophosphatidic acid promotes wound healing in vivo.
The lipid mediator lysophosphatidic acid (LPA) regulates cell proliferation and enhances cell motility in vitro, both of which are important events in wound healing. To evaluate the effects of LPA in vivo, it was applied to a full-thickness wound of rat skin. LPA in micromolar concentrations, or solvent, was applied daily. Animals were killed at 1, 3, 6, and 9 days after wounding and processed for histological evaluation, including hematoxylin-eosin staining and histochemical markers for macrophage-histiocytes, proliferating cells, and capillary endothelial cells. LPA treatment accelerated wound closing and increased neoepithelial thickness. Cytological evaluation showed no evidence for a secondary inflammation-mediated injury, infection, or increased keloid formation. Whereas LPA caused only a modest dose-dependent increase in proliferating cells, a marked increase in the immigration of histiocyte-macrophage cells was observed as early as day 1. The peaks of several cytological features and immunohistological markers preceded those of the untreated side. Our data suggest that exogenously applied LPA in this model promotes healing and that macrophage-histiocytes are the primary LPA-responsive cells in vivo.


Nutrient malabsorption in the Zollinger-Ellison syndrome. Normalization during long-term cimetidine therapy.
Nutrient malabsorption occasionally occurs in the setting of acid hypersecretion with the Zollinger-Ellison syndrome. Previous incomplete reversal of this malabsorption with therapy has probably been due to inadequate suppression of acid secretion with medical therapy or disturbances of anatomy and physiology occurring as a result of surgical therapy. A patient whose primary manifestations of this syndrome were nutrient malabsorption and diarrhea was afforded complete reversal of the malabsorption on receiving long-term cimetidine therapy. This effective medical therapy has thus demonstrated that nutrient malabsorption in the Zollinger-Ellison syndrome is due solely to the deleterious effects of acid hypersecretion.


A toxic diet: transfer of contaminants to offspring through a parental care mechanism.
The transfer of maternal contaminants to offspring during oogenesis and gestation is documented in many animals, and in mammals, contaminants may pass from mother to offspring during lactation. Although other non-mammalian vertebrates provide parental care in the form of nutritive secretions for offspring to feed from, the potential for toxicant transfer during non-mammalian parental care is rarely considered. The discus fish, Symphysodon spp., employs an unusual parental care strategy where fry feed on parental epidermal mucus for several weeks after hatching. This strategy has the potential to act as a method of contaminant transfer. In discus adults, both waterborne and dietary toxicants are sequestered and secreted into their epidermal mucus, the food on which fry depend. To determine whether parents could channel these contaminants directly to offspring, we exposed parents to aqueous cadmium (Cd) and recorded the subsequent feeding behaviour and Cd content of fry. Fry continued to feed normally from contaminated mucus and accumulated significant tissue concentrations of Cd. In conclusion, this parental care mechanism of the discus fish can expose offspring to harmful contaminants during the sensitive early stages of life and highlights that parent to offspring contaminant transfer after birth may be more widespread than previously thought.


Effects of sildenafil on retinal blood flow and flicker-induced retinal vasodilatation in healthy subjects.
Sildenafil is a specific inhibitor of phosphodiesterase V, which is widely used for the treatment of erectile dysfunction. Sildenafil has been shown to induce vasodilation in several vascular beds by inhibiting the cGMP breakdown. The present study was conducted to investigate whether sildenafil increases blood flow in the human retina. In a randomized, double-masked, placebo-controlled, two-way crossover study in 12 healthy male volunteers the effects of a single dose of 100 mg sildenafil were studied. Subjects received sildenafil or placebo on two different study days. After administration, retinal hemodynamic parameters were measured every 20 minutes. Retinal vessel diameters and retinal blood velocity were assessed with the retinal vessel analyzer and bidirectional laser Doppler flowmetry, respectively. In addition, the response of retinal vessel diameters to stimulation with diffuse flicker light was studied. Blood pressure and intraocular pressure were measured with noninvasive techniques. Sildenafil had no effect on mean arterial pressure, pulse rate, intraocular pressure, retinal blood velocity, or retinal arterial diameter. However, a significant increase in retinal venous diameters (4.7% +/- 3.2%; P=0.0028 versus placebo) and retinal blood flow 15.7% +/- 18.0%; P=0.029 versus placebo) was observed. Sildenafil had no effect on flicker-induced vasodilation in retinal arteries or veins. The data indicate that sildenafil increases retinal venous diameters and retinal blood flow in healthy subjects. By contrast, it does not affect intraocular pressure and flicker-induced retinal vasodilation. Further studies are needed to elucidate whether this drug may be therapeutically used in retinal ischemic disease.


Complete biliary obstruction without jaundice due to an anatomic variation.
An aberrant right posterior hepatic duct is present in 4.8-8.4% of the population. It is one of the causes of bile duct injury during laparascopic cholecystectomy. Herein we present a patient with complete transection of the common hepatic duct during laparascopic cholecystectomy (Stewart-Way class 3). Interestingly, the patient had an intact aberrant right posterior duct draining into the common hepatic duct distal to the obstruction site that prevented early diagnosis of the biliary injury because of drainage of the liver sufficient to prevent the development of jaundice.


Medication issues for nursing older people (part 1).
This article aims to raise awareness about professional responsibility and accountability in medication issues that impact on older people. Nurses must recognise their responsibilities in regard to the safe administration of medicines and challenge poor drug administration practices.


An assessment of daily production and significance of thyroidal secretion of 3, 3', 5'-triiodothyronine (reverse T3) in man.
While 3, 3', 5'-triiodothyronine (reverse T3, rT3) has been detected both in human serum and in thyroglobulin, no quantitative assessment of its metabolic clearance rate (MCR), production rate (PR), or secretion by the thyroid is yet available. This study examines this information in euthyroid subjects and evaluates it in light of similar information about two other iodothyronines in the thyroid: 3, 5, 3'-triiodothyronine (T3) and thyroxine (T4). Thus, it was noted that rT3 is cleared from human serum at a much faster rate than are T3 and T4; the mean (+/-SE) MCR of rT3 was 76.7+/-5.4 liters/day in 10 subjects, whereas MCR-T3 and MCR-T4 in 8 of them were 26.0+/-2.2 liters/day and 1.02+/-0.06 liters/day, respectively. Therefore, even though the mean serum concentration of rT3, 48+/-2.8 ng/100 ml, was much lower than that (128+/-6.7 ng/100 ml) of T3, the mean PR-rT3 (36.5+/-2.8 mug/day) and the mean PR-T3 (33.5+/-3.7 mug/day) were similar; in comparison, the mean serum concentration and PR of T4 were 8.6+/-0.5 mug/100 ml and 87.0+/-3.9 mug/day, respecitvely. These data and those on the relative proportion of rT3, T3, and T4 in 10 thyroid glands were used to assess the significance of the contribution of thyroidal secretion to PR-rT3 and PR-T3. It was estimated that whereas thyroidal secretion may account for about 23.8% of serum T3 (or PR-T3), it may account for only about 2.5% of serum rT3 (or PR-rT3). Since peripheral metabolism of T4 is the only known source of rT3 and T3 other than the thyroidal secretion, it could be calculated that as much as 73.0 mug or 84% of daily PR-T4 may normally be metabolized by monodeiodination either to T3 or to rT3. MCR and PR of various iodothyronines were also examined in five cases with hepatic cirrhosis, where, as documented previously, serum rT3 may be elevated while serum T3 is diminished. The mean MCR-rT3 in these cases (41.0 liters/day) was clearly (P is less than 0.005) less than that (76.7 liters/day) in normal subjects. This was the case at a time when the mean MCR-T3 (26.7 liters/day) and the mean MCR-T4 (1.19 liters/day) did not differ from those (vide supra) in normal subjects. Distinct from changes in MCRs, the mean PR-rT3 (33.0 mug/day) was similar to, and the mean PR-T3 (10.1 mug/day) and the mean PR-T4 (66.4 mug/day) were much less than, the corresponding value in normal subjects. Furthermore, while the ratio of PR-rT3 and PR-T4 (rT3/T4) in individual patients was either supranormal or normal, the ratio of PR-T3 and PR-T4 (T3/T4) was clearly subnormal. The various data suggest that: (a) just as in the case of T3, the thyroid gland is a relatively minor source of rT3; peripheral metabolism of T4 is apparently its major source; (b) the bulk of T4 metabolized daily is monodeiodinated to T3 or to rT3; (c) monodeiodination may be an obligatory step in metabolism of T4; (d) monodeiodination of T4 to rT3 is maintained normal or is increased in hepatic cirrhosis at a time when monodeiodination of T4 to T3 is decreased.


Action of curcumin on the cytochrome P450-system catalyzing the activation of aflatoxin B1.
Curcumin, in a dose-dependent manner, inhibited the formation of covalent adduct between aflatoxin B1 and DNA, as catalyzed by microsomes or a reconstituted microsomal monooxygenase system. Its effect on the cytochrome P450-system was investigated in the latter system. The inhibition (50%) of aflatoxin B1-DNA adduct formation by curcumin in this system could be reversed by increasing the amount of cytochrome P450 but not by that of NADPH-cytochrome P450 reductase. Curcumin inhibited the reductase activity when measured by the reduction of cytochrome C but not when measured by the reduction of dichlorophenolindophenol, an artificial electron acceptor. These results, as well as the reversal of curcumin-induced inhibition of P450 reductase activity by higher amounts of cytochrome C, indicated a strong affinity of curcumin towards cytochromes. This was further substantiated from the observation that curcumin-pretreated cytochrome P450 had reduced ability to catalyze aflatoxin B1-DNA adduct formation in the reconstituted system. Curcumin, thus, may inhibit chemical carcinogenesis by modulating cytochrome P450 function.


Recognition of paleoearthquakes on the Puente Hills blind thrust fault, California.
Borehole data from young sediments folded above the Puente Hills blind thrust fault beneath Los Angeles reveal that the folding extends to the surface as a discrete zone (</=145 meters wide). Buried fold scarps within an upward- narrowing zone of deformation, which extends from the upward termination of the thrust ramp at 3 kilometers depth to the surface, document the occurrence of at least four large (moment-magnitude 7.2 to 7.5) earthquakes on this fault during the past 11,000 years. Future events of this type pose a seismic hazard to metropolitan Los Angeles. Moreover, the methods developed in this study can be used to refine seismic hazard assessments of blind thrusts in other metropolitan regions.


Validated Stability-indicating High-performance Liquid Chromatographic Method for Estimation of Degradation Behaviour of Eberconazole Nitrate and Mometasone Furoate in Cream Formulation.
The objective of current investigation was to study the degradation behaviour of eberconazole nitrate and mometasone furoate under different International Conference on harmonisation recommended stress condition using reverse phase high performance liquid chromatographic method and to establish validated stability-indicating high performance liquid chromatographic method to determine purity of eberconazole nitrate and mometasone furoate in presence of its impurities, forced degradation products and placebo in pharmaceutical dosage forms. The method was developed using Hypersil BDS, C18, 150Χ4.6 mm, 5 μ as stationary phase with mobile phase containing a gradient mixture of solvent A and B. 0.01 M phosphate buffer with 0.1% triethyl amine, adjusted pH 7.0 with phosphoric acid was used as buffer. Buffer pH 7.0 was used as solvent A and methanol:acetonitrile in 150:850 v/v ratios were used as solvent B. The eluted compounds were monitored at 240 nm. The run time was 50 min. The developed method was validated as per international conference on harmonization guidelines with respect to specificity, linearity, limit of detection, limit of quantification, accuracy, precision and robustness.


Using a Single Peptide to Electrochemically Sense Multiple Kinases.
Kinases are responsible for regulating cellular and physiological processes, and abnormal kinase activity is associated with various diseases. Therefore, kinases are being used as biomarkers for disease and developing methods for their sensing is highly important. Usually more than one kinase is involved in phosphorylating a target protein. However, kinase detection methods usually detect the activity of only one specific kinase. Here we describe an electrochemical kinase sensing tool for the selective detection of two kinases using the same target peptide. We demonstrate the sensing of kinases ERK2 and PKCδ. This is based on a single sensing element, a peptide that contains two distinct phosphorylation sites of these two kinases. Reversibility experiments with alkaline phosphatase and reaction with the electrochemically active ferrocene-labeled ATP showed that the mechanism of sensing is by detecting the enzymatic phosphorylation. Our approach can be further utilized to develop devices for the detection of multiple kinases and can be expanded to other types of enzymes involved in disease.


Hierarchical Bayesian modeling of contrast sensitivity functions in a within-subject design.
Recent development of the quick contrast sensitivity function (qCSF) method has made it possible to obtain accurate, precise, and efficient contrast sensitivity function (CSF) assessment. To improve statistical inference on CSF changes in a within-subject design, we developed a hierarchical Bayesian model (HBM) to compute the joint distribution of CSF parameters and hyperparameters at test, subject, and population levels, utilizing information within- and between-subjects and experimental conditions. We evaluated the performance of the HBM relative to a non-hierarchical Bayesian inference procedure (BIP) on an existing CSF dataset of 112 subjects obtained with the qCSF method in three luminance conditions (Hou, Lesmes, Kim, Gu, Pitt, Myung, & Lu, 2016). We found that the average d's of the area under log CSF (AULCSF) and CSF parameters between pairs of luminance conditions at the test-level from the HBM were 33.5% and 103.3% greater than those from the BIP analysis of AULCSF. The increased d' resulted in greater statistical differences between experimental conditions across subjects. In addition, simulations showed that the HBM generated accurate and precise CSF parameter estimates. These results have strong implications for the application of HBM in clinical trials and patient care.


Suppression of the bitterness of enteral nutrients using increased particle sizes of branched-chain amino acids (BCAAs) and various flavours: a taste sensor study.
An improved formulation of the enteral nutrient Aminoleban EN (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan), has been commercially available since Spring 2004. Like the previous formulation, the improved product contains branched-chain amino acids (BCAAs) L-isoleucine (L-Ile), L-leucine (L-Leu), and L-valine (L-Val), but the average particle size of these amino acids has been increased to 180 to 250 microm in the improved formulation, compared with 40 to 90 microm in the old product. The improved formulation has a significantly lower bitterness intensity score than the older formulation, as evaluated both in human gustatory tests and using the artificial taste sensor. We propose that this improved taste masking is due to the larger particle size of the BCAA crystals, due to which their release rates are reduced. The addition of improved flavours has also helped to reduce the bitterness of the improved Aminoleban EN formulation significantly. Analysis of the taste sensor data suggests that the sourness and sweetness of the added flavours were critical in diminishing the bitterness of Aminoleban EN.


Canine oral lesions: a decision-tree approach to ulcers, leukoplakia, and pigmented lesions.
Lesions in the oral cavity of dogs can be erythematous, leukoplakic, or pigmented in coloration. The diagnosis of oral erosions, ulcers, and white lesions in contrast to pigmented lesions in veterinary practice can be challenging. The most benign-looking oral ulcers can be associated with local malignant or systemic disease. Many factors are important in the evaluation and correct diagnosis of oral lesions, including medical and drug history, description of the lesion, number of lesions, depth of the lesion, biopsy technique, and correct histologic interpretation. The goal of this paper is to create a decision tree to guide the classification and proper diagnosis of canine oral mucosal lesions.


Cross-sectional observational assessment of quality of newborn care immediately after birth in health facilities across six sub-Saharan African countries.
To present information on the quality of newborn care services and health facility readiness to provide newborn care in 6 African countries, and to advocate for the improvement of providers' essential newborn care knowledge and skills. Cross-sectional observational health facility assessment. Ethiopia, Kenya, Madagascar, Mozambique, Rwanda and Tanzania. Health workers in 643 facilities. 1016 health workers were interviewed, and 2377 babies were observed in the facilities surveyed. Indicators of quality of newborn care included (1) provision of immediate essential newborn care: thermal care, hygienic cord care, and early and exclusive initiation of breast feeding; (2) actual and simulated resuscitation of asphyxiated newborn infants; and (3) knowledge of health workers on essential newborn care, including resuscitation. Sterile or clean cord cutting instruments, suction devices, and tables or firm surfaces for resuscitation were commonly available. 80% of newborns were immediately dried after birth and received clean cord care in most of the studied facilities. In all countries assessed, major deficiencies exist for essential newborn care supplies and equipment, as well as for health worker knowledge and performance of key routine newborn care practices, particularly for immediate skin-to-skin contact and breastfeeding initiation. Of newborns who did not cry at birth, 89% either recovered on their own or through active steps taken by the provider through resuscitation with initial stimulation and/or ventilation. 11% of newborns died. Assessment of simulated resuscitation using a NeoNatalie anatomic model showed that less than a third of providers were able to demonstrate ventilation skills correctly. The findings shared in this paper call attention to the critical need to improve health facility readiness to provide quality newborn care services and to ensure that service providers have the necessary equipment, supplies, knowledge and skills that are critical to save newborn lives.


Stringent requirement for Ca2+ in the removal of Z-lines and alpha-actinin from isolated myofibrils by Ca2+-activated neutral proteinase.
Treatment of isolated myofibrils with Ca2+-activated neutral proteinase (CANP) results in specific removal of Z-line and of alpha-actinin. To investigate the ionic requirement for these processes, we measured Z-line removal by phase-contrast and interference microscopy and alpha-actinin removal by sodium dodecyl sulphate/polyacrylamide-gel electrophoretic analysis of myofibrillar proteins. The proteolytic digestion of native purified proteins was measured directly on polyacrylamide gels and by the fluorescamine technique. We found that the removal of Z-line and alpha-actinin as well as the release of proteolytic degradation products from isolated myofibrils by CANP occur only in the presence of Ca2+; Sr2+, Ba2+, Mn2+, Mg2+, Co2+ and Zn2+ are all ineffective. In contrast with this stringent requirement for Ca2+, the proteolytic activity of CANP measured with denatured casein, native and denatured haemoglobin, native actin and tropomyosin also occurs in the presence of other bivalent cations, in the following order: Ca2+ greater than Sr2+ greater than Ba2+. These data suggest that only Ca2+ can produce the conformational change in myofibrils that renders them susceptible to the action of CANP, whereas its proteolytic activity is stimulated by several bivalent ions.


A statistical approach to inverting the Born ratio.
We examine the problem of fluorescence molecular tomography using the normalized Born approximation, termed herein the Born ratio, from a statistical perspective. Experimentally verified noise models for received signals at the excitation and emission wavelengths are combined to generate a stochastic model for the Born ratio. This model is then utilized within a maximum likelihood framework to obtain an inverse solution based on a fixed point iteration. Results are presented for three experimental scenarios: phantom data with a homogeneous background, phantoms implanted within a small animal, and in vivo data using an exogenous probe.


A resin-modified glass ionomer restorative: three-year clinical results.
Resin modified glass ionomer (RMGI) restorative materials have gained popularity in recent years. Their use is most often indicated in Class III and Class V cavities in adults and in numerous applications in children. This popularity in use has taken place in the absence of scientific knowledge of the RMGI materials. Lacking are adequate clinical trials to validate the proposed indications. The purpose of this study was to examine a representative RMGI in cervical abrasions and root caries in adults. Patients were recalled up to three years to evaluate standard clinical criteria. Results found the RMGI to be inferior to conventional composite resin in similar applications. The most noted deficiencies were in color stability and anatomic form, or wear of the RMGI. The results of this prospective clinical trial would suggest a limited longevity for RMGI compared to traditional restorative materials. This study also reinforces the need for evidence of clinical performance prior to making decisions regarding material selections.


Evaluation of sham-CPAP as a placebo in CPAP intervention studies.
To evaluate the use of sham-continuous positive airway pressure (CPAP) treatment as a placebo intervention. Analysis of polysomnograms performed in fixed order without sham-CPAP and on the first night of the sham-CPAP intervention in participants in the CPAP Apnea Trial North American Program (CATNAP), a randomized, placebo controlled trial evaluating the effects of CPAP treatment on daytime function in adults with newly diagnosed mild to moderate obstructive sleep apnea (apnea hypopnea index (AHI) 5-30). The first 104 CATNAP participants randomized to the sham-CPAP intervention arm. Compared to the polysomnographic measures without sham-CPAP, the study on the first night with sham-CPAP had statistically significant differences that suggested a decrease in sleep quality: decreased sleep efficiency, increased arousal index, increased time in stage 1 NREM sleep, and prolonged latency to REM sleep. However, all of these differences had a relatively small effect size. Compared to the polysomnogram without sham-CPAP, the number of hypopneas on the sham-CPAP polysomnogram was significantly increased and the number of apneas significantly decreased. Relatively minor differences in AHI with and without sham-CPAP were present and were dependent on the criteria used to score hypopneas. Comparison of polysomnograms with and without sham-CPAP revealed differences that, although statistically significant, were small in magnitude and had relatively low effect sizes suggesting minimal clinical significance. The results support the use of sham-CPAP as a placebo intervention in trials evaluating the effects of CPAP treatment in patients with obstructive sleep apnea. This paper was a secondary analysis of clinical trial data. CATNAP: CPAP Apnea Trial North American Program, the trial from which the data were obtained, is registered with clinicaltrial.gov. Registration #NCT00089752.


Developmental trajectories of childhood symptoms of hyperactivity/inattention and suicidal behavior during adolescence.
Hyperactive/inattentive symptoms (ADHD symptoms) are associated with suicidal behavior in clinical studies, but there is still a lack of population-based longitudinal investigations on the developmental aspects of this association. Additionally, it is unclear whether the association is similar for boys and girls. The objectives of the study were to test the association between the ADHD symptoms during childhood and suicidal ideation and attempt during adolescence, and to investigate sex differences. 1407 children from the Québec Longitudinal Study of Child Development were followed up from 5 months to 17 years of age. We used teacher-reports of ADHD symptoms from 6 to 12 years, and self-report of suicidal ideation and attempt at 13, 15, and 17 years. We identified three ADHD symptoms trajectories: low (boys: 32.2%, girls: 48.7%), moderate (boys: 44.6%; girls: 42.2%) and high (boys: 23.2%; girls: 9.1%). Compared to boys on a low trajectory, boys on a moderate trajectory were at higher risk for suicidal ideation (OR 4.2, 95% CI 1.2-14.8), and boys on a high trajectory were at higher risk for suicide attempts (OR 4.5, 95% CI 1.1-17.9). Girls on moderate or high ADHD symptoms trajectories were not at higher risk for suicidal ideation or attempts than girls on low trajectories. For boys, but not for girls, moderate-to-high ADHD symptoms increased the suicidal risk in adolescence. Interventions with boys showing ADHD symptoms should include a suicide prevention component.


The effect of elevated intraocular oxygen on organelle degradation in the embryonic chicken lens.
In the vertebrate lens, nuclei and other cytoplasmic organelles are degraded in fiber cells situated in the center of the tissue. This is believed to ensure the transparency of the tissue. The mechanism that triggers this process is unknown. We hypothesized that standing gradients of oxygen generated within the tissue may serve as a spatial cue for organelle degradation. To examine this possibility, we incubated fertilized chicken eggs under hyperoxic (50% O(2)) or normoxic (21% O(2)) conditions. Hyperoxic treatment was initiated on the seventh day of embryonic development (E7), five days before organelle degradation normally commences in the lens core. Hyperoxia was maintained until E17. Under normoxic conditions, the partial pressure of oxygen (P(O)) within the vitreous compartment was low. Direct measurement of P(O) using an optode oxygen sensor indicated values of 1.3 kPa and 0.4 kPa for the mid- and anterior vitreous, respectively. Similarly, treatment with pimonidazole, a bio-reductive hypoxia marker, led to the formation of immuno-positive protein adducts within the lens, suggesting that the embryonic lens is chronically hypoxic in situ. Following hyperoxic treatment, vitreous P(O) significantly increased, although pimonidazole staining in the lens was not markedly affected. Confocal microscopy of slices prepared from hyperoxic lenses revealed a significant increase in the size of the lens relative to age-matched normoxic controls. By E13, an organelle-free zone (OFZ) was present in the center of normoxic and hyperoxic lenses. However, in hyperoxic lenses, the OFZ was consistently smaller, and the distance from the lens surface to the border of the OFZ significantly larger, than in normoxic controls. These observations suggest that hyperoxia delays organelle breakdown and are consistent with a model in which hypoxia in the deep cortical layers of the normal lens serves as a trigger for the organelle loss process.


miRNA-200c and miRNA-141 as potential prognostic biomarkers and regulators of epithelial-mesenchymal transition in eyelid sebaceous gland carcinoma.
MicroRNA (miRNA)-200c and miRNA-141 are tumour suppressors, which regulate epithelial-mesenchymal transition (EMT), leading to tumour invasion and metastasis in various malignancies. miRNA-200c and miRNA-141 maintain the epithelial phenotype by post-transcriptionally inhibiting the E-cadherin repressors, zinc finger E-box binding homeobox (ZEB)1 and ZEB2. The present study was performed to determine the prognostic significance of miRNA-200c and miRNA-141, and their association with EMT markers ZEB1, ZEB2 and E-cadherin in eyelid sebaceous gland carcinoma (SGC). Expression levels of miRNA-200c and miRNA-141 were determined in 42 eyelid SGC cases by quantitative real-time PCR (qPCR). Their association with ZEB1, ZEB2 and E-cadherin was determined by qPCR and immunohistochemistry. Kaplan-Meier plots and Spearman's rank correlation tests were applied to analyse the data. Patients were followed up for 7-44 months. Low expression levels of miRNA-200c and miRNA-141 were seen in 36/42 (86%) and 28/42 (67%) cases, respectively. Low miRNA-200c correlated significantly with large tumour size (p=0.03) and poor differentiation (p=0.03). Low miRNA-141 correlated significantly with large tumour size (p=0.02) and lymph node metastasis (p=0.04). Survival analysis revealed that patients with low miRNA-200c (p<0.05) and miRNA-141 expression (p=0.07) had shorter disease-free survival. There was a significant association of both miRNA-200c and miRNA-141 with E-cadherin and ZEB2 expression. Low levels of miRNA-200c and miRNA-141 in patients with eyelid SGC facilitates tumour progression by promoting EMT and miRNA-200c has emerged as a novel potential predictor of survival.


Ursolic acid from Oldenlandia diffusa induces apoptosis via activation of caspases and phosphorylation of glycogen synthase kinase 3 beta in SK-OV-3 ovarian cancer cells.
Although ursolic acid isolated from Oldenlandia diffusa (Rubiaceae) was known to have anticancer activities in prostate, breast and liver cancers, the underlying mechanism of ursolic acid in ovarian cancer cells was not investigated so far. In the present study, the apoptotic mechanism of ursolic acid was elucidated in SK-OV-3 ovarian cancer cells by 2,3-bis(2-methoxy-4-nitro-5-sulphophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay, cell cycle analysis and Western blotting. Ursolic acid exerted cytotoxicity against SK-OV-3 and A2780 ovarian cancer cells with IC₅₀ of ca. 50 and 65 µM, respectively. Apoptotic bodies were observed in ursolic acid treated SK-OV-3 cells. Also, ursolic acid significantly increased ethidium homodimer stained cells and sub-G1 apoptotic portion in SK-OV-3 cells. Consistently, Western blotting revealed that ursolic acid effectively cleaved poly(ADP-ribose) polymerase (PARP), caspase-9 and -3, suppressed the expression of survival genes such as c-Myc, Bcl-x(L) and astrocyte elevated gene (AEG)-1, and upregulated phosphorylation of extracellular signal-regulated kinase (ERK) in SK-OV-3 cells. Interestingly, ursolic acid suppressed β-catenin degradation as well as enhanced phosphorylation of glycogen synthase kinase 3 beta (GSK 3β). Furthermore, GSK 3β inhibitor SB216763 blocked the cleavages of caspase-3 and PARP induced by ursolic acid and proteosomal inhibitor MG132 disturbed down-regulation of β-catenin, activation of caspase-3 and decreased mitochondrial membrane potential (MMP) induced by ursolic acid in SK-OV-3 cells. Overall, our findings suggest that ursolic acid induces apoptosis via activation of caspase and phosphorylation of GSK 3β in SK-OV-3 cancer cells as a potent anti-cancer agent for ovarian cancer therapy.


An experimental model of focal ischemia using an internal carotid artery approach.
Animal models of cerebral ischemia represent an important contribution to both our understanding of stroke mechanism and the development of new therapies. The technique of MCAO (middle cerebral artery occlusion) via ECA (external carotid artery) occlusion is widely utilized. Disruption of the ECA and its branches leads to impaired mastication and oral intake, post-surgical body weight loss, and poor neurological recovery which can possibly confound one's interpretation of rats' neurological outcome. Here, we developed a novel modified technique for MCAO without ligation or coagulation of the ECA and its branches using an approach via the internal carotid artery (ICA). In our modified technique, we perform an additional fixation of the filament in the ICA which improves the stability of the model and increases the homogeneity in stroke size. Compared with the original MCAO technique via the ECA, our modified technique via the ICA demonstrated decreased variability in the percent infarcted volume and brain edema, as well as a decreased mortality. Additionally, we observed that with our modified technique, rats gained more weight after surgery and there was less initial weight loss after the surgical preparation. Our new approach may serve as an effective model for stroke, and may lead to a better understanding of stoke pathophysiology and to the future development of new drugs and other neuroprotective agents.


Carcinoma of the gallbladder and anomalous arrangement of the pancreaticobiliary ductal system: cell kinetic studies of gallbladder epithelial cells.
Anomalous arrangement of the pancreaticobiliary ductal system (AAPB), a congenital anomaly defined as a union of the pancreatic and biliary ducts located outside the duodenal wall, is a newly designated disease entity, and is frequently found in adult patients with gallbladder carcinoma (GBX). In the present study, the relationship of AAPB and GBX was investigated. We studied 27 patients with GBX and AAPB, 34 patients with AAPB and without GBX, and as a control group, 56 patients without AAPB (10 with GBX, 24 with cholecystolithiasis, and 22 with normal gallbladder). Tissue sections from cancerous and non-cancerous mucosa of the gallbladder of all of these patients were stained for proliferating cell nuclear antigen (PCNA), Ki-67 nuclear antigen, and bromodeoxyuridine (BrdU). The Ki-67 labeling index (Ki-67-LI), PCNA labeling index (PCNA-LI), and BrdU labeling index (BrdU-LI) of the noncancerous mucosa in the patients with AAPB and/or GBX were significantly higher than those in the patients without GBX and AAPB (P < 0.01). These indices of the noncancerous mucosa in the patients with AAPB and GBX were significantly higher than those in the patients with either AAPB or GBX (P < 0.05). Cell proliferation in the gallbladder epithelia was accelerated in patients with AAPB. Consequently, AAPB appears to be an important risk factor for the occurrence of GBX.


Negatively calcium-modulated membrane guanylate cyclase signaling system in the rat olfactory bulb.
The mechanism by which the individual odor signals are translated into the perception of smell in the brain is unknown. The signal processing occurs in the olfactory system which has three major components: olfactory neuroepithelium, olfactory bulb, and olfactory cortex. The neuroepithelial layer is composed of ciliated sensory neurons interspersed among supportive cells. The sensory neurons are the sites of odor transduction, a process that converts the odor signal into an electrical signal. The electrical signal is subsequently received by the neurons of the olfactory bulb, which process the signal and then relay it to the olfactory cortex in the brain. Apart from information about certain biochemical steps of odor transduction, there is almost no knowledge about the means by which the olfactory bulb and cortical neurons process this information. Through biochemical, functional, and immunohistochemical approaches, this study shows the presence of a Ca(2+)-modulated membrane guanylate cyclase (mGC) transduction system in the bulb portion of the olfactory system. The mGC is ROS-GC1. This is coexpressed with its specific modulator, guanylate cyclase activating protein type 1 (GCAP1), in the mitral cells. Thus, a new facet of the Ca(2+)-modulated GCAP1--ROS-GC1 signaling system, which, until now, was believed to be unique to phototransduction, has been revealed. The findings suggest a novel role for this system in the polarization and depolarization phenomena of mitral cells and also contradict the existing belief that no mGC besides GC-D exists in the olfactory neurons.


Constructing the major biosynthesis pathways for amino acids in the brown planthopper, Nilaparvata lugens Stål (Hemiptera: Delphacidae), based on the transcriptome data.
Nilaparvata lugens is a serious phloem-feeding pest of rice throughout Asia. Rice phloem sap can meet its nutrition requirement for sugars but not for some essential amino acids such as isoleucine, leucine, methionine, phenylalanine, tryptophan, lysine, arginine and histidine. N. lugens harbours yeast-like symbionts in mycetocytes formed by abdominal fat body cells. Removal of the symbionts results in negative physiological effects, suggesting that the symbionts play a pivotal role in the nitrogen metabolism. In the present paper, 521 mRNA expressed sequence tags (ESTs) encoding 126 enzymes that were involved in amino acid biosynthesis were identified based on a transcriptome data, reverse transcription (RT)-PCR and rapid amplification of cDNA ends. Similarity analysis, codon usage bias, along with tissue-biased expression and phylogenetic analysis of a subset of ESTs, suggest that 437 ESTs out of the 521 originate from symbionts, and the remaining 84 mRNA fragments come from N. lugens. Accordingly, the biosynthesis pathways for 20 amino acids were manually constructed. It is postulated that both N. lugens and its symbiont can independently assimilate ammonia and biosynthesize seven non-essential amino acids: glutamate; glutamine; aspartate; asparagine; alanine; serine; and glycine. N. lugens and symbiont enzymes may work collaboratively to catalyse the biosynthesis of proline, methionine, valine, leucine, isoleucine, phenylalanine and tyrosine. We infer from this that symbionts function in the biosynthesis of lysine, arginine, tryptophan, threonine, histidine and cysteine. Our data support the previously proposed hypothesis, i.e. the yeast-like symbionts compensate for, at least partially, the amino acid needs of N. lugens.


Physical medicine modalities for mechanical neck disorders.
Multiple physical medicine modalities are commonly included as part of therapeutic interventions for mechanical neck disorders (neck pain). The objective of this review was to assess the effects of physical medicine modalities for pain in adults with mechanical neck disorders. We searched Medline, Embase, Chirolars, Index to Chiropractic Literature, Cinahl, Science Citation Index, Conference Proceedings Index, National Technical Information Services and reference lists of the retrieved articles from 1985 to December 1993 and we contacted content experts. Randomised trials and controlled trials of physical medicine modalities in adults with mechanical neck disorder. Three reviewers independently assessed trial quality and two reviewers independently extracted data. Investigators were contacted to obtain information or data that could not be found in the published reports. Thirteen trials were included. The overall quality of the included trials was generally good. Two trials using electromagnetic therapy produced a significant reduction in pain (p <0.01) with three to four weeks of daily (eight hours per day) therapy sessions; and three using laser therapy did not differ significantly from a placebo (p=0.20) for six to 10 sessions of treatment. Not enough scientific testing exists to clearly determine the effectiveness of other therapies. This includes treatments such as exercise, traction, acupuncture, heat / cold applications, electrotherapies, cervical orthoses and chronic pain / cognitive behavioural rehabilitation strategies. There is little information available from trials to support the use of physical medicine modalities for mechanical neck pain. There is some support for the use of electromagnetic therapy and against the use of laser therapy with respect to pain reduction.


Blue-yellow deficiency in workers exposed to low concentrations of organic solvents.
To evaluate the effects of low concentrations of organic solvents on color vision. Color vision was examined in 24 workers exposed to mixtures of solvents and in 24 control subjects. Exposure to mixtures was below the threshold-limit values. Color vision ability was assessed using the Ishihara plates (to screen for congenital dyschromatopsia), the Farnsworth panel D-15 test, the Lanthony desaturated panel D-15 test, and the Standard Pseudoisochromatic Plates part 2 (SPP2 test). The comparatively less sensitive Farnsworth panel D-15 test failed to show any difference between the groups, but the Lanthony panel D-15 desaturated test as well as the SPP2 test showed a significant impairment in the exposed group. Errors were of the blue-yellow type. This study gives further evidence that even mixtures of organic solvents at concentrations below the threshold-limit values may impair color vision.


The tandemly repeated sequences of cartilage link protein contain the sites for interaction with hyaluronic acid.
The ternary complex involving link protein (LP), proteoglycan monomer, and hyaluronic acid (HA) is an important component of the extracellular matrix of cartilage. LP contains tandemly repeated sequences that were tested for their ability to interact with HA. A solid-phase assay was developed in which LP could specifically bind to immobilized HA. Detection of LP was by means of an antiserum directed against a peptide from the NH2-terminal half of LP. LP binding to HA could be inhibited with mAb 8A4 (Caterson, B., J. R. Baker, J. E. Christner, Y. Lee, and M. Lentz. 1985. J. Biol. Chem. 260:11348-11356). Using synthetic peptides that correspond to specific amino acid sequences of chicken LP (Deák, F., I. Kiss, K. J. Sparks, W. S. Argraves, G. Hampikian, and P. F. Goetinck. 1986. Proc. Natl. Acad. Sci. USA. 83:3766-3770) the epitopes for mAb 8A4 were determined to reside in peptides Gly217-Pro226 and Arg316-Arg325. These two peptides were also capable of inhibiting the interaction between LP and HA. The peptide Trp242-Val251 and Pro339-Val348 could also inhibit the interaction between LP and HA. All four peptides reside in the tandemly repeated domains of LP and they contain clusters of positively charged amino acids. Polylysine could not inhibit the interaction of LP with HA. The results indicate that the sites for interaction with HA are in the tandemly repeated sequences of LP and that there are four potential sites available for that interaction.


Indications and uses of the noninvasive vascular laboratory: extremity or visceral arterial evaluation.
The tests in the noninvasive vascular laboratory are highly accurate for assessing the patient with extremity or visceral artery disease. Once the location and severity of any arterial disease in patients with claudication or critical limb ischemia (ie, gangrene, ulceration, rest pain) is determined by the noninvasive tests, a treatment plan can be developed and then discussed with the patient, with consent obtained prior to any invasive procedure. The presence of hypertension from renal artery stenosis, or chronic mesenteric ischemia from visceral artery stenosis, can be evaluated by duplex scanning, without the need for invasive contrast angiography. Monitoring the function of revascularization procedures, such as angioplasty or bypass grafts, is also possible and significantly improves long-term patency and organ or limb salvage by identifying the need for elective revision of failing reconstructions prior to thrombosis. Noninvasive vascular laboratory tests are the initial procedures of choice for the evaluation of patients with extremity or visceral arterial disease.


Increasing hybridization rate and sensitivity of DNA microarrays using isotachophoresis.
We present an on-chip electrokinetic method to increase the reaction kinetics and sensitivity of DNA microarray hybridization. We use isotachophoresis (ITP) to preconcentrate target molecules in solution and transport them over the immobilized probe sites of a microarray, greatly increasing the binding reaction rate. We show theoretically and experimentally that ITP-enhanced microarrays can be hybridized much faster and with higher sensitivity than conventional methods. We demonstrate our assay using a microfluidic system consisting of a PDMS microchannel superstructure bonded onto a glass slide on which 60 spots of 20-27 nt ssDNA oligonucleotide probes are immobilized. Our 30 min assay results in an 8.2 fold higher signal than the conventional overnight hybridization at 100 fM target concentration. We show rapid and quantitative detection over 4 orders of magnitude dynamic range of target concentration with no increase in the nonspecific signal. Our technique can be further multiplexed for higher density microarrays and extended for other reactions of target-surface immobilized ligands.


Performance comparison of structured [Formula: see text] based looptune and LQR for a 4-DOF robotic manipulator.
We explore looptune, a MATLAB-based structured [Formula: see text] synthesis technique in the context of robotics. Position control of a 4 Degree of Freedom (DOF) serial robotic manipulator developed using Simulink is the problem under consideration. Three full state feedback control systems were developed, analyzed and compared for both steady-state and transient performance using the Linear Quadratic Regulator (LQR) and looptune. Initially, a single gain feedback controller was synthesized using LQR. This system was then modified by augmenting the state feedback controller with Proportional Integral (PI) and Integral regulators, thereby creating a second and third control system respectively. In both the second and third control systems, the LQR synthesized gain and additional gains were further tuned using looptune to achieve improvement in performance. The second and third systems were also compared in terms of tracking a time-dependent trajectory. Finally, the LQR and looptune synthesized controllers were tested for robustness by simultaneously increasing the mass of each manipulator link. In comparison to LQR, the second system consisting of Single Input Single Output (SISO) PI controllers and the state feedback matrix succeeded in meeting the control objectives in terms of performance, optimality, trajectory tracking, and robustness. The third system did not improve performance in contrast to LQR, but still showed robustness under mass variation. In conclusion, our results have shown looptune to have a comparatively better performance over LQR thereby highlighting its promising potential for future emerging control system applications.


[Typology of incarcerated intimate partner aggressors].
Typology of incarcerated intimate partner aggressors. People who engage in intimate partner violence do not constitute a homogeneous group. Many studies in the Anglo-Saxon countries back the possibility of differentiating several subtypes of aggressors, but there are differences among them. One of the main applications of these typologies is the adaptation of the treatments to the subjects' characteristics. The aim of the present pilot study was to empirically establish a typology of batterers in Spain. The sample of 50 convicted violent intimate partner offenders was obtained from the Brians-2 penitentiary (Barcelona). Self-esteem, anger, cognitive distortions, and personality disorders were evaluated, as well as the frequency and type of violence. The results suggest the existence of two subtypes, distinguishable on the basis of the predictive dimensions, and so, partially confirm the typological proposals.


Are Circulating Mg2+ Levels Associated with Glucose Tolerance Profiles and Incident Type 2 Diabetes?
Magnesium (Mg2+) is an enzyme co-factor that plays a key role in many biochemical reactions, as well as in glucose metabolism. Clinical evidences have demonstrated that depletion of serum Mg2+ increases exponentially with the duration of type 2 diabetes mellitus (T2DM). Diabetes is associated with low Mg2+, and hypomagnesemia is associated with insulin resistance, inflammation, and increased risk for cardiovascular disease. In subjects at high risk of inflammation and insulin resistance, supplementation of Mg2+ alone ameliorates both phenotypes, slowing the development and progression of hepatic steatosis. We analyze the relationship between serum Mg2+ levels and the onset of T2DM in a large cohort of well-characterized adult white individuals participating in the CATAMERI study, who were reexamined after a mean follow-up of 5.6 ± 0.9 years. In our analysis we acquired a significant negative correlation between Mg2+ levels, fasting glucose, and 2h-post load glucose in subjects who underwent an OGTT. Moreover, Mg2+ levels correlated negatively with fasting insulin levels, and positively with the lipid profile. As for the detrimental effect of lower circulating Mg2+ levels, our data revealed a significant reduction of T2DM risk of about 20% for each 1 mg/dL increase of circulating Mg2+. The present results are consistent with the theory that Mg2+ supplementation could ameliorate insulin sensitivity reducing the risk to develop T2DM.


Association of type 3 protein kinase C with focal contacts in rat embryo fibroblasts.
We have used immunocytofluorescence techniques to determine the subcellular distribution of the Ca2+, phospholipid-dependent protein kinase, protein kinase C (PKC). Using monoclonal antibodies that are specific for Type 3 (alpha) PKC, we have determined that there are least two pools of PKC in normal rat embryo fibroblasts (REF52 cells): diffuse cytoplasmic and fiber-associated. Extraction with chelators and detergent before fixing and staining removes the cytoplasmic PKC. The fiber-associated staining remains in these cytoskeleton preparations. The cytoskeleton Type 3 PKC staining closely resembles that of the focal contact protein vinculin and colocalizes with another focal contact protein, talin. Cytochalasin, but not colchicine, coordinately disrupts the staining pattern of vinculin and PKC. Activation of PKC by treatment with phorbol esters causes depolymerization of microfilaments and reorganization of vinculin staining. We propose that Type 3 PKC is a modulatory component of the focal contact and has a primary role in regulation of the association of microfilament bundles with the plasma membrane.


Ins1-Cre and Ins1-CreER Gene Replacement Alleles Are Susceptible To Silencing By DNA Hypermethylation.
Targeted gene ablation studies of the endocrine pancreas have long suffered from suboptimal Cre deleter strains. In many cases, Cre lines purportedly specific for beta cells also displayed expression in other islet endocrine cells or in a subset of neurons in the brain. Several pancreas and endocrine Cre lines have experienced silencing or mosaicism over time. In addition, many Cre transgenic constructs were designed to include the hGH mini-gene, which by itself increases beta-cell replication and decreases beta-cell function. More recently, driver lines with Cre or CreER inserted into the Ins1 locus were generated, with the intent of producing β cell-specific Cre lines with faithful recapitulation of insulin expression. These lines were bred in multiple labs to several different mouse lines harboring various lox alleles. In our hands, the ability of the Ins1-Cre and Ins1-CreER lines to delete target genes varied from that originally reported, with both alleles displaying low levels of expression, increased levels of methylation compared to the wild-type allele, and ultimately inefficient or absent target deletion. Thus, caution is warranted in the interpretation of results obtained with these genetic tools, and Cre expression and activity should be monitored regularly when using these lines.


Mild cognitive impairment: searching for the prodrome of Alzheimer's disease.
The concept of mild cognitive impairment (MCI) identifies persons who are neither cognitively normal nor demented. There is increasing evidence that MCI defines a group of persons who are at near-term risk of developing dementia and particularly Alzheimer's disease (AD). MCI thus constitutes an attractive target population for preventive treatments of AD. MCI is associated with aging and is more prevalent than dementia. There are several clinical and biological markers that are predictive of MCI prognosis, including depressive symptoms, cognitive deficits, brain imaging and neurochemical findings. The clinician needs to be especially alert to depressive and other mood symptoms which are common in MCI and potentially treatable. Trials of current medications for prevention of MCI progression to dementia have been largely negative. There are observational data suggesting that lifestyle modifications including exercise, leisure activities, cognitive stimulation, and social activities may be effective for prevention of MCI progression. There are many novel therapies currently in trials for early AD, and if effective they may prove to be helpful in prevention of MCI progression as well.


Pelvic lymph node dissection during radical cystectomy for muscle-invasive bladder cancer.
Radical cystectomy is the gold-standard treatment option for muscle-invasive and metastatic bladder cancer. At the time of cystectomy, up to 25% of patients harbour metastatic lymph node deposits. These deposits most frequently occur in the obturator fossa, but can be as proximal as the interaortocaval region. Thus, the use of concurrent pelvic lymph node dissection (PLND) with cystectomy has been increasingly reported. Data from studies including many patients suggest substantial oncological benefit in PLND cohorts versus non-PLND cohorts, irrespective of pathological nodal status. Additionally, PLND provides useful prognostic information, including disease burden, lymph node density, and extracapsular extension of metastatic lymph nodes. Accordingly, the National Comprehensive Cancer Network guidelines advocate the use of PLND during radical cystectomy for muscle-invasive bladder cancer. Despite this recommendation, a lack of consensus exists regarding the optimal PLND template. Comparative series suggest that extended PLND provides improved recurrence-free survival and cancer-specific survival compared with more limited PLND templates. More extensive templates (such as super-extended PLND) provide no additional survival benefit at the potential cost of increased operative time and patient morbidity. In addition to extended PLND templates, increased nodal harvest confers an oncological benefit in patients with node-positive disease or in patients with node-negative disease. Accordingly, recommendations for a minimum nodal yield have been proposed. Despite the growing body of evidence, formal recommendations by oncological and urological authoritative bodies have been limited owing to the lack of randomized data and level I evidence.


Defective Aspergillus killing by neutrophil leucocytes in a case of systemic aspergillosis.
A persistent defect of Aspergillus killing was observed in the neutrophils of a 6-year-old patient with a systemic A. fumigatus infection which was highly refractory to anti-mycotic therapy. Aspergillus phagocytosis in vitro was normal, but nearly 80% of the ingested organisms (versus 30% in the controls) survived intracellularly during the 2-hr assay period. The patient's neutrophils showed a subnormal frequency of nitroblue tetrazolium reduction and a subnormal hexose monophosphate shunt activation in response to phagocytosis. The metabolic responsiveness, however, was clearly superior to that of chronic granulomatous disease neutrophils tested for comparison. The immune status of the patient and the following properties of his neutrophils were found to be normal: random and chemotactic motility, killing of S. aureus and C. albicans, and the contents of several granula enzymes. Our findings suggest the existence of neutrophil factors or functions which are required for killing Aspergillus, but not S. aureus and C. albicans.


The light-harvesting chlorophyll a/b protein acts as a torque aligning chloroplasts in a magnetic field.
Displacement of particles from the purified light-harvesting chlorophyll a/b protein aggregate (LHC) was studied in magnetic fields of various strengths (0 to 1.6 T) by polarized fluorescence measurements. Macromolecular aggregates of LHC have a considerable magnetic susceptibility which enables the particles to rotate and align with their nematic axes parallel with H. As LHC is embedded in a transmembrane direction thylakoids should align perpendicular to H, the mode of alignment experimentally observed in thylakoids. The value of the magnetic susceptibility could be estimated by relating it to the integral susceptibility of the chlorophyll molecules in LHC. The fitting of this value with the field strength dependency of the fluorescence polarization ratio (FP) revealed a relationship between the LHC content of various photosynthetic membranes and their capacity for alignment, which suggested that LHC might be the torque ordering chloroplasts in a magnetic field.


Temperature-induced droplet coalescence in microchannels.
This paper reports a technique for temperature-induced merging of droplets in a microchannel. The multiphase system consists of water droplet and oil as the dispersed phase and the carrying continuous phase. A resistive heater provides heating in a rectangular merging chamber. The temperature of the chamber is controlled by the voltage applied to the heater. The merging process of two neighboring droplets was investigated with different applied voltage, flow rate ratio between water and oil and total flowrate. Merging is found to be effective at high flow rate ratio, high temperature, and low total flowrate. The presented technique could be used for merging and mixing in droplet-based lab-on-a-chip platforms.


Validation and perception of a key feature problem examination in neurology.
To validate a newly-developed Key Feature Problem Examination (KFPE) in neurology, and to examine how it is perceived by students. We have developed a formative KFPE containing 12 key feature problems and 44 key feature items. The key feature problems covered four typical clinical situations. The items were presented in short- and long-menu question formats. Third- and fourth-year medical students undergoing the Neurology Course at our department participated in this study. The students' perception of the KFPE was assessed via a questionnaire. Students also had to pass a summative multiple-choice question examination (MCQE) containing 39 Type-A questions. All key feature and multiple-choice questions were classified using a modified Bloom's taxonomy. The results from 81 KFPE participants were analyzed. The average score was 6.7/12 points. Cronbach's alpha for the 12 key-feature problems was 0.53. Item difficulty level scores were between 0.39 and 0.77, and item-total correlations between 0.05 and 0.36. Thirty-two key feature items of the KFPE were categorized as testers of comprehension, application and problem-solving, and 12 questions as testers of knowledge (MCQE: 15 comprehension and 24 knowledge, respectively). Overall correlations between the KFPE and the MCQE were intermediate. The KFPE was perceived well by the students. Adherence to previously-established principles enables the creation of a valid KFPE in the field of Neurology.


Using Autobiography a Pedagogical tool in Pharmacology: Traversing the Un-explored.
This article was migrated. The article was marked as recommended. In today's era, medical teaching is becoming increasingly complex and challenging. Out of all subjects in the medical curriculum, Pharmacology is one of the major disciplines undergoing constant development and advancement. A strong foundation of pharmacological knowledge is needed to help students improve upon their understanding and thereby manage clinical conditions in a more effective manner. Unfortunately, Pharmacology is perceived as a dry and volatile subject by medical students. This calls for a need to explore various pedagogical tools at medical schools, so as to best identify methods effective for active learning. Efforts need to be directed towards the objective of making Pharmacology teaching interesting and learner-centered by formulating creative and innovative teaching-learning modules in and outside the classrooms. Learner-centered teaching can foster students' interest in the subject and contribute to knowledge acquisition as well as future application. In context to this, the current piece explores and addresses the application of "Autobiography of drugs" as one of the pedagogical tools in the subject of Pharmacology.


A Turkish patient with large 17p11.2 deletion presenting with Smith Magenis syndrome.
Smith-Magenis syndrome (SMS), which occurs as a result of an interstitial deletion within chromosome 17p11.2-p12, is a disorder that presents itself with minor dysmorphic features, brachydactyly, short stature, hypotonia, delayed speech, cognitive deficits and neurobehavioral problems including sleep disturbances and maladaptive repetitive and self-injurious behavior. We present a girl with full SMS phenotype. G-banding cytogenetic analysis showed normal 46,XX karyotype. Whole-genome array comparative genomic hybridization (CGH) was performed due to the severity of the phenotype and the unusual features present in the patient. An interstitial deletion in 17p11.2-p12, approximately 4.73 Mb in size was determined. Characteristic physical and behavioral phenotype strongly suggested SMS. This, to the best of our knowledge is the first patient with SMS reported in Turkey. We emphasize the need for whole genome analysis in multiple congenital abnormalities/mental retardation disorders with unusual and severe phenotypes.


Using logistic regression to improve the prognostic value of microarray gene expression data sets: application to early-stage squamous cell carcinoma of the lung and triple negative breast carcinoma.
Numerous microarray-based prognostic gene expression signatures of primary neoplasms have been published but often with little concurrence between studies, thus limiting their clinical utility. We describe a methodology using logistic regression, which circumvents limitations of conventional Kaplan Meier analysis. We applied this approach to a thrice-analyzed and published squamous cell carcinoma (SQCC) of the lung data set, with the objective of identifying gene expressions predictive of early death versus long survival in early-stage disease. A similar analysis was applied to a data set of triple negative breast carcinoma cases, which present similar clinical challenges. Important to our approach is the selection of homogenous patient groups for comparison. In the lung study, we selected two groups (including only stages I and II), equal in size, of earliest deaths and longest survivors. Genes varying at least four-fold were tested by logistic regression for accuracy of prediction (area under a ROC plot). The gene list was refined by applying two sliding-window analyses and by validations using a leave-one-out approach and model building with validation subsets. In the breast study, a similar logistic regression analysis was used after selecting appropriate cases for comparison. A total of 8594 variable genes were tested for accuracy in predicting earliest deaths versus longest survivors in SQCC. After applying the two sliding window and the leave-one-out analyses, 24 prognostic genes were identified; most of them were B-cell related. When the same data set of stage I and II cases was analyzed using a conventional Kaplan Meier (KM) approach, we identified fewer immune-related genes among the most statistically significant hits; when stage III cases were included, most of the prognostic genes were missed. Interestingly, logistic regression analysis of the breast cancer data set identified many immune-related genes predictive of clinical outcome. Stratification of cases based on clinical data, careful selection of two groups for comparison, and the application of logistic regression analysis substantially improved predictive accuracy in comparison to conventional KM approaches. B cell-related genes dominated the list of prognostic genes in early stage SQCC of the lung and triple negative breast cancer.


Pathogenesis of parathyroid hyperplasia in renal failure.
In chronic kidney disease, secondary hyperparathyroidism (HPTH) is characterized by parathyroid hyperplasia and enhanced synthesis and secretion of parathyroid hormone (PTH). Elevated PTH levels cause renal osteodistrophy and cardiovascular complications, with significantly increased morbidity and mortality in renal failure. The three main direct causes of renal HPTH are hypocalcemia, hyperphosphatemia and vitamin D deficiency. A link between the mechanisms controlling proliferation and hormonal production also exists in normal parathyroid cells which respond to the stimulus of chronic hypocalcemia, not only by an increase in PTH release but also with a consequent parathyroid cell proliferation. The mechanisms responsible for this link, however, remain poorly understood. In this review, we analyze the current understanding concerning the new insights into the molecular mechanisms of parathyroid hyperplasia and PTH secretion in renal failure regulated by calcium, phosphate and vitamin D.


mGluR5 in Astrocytes in the Ventromedial Hypothalamus Regulates Pituitary Adenylate Cyclase-Activating Polypeptide Neurons and Glucose Homeostasis.
The ventromedial hypothalamus (VMH) is a functionally heterogeneous nucleus critical for systemic energy, glucose, and lipid balance. We showed previously that the metabotropic glutamate receptor 5 (mGluR5) plays essential roles regulating excitatory and inhibitory transmission in SF1+ neurons of the VMH and facilitating glucose and lipid homeostasis in female mice. Although mGluR5 is also highly expressed in VMH astrocytes in the mature brain, its role there influencing central metabolic circuits is unknown. In contrast to the glucose intolerance observed only in female mice lacking mGluR5 in VMH SF1 neurons, selective depletion of mGluR5 in VMH astrocytes enhanced glucose tolerance without affecting food intake or body weight in both adult female and male mice. The improved glucose tolerance was associated with elevated glucose-stimulated insulin release. Astrocytic mGluR5 male and female mutants also exhibited reduced adipocyte size and increased sympathetic tone in gonadal white adipose tissue. Diminished excitatory drive and synaptic inputs onto VMH Pituitary adenylate cyclase-activating polypeptide (PACAP+) neurons and reduced activity of these cells during acute hyperglycemia underlie the observed changes in glycemic control. These studies reveal an essential role of astrocytic mGluR5 in the VMH regulating the excitatory drive onto PACAP+ neurons and activity of these cells facilitating glucose homeostasis in male and female mice.SIGNIFICANCE STATEMENT Neuronal circuits within the VMH play chief roles in the regulation of whole-body metabolic homeostasis. It remains unclear how astrocytes influence neurotransmission in this region to facilitate energy and glucose balance control. Here, we explored the role of the metabotropic glutamate receptor, mGluR5, using a mouse model with selective depletion of mGluR5 from VMH astrocytes. We show that astrocytic mGluR5 critically regulates the excitatory drive and activity of PACAP-expressing neurons in the VMH to control glucose homeostasis in both female and male mice. Furthermore, mGluR5 in VMH astrocytes influences adipocyte size and sympathetic tone in white adipose tissue. These studies provide novel insight toward the importance of hypothalamic astrocytes participating in central circuits regulating peripheral metabolism.


Evaluating vaspin and adiponectin in postmenopausal women with endometrial cancer.
Insulin resistance is a well-documented risk factor for the development of endometrial cancer. Adiponectin and vaspin are insulin-sensitizing proteins that are secreted from adipose tissue. A clear association between serum levels of adipokines and endometrial cancer has yet to be established. The study group consisted of postmenopausal women with confirmed endometrial cancer, whereas patients with benign endometrial conditions constituted the control group. The two groups were compared in terms of insulin resistance and serum levels of adiponectin and vaspin. A total of 60 patients with confirmed endometrial cancer and 70 controls with benign endometrial conditions (polyps and atrophy) were enrolled. Median homeostasis model assessment of insulin resistance value was significantly higher in the study group compared with the control group (2.93 vs 1.27, P<0.0001), whereas mean quantitative insulin sensitivity check index value was significantly lower (0.33 ± 0.02 vs 0.37 ± 0.37, P<0.0001). Median values for both adiponectin and vaspin were significantly lower in patients with endometrial cancer compared with the control group (4.09 vs 17.13 μg/ml, P<0.0001 and 0.21 vs 0.39 ng/ml, P<0.0001 respectively). Low levels of both adiponectin and vaspin were found to be significantly associated with an increased risk for endometrial cancer. Following adjustment for confounding factors, the respective odds ratios for endometrial cancer in patients in the first tertile compared with those in the third tertile were 10.80 (2.76-42.24; P=0.001) and 13.23 (2.94-59.64; P=0.001). Our results show that lower levels of circulating adiponectin and vaspin levels are associated with an increased risk of developing endometrial cancer.


Transcatheter Edge-to-Edge Repair in Patients With End-Stage Renal Disease on Dialysis: A USRDS Registry Study.
Transcatheter edge-to-edge repair (TEER) of the mitral valve has become standard of care for the treatment of high-risk patients with severe mitral regurgitation. Patients with end stage renal disease (ESRD) on hemodialysis were either excluded or severely underrepresented in all seminal trials proving the safety and efficacy of TEER. There have been few studies that evaluated the effectiveness or complications of TEER in ESRD patients. Using the United States Renal Data System (USRDS), we identified all ESRD patients who underwent TEER from October 2015 to December 31, 2019. Major comorbidities were recorded and Kaplan-Meier curves were generated for survival and freedom from hospitalization or death. The study population included 965 patients, of which 576 (59.7%) were male. The median age at the time of TEER was 72.5 (IQR: 64.4-79.1) years. There were 130 (13.2%) patients with heart failure with reduced ejection fraction (HFrEF), 110 (11.2%) with heart failure with preserved ejection fraction (HFpEF) and 745 (74.6%) with an indeterminate ejection fraction. During follow-up, strokes occurred in 61 (6.3%) patients, infective endocarditis in 42 (4.4%) patients, mitral stenosis in 13 (1.3%) and valve embolism in less than 11 patients. One-year survival was 56.9%, and 2-year survival was 33.9%. In patients with ESRD undergoing TEER, only a preserved ejection fraction (HR: 0.70, 95% CI: 0.50-0.99, P = 0.041) was a significant predictor of survival in a cox proportional hazards model. Despite favorable in-hospital outcomes one-year mortality rates surpass those reported in broader patient cohorts. The increased incidence of infective endocarditis and mitral stenosis is likely related to increased risk intrinsic to those with ESRD.


Topical treatment of recurrent genital herpes simplex virus infections with trisodium phosphonoformate (foscarnet): double blind, placebo controlled, multicentre study.
A double blind, placebo controlled trial was performed in nine sexually transmitted diseases (STD) clinics in the United Kingdom and the Netherlands to investigate the efficacy of trisodium phosphonoformate (foscarnet) cream in treating recurrent genital herpes simplex virus (HSV) infection. The study group comprised 145 male and 85 female patients. Men received 0.3% foscarnet cream and women 1% foscarnet cream for five days. The difference in time to healing between patients receiving foscarnet or placebo was not significant. Fewer patients treated with foscarnet had positive viral cultures after treatment, but the difference was not significant. The development of new lesions, however, was significantly less common in patients given foscarnet. Though topical foscarnet is a safe drug, no appreciable efficacy in treating recurrent genital HSV infection could be shown.


Thermo-mechanical characterization of polypyrrole compliance using stochastic system identification.
Conducting polymers such as polypyrrole are studied as novel biologically inspired actuators. Their capacity to generate stresses of up to 5 MPa, strains of up to 10% at low voltages (2 V) make them ideal candidates to be used as artificial muscle materials. It has been shown that the modulus of polypyrrole can change when the material is electrochemically excited. In this paper we develop a technique that uses a stochastic stress input that can be used to measure the compliance frequency response (between 10(-2) Hz and 100 Hz) of polypyrrole in-situ. We validate the compliance calculated from the stochastic stress input by comparing it with the compliance calculated from a single sinusoidal stress input. We also measure the compliance as a function of temperature using both techniques and show that the stochastic compliance follows the same trends as the compliance calculated from single sinusoidal stress input.


Targeting of integrin beta1 and kinesin 2alpha by microRNA 183.
MicroRNA 183 (miR-183) has been reported to inhibit tumor invasiveness and is believed to be involved in the development and function of ciliated neurosensory organs. We have recently found that expression of miR-183 increased after the induction of cellular senescence by exposure to H(2)O(2). To gain insight into the biological roles of miR-183 we investigated two potential novel targets: integrin beta1 (ITGB1) and kinesin 2alpha (KIF2A). miR-183 significantly decreased the expression of ITGB1 and KIF2A measured by Western blot. Targeting of the 3'-untranslated region (3'-UTR) of ITGB1 and KIF2A by miR-183 was confirmed by luciferase assay. Transfection with miR-183 led to a significant decrease in cell invasion and migration capacities of HeLa cells that could be rescued by expression of ITGB1 lacking the 3'-UTR. Although miR-183 had no effects on cell adhesion in HeLa cells, it significantly decreased adhesion to laminin, gelatin, and collagen type I in normal human diploid fibroblasts and human trabecular meshwork cells. These effects were also rescued by expression of ITGB1 lacking the 3'-UTR. Targeting of KIF2A by miR-183 resulted in some increase in the formation of cells with monopolar spindles in HeLa cells but not in human diploid fibroblast or human trabecular meshwork cells. The regulation of ITGB1 expression by miR-183 provides a new mechanism for the anti-metastatic role of miR-183 and suggests that this miRNA could influence the development and function in neurosensory organs, and contribute to functional alterations associated with cellular senescence in human diploid fibroblasts and human trabecular meshwork cells.


Fatal, overwhelming sepsis after splenectomy in the community hospital.
Charts of all patients who underwent splenectomy between 1965 and 1981 at the Orillia Soldiers' Memorial Hospital were reviewed. At the end of 1983, the patient, relatives or family physician were contacted for follow-up. Eighty spleens were removed, 36 for medical reasons, 30 for trauma and 14 because of iatrogenic injury. Of the patients followed up, 51 were alive and 13 had died. Three died in the postoperative period and seven died of unrelated causes. Three patients died of overwhelming sepsis, 1, 3 and 7 years after splenectomy. If the three postoperative deaths are excluded and it is assumed none of the 16 untraced patients died of overwhelming sepsis, the incidence of death from this cause was 3.9%.


T1-weighted MRI for the detection of coronary artery plaque haemorrhage.
Hyperintense areas in atherosclerotic plaques on pre-contrast T1-weighted MRI have been shown to correlate with intraplaque haemorrhage. We evaluated the presence of T1 hyperintensity in coronary artery plaques in coronary artery disease (CAD) patients and correlated results with multi-detector computed tomography (MDCT) findings. Fifteen patients with CAD were included. Plaques detected by MDCT were categorised based on their Hounsfield number. T1-weighted inversion recovery (IR) MRI prepared coronary MRI for the detection of plaque and steady-state free-precession coronary MR-angiography for anatomical correlation was performed. After registration of MDCT and MRI, regions of interest were defined on MDCT-visible plaques and in corresponding vessel segments acquired with MRI. MDCT density and MR signal measurement were performed in each plaque. Forty-three plaques were identified with MDCT. With IR-MRI 5/43 (12%) plaques were hyperintense, 2 of which were non-calcified and 3 mixed. Average signal-to-noise and contrast-to-noise ratios of hyperintense plaques were 15.7 and 9.1, compared with 5.6 and 1.2 for hypointense plaques. Hyperintense plaques exhibited a significantly lower CT density than hypointense plaques (63.6 vs. 140.8). There was no correlation of plaque signal intensity with degree of stenosis. T1-weighted IR-MRI may be useful for non-invasive detection and characterisation of intraplaque haemorrhage in coronary artery plaques.


Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition.
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are the most recently approved antihyperglycemic medications. We sought to describe their association with euglycemic diabetic ketoacidosis (euDKA) in hopes that it will enhance recognition of this potentially life-threatening complication. Cases identified incidentally are described. We identified 13 episodes of SGLT-2 inhibitor-associated euDKA or ketosis in nine individuals, seven with type 1 diabetes and two with type 2 diabetes, from various practices across the U.S. The absence of significant hyperglycemia in these patients delayed recognition of the emergent nature of the problem by patients and providers. SGLT-2 inhibitors seem to be associated with euglycemic DKA and ketosis, perhaps as a consequence of their noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion. Patients with type 1 or type 2 diabetes who experience nausea, vomiting, or malaise or develop a metabolic acidosis in the setting of SGLT-2 inhibitor therapy should be promptly evaluated for the presence of urine and/or serum ketones. SGLT-2 inhibitors should only be used with great caution, extensive counseling, and close monitoring in the setting of type 1 diabetes.


[Urinary infection and urethral stenosis in males].
Urinary infections are the most frequent ones in males second to viral acute respiratory infections. There is a high incidence of association to urethral stenosis. Urethral stenosis, whether congenital or acquired, conditions urinary stasis, with urethro-vesical-canaliculus-glandular mictional reflux resulting in urinary infection. Besides, urinary infection is a major etiological factor in the genesis of urethral stenosis, up to 26-30% of which can be directly attributable to post-infection conditions. The present work analyses the incidence of urinary infection in a group of 175 patients diagnosed with male urethral stenosis. Sixty-three patients (36%) presented infection, of which 90% were single microorganism infections, 44% being caused by E. coli. As a result of urethral stenosis associated to urinary infection, there were 56 complications in 42 patients (67%) which required 19 surgical interventions.


Colon cancer with micropapillary carcinoma component: a clinopathologic study of 9 cases.
Recently, colon cancer with micropapillary pattern (MPP) has been identified. MPP is defined as tight tufts surrounded by cleft-like space and lacking true fibrovascular cores and showing reverse polarity. In this article, we studied nine cases of colon cancer with MPP. MPP usually accounted for a minor component in total tumour volume, which ranged from 3 to 40% with a mean percentage of 19.2%. Associated histological subtype showed moderately differentiated tubular adenocarcinoma in all cases. The reverse polarity of villin (9/9, diffuse) in MPP component was superior to that of CA125 (5/9, focal) or CD10 (5/9, diffuse 2/9, focal 3/9). In clinicopathological indicators such as sex, tumour location, tumour depth, lymphovascular invasion, lymph node metastasis, or pathological stage and clinical behaviour, there was statistically no difference between the MPP group and the non-MPP group of the colon. In conclusion, colon cancer with MPP is characterised by frequent association with moderately differentiated tubular adenocarcinoma as a minor component. Villin immunohistochemistry is useful in the detection of reverse polarity of MPP of colon cancer.