A Dose-Response Study Examining the Use of Methacholine Challenge to Demonstrate Local Therapeutic Equivalence of the Salmeterol Component of Generic Inhaled Fluticasone Propionate/Salmeterol Combination Products.
Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta agonist (LABA) combinations, for example, fluticasone propionate/salmeterol (FPS) dry powder inhaler, marketed as Advair® Diskus®. Some regulators require generics to demonstrate local (lung) therapeutic equivalence (LTE) for each component of the FPS reference, ideally with a dose-response within the approved FPS dose range. We sought to develop a methacholine challenge (MeCh) LTE methodology for assessing the LABA (salmeterol) component of FPS. Methods: Forty-six patients with asthma received single doses of albuterol (active control; 90 or 180 μg), FPS (100/50 or 200/100 μg), and placebo on 5 separate study days. Spirometry and MeCh were performed 1, 6, and 10 hours after study drug inhalation. Primary endpoint was provocative concentration of methacholine producing a 20% fall in forced expiratory volume in 1 second (PC20). Study entry required screening PC20 ≤8 mg/mL, with a greater than fourfold increase (and PC20 ≤128 mg/mL) after 180 μg albuterol. Results: Both albuterol (90 and 180 μg) and FPS (100/50 and 200/100 μg) significantly increased PC20 compared with placebo (sustained 6 and 10 hours postdose with FPS but not albuterol). The dose-response slopes (95% confidence interval) estimated 1 hour after treatment were 0.374 (-0.068 to 0.815) and 0.310 (-0.135 to 0.754) between low and high doses of albuterol and FPS, respectively, both nonsignificant. Slopes were shallower than those available in the literature for albuterol and formoterol, but similar to those for salmeterol. Conclusions: These data confirm that the bronchoprotective effect of FPS lasts longer than that of albuterol. The shallow dose-response slope we observed for albuterol is contrary to previous reports, probably due to the measurement of PC20 beginning at 1 hour postdose. The results suggest that use of MeCh to assess LTE for salmeterol formulations may be more difficult to accomplish than it is for albuterol and formoterol products.


Activation of the AT1R/HIF-1 α /ACE axis mediates angiotensin II-induced VEGF synthesis in mesenchymal stem cells.
A local renin-angiotensin system (RAS) is expressed in mesenchymal stem cells (MSCs) and regulates stem cell function. The local RAS influences the survival and tissue repairing ability of transplanted stem cells. We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R). However, the role of angiotensin-converting enzyme (ACE) has not been clarified. Furthermore, whether Ang II pretreatment activates hypoxia-inducible factor-1α (HIF-1α) in MSCs has not been elucidated. Our data show that both ACE and HIF-1α are involved in promoting VEGF expression in MSCs, and that both are upregulated by Ang II stimulation. The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II. On the other hand, the ACE inhibitor, captopril, attenuated Ang II-enhanced HIF-1α upregulation, while HIF-1α suppression markedly attenuated ACE expression. This interesting finding suggests an interaction between ACE and HIF-1α. We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs.


Comparison between the effects of one-day treatment regimen with cisplatin on renal function and various biochemical parameters in patients with gastric and lung cancer compared with two-days divided cisplatin treatment regimen.
Cisplatin is an efficient chemotherapeutic drug used for the treatment of different cancers. Clinical trials represents cisplatin-induced nephrotoxicity in a dose dependent manner. This study aimed to compare the effects of 1-day treatment regimen with cisplatin on renal function, potassium, calcium, magnesium and uric acid in patients with gastric and lung cancer compared with 2-day divided cisplatin treatment regimen to suggest appropriate management for decrease nephrotoxic effects and >electrolyte abnormalities. The study was conducted as a randomized clinical trial. The sample consisted of 60 patients with gastric and lung cancer treated with cisplatin in Ahvaz Shafa hospital. Patients were randomly divided into 2 equal groups. Both groups were treated with cisplatin over a period of 6 to 18 weeks. The first group received 50 mg/m(2)/day of cisplatin during one day and the second group received 25 mg/m(2)/day in 2 days. Electrolytes in each period and renal function at baseline and 6 months after starting treatment was assessed. Difference of mean of renal function and nephrotoxicity incidence in the 2 groups was statistically significant. The odds of hypokalemia in 1-day group was higher than 2-day group (odds ratio [OR] = 6.5), which was statistically significant. However there was no significant relationship between the types of treatment and the risk of hypocalcemia, hypomagnesemia and hyperuricemia. The result of this study showed that, the divided administration of cisplatin reduces the nephrotoxic and hypokalemia effects of this drug, however it had not significant influence on hypomagnesemia, hypocalcaemia, and hyperuricemia.


Interrelationship among prognostic factors in carcinoma breast.
Presentation of breast cancer at an advanced stage is a rule than exception in rural West Bengal. It was observed that 65.6% of fresh cases presented with history of breast lump with a duration of over 12 months. Of the total 32 cases, 27 (84.4%) had breast lump of more than 5 cm size and had 4 or more pathologically positive axillary nodes. In 28 cases (87.5%) largest node measured was 2 cm or more. In histology of breast specimen, 12 (37.5%) showed high degree of lymph vessel invasion while 31 (96.9%) had at least some lymphatic invasion. Blood vessel invasion of high degree was observed in 18 cases (56.2%) while 29 cases (90.6%) showed at least some blood vessel invasion.


Life under the Microscope: Single-Molecule Fluorescence Highlights the RNA World.
The emergence of single-molecule (SM) fluorescence techniques has opened up a vast new toolbox for exploring the molecular basis of life. The ability to monitor individual biomolecules in real time enables complex, dynamic folding pathways to be interrogated without the averaging effect of ensemble measurements. In parallel, modern biology has been revolutionized by our emerging understanding of the many functions of RNA. In this comprehensive review, we survey SM fluorescence approaches and discuss how the application of these tools to RNA and RNA-containing macromolecular complexes in vitro has yielded significant insights into the underlying biology. Topics covered include the three-dimensional folding landscapes of a plethora of isolated RNA molecules, their assembly and interactions in RNA-protein complexes, and the relation of these properties to their biological functions. In all of these examples, the use of SM fluorescence methods has revealed critical information beyond the reach of ensemble averages.


In utero adrenal hemorrhage associated with fetal distress, subsequent transient neonatal hypertension, and a nonfunctioning ipsilateral kidney.
We present an unusual case of in utero adrenal hemorrhage associated with fetal distress. This case was further complicated by transient neonatal hypertension that resolved spontaneously and a nonfunctioning ipsilateral kidney. We discuss the possible underlying pathophysiology.


[Bioavailability of cyclophosphamide following oral administration in high doses].
Mean rate of absorption of cyclophosphamide after oral administration from studies in which the drug is given in doses of 0,7 g/m2 body surface both orally and intravenously to the same 18 tumor patients is 87.7% (s - 21.1%). The drug may be administered orally with good bioavailability at the high dose.


Accuracy of rate coding: When shorter time window and higher spontaneous activity help.
It is widely accepted that neuronal firing rates contain a significant amount of information about the stimulus intensity. Nevertheless, theoretical studies on the coding accuracy inferred from the exact spike counting distributions are rare. We present an analysis based on the number of observed spikes assuming the stochastic perfect integrate-and-fire model with a change point, representing the stimulus onset, for which we calculate the corresponding Fisher information to investigate the accuracy of rate coding. We analyze the effect of changing the duration of the time window and the influence of several parameters of the model, in particular the level of the presynaptic spontaneous activity and the level of random fluctuation of the membrane potential, which can be interpreted as noise of the system. The results show that the Fisher information is nonmonotonic with respect to the length of the observation period. This counterintuitive result is caused by the discrete nature of the count of spikes. We observe also that the signal can be enhanced by noise, since the Fisher information is nonmonotonic with respect to the level of spontaneous activity and, in some cases, also with respect to the level of fluctuation of the membrane potential.


Comparison of serological assays to titrate Hantaan and Seoul hantavirus-specific antibodies.
Hantaan and Seoul viruses, in the Hantavirus genus, are known to cause hemorrhagic fever with renal syndrome (HFRS). The plaque reduction neutralization test (PRNT), as conventional neutralization test for hantaviruses, is laborious and time-consuming. Alternatives to PRNT for hantaviruses are required. In this study, the methods for Hantaan and Seoul viruses serological typing including microneutralization test (MNT), pseudoparticle neutralization test (PPNT) and immunofluorescence assay based on viral glycoproteins (IFA-GP) were developed and compared with PRNT using a panel of 74 sera including 44 convalescent sera of laboratory confirmed HFRS patients and 30 patients sera of non-hantavirus infection. Antibody titres and serotyping obtained with different methods above were analyzed by paired-t, linear correlation, McNemar χ2 and Kappa agreement tests. Antibody titres obtained with MNT50, PPNT50 and IFA-GP were significantly correlated with that obtained with PRNT50 (p < 0.001). GMT determined by PPNT50 was statistically higher than that determined by PRNT50 (p < 0.001), while GMT determined by MNT50 and IFA-GP were equal with (p > 0.05) and less than (p < 0.001) that obtained with PRNT50 respectively. Serotyping obtained with MNT50 and PRNT50, PPNT50 and PRNT50 were highly consistent (p < 0.001), whereas that obtained with IFA-GP and PRNT50 were moderately consistent (p < 0.001). There were no significant differences for serotyping between PRNT50 and MNT50, as well as PRNT50 and PPNT50 (p > 0.05). IFA-GP was less sensitive than PRNT50 and MNT50 for serotyping of hantaviruses infection (p < 0.05). However, for 79.5% (35/44) samples, serotyping determined by IFA-GP and PRNT50 were consistent. MNT50 and PPNT50 both can be used as simple and rapid alternatives to PRNT50, and MNT50 is more specific while PPNT50 is more sensitive than other assays for neutralizing antibody determination. So far, this work has been the most comprehensive comparison of alternatives to PRNT.


Identification of enteroviruses in naturally infected captive primates.
In a recent study, we investigated cases of diarrheal disease among monkeys at a U.S. primate center. In that study, enteroviruses were detected in a high proportion of the fecal specimens tested. To determine whether the enterovirus detections represented the circulation of one or more simian enteroviruses within the colony or the transmission of human enteroviruses from animal handlers, we determined in the present study the serotype identity of each virus by reverse transcription-PCR and sequencing of a portion of the VP1 gene, a region whose sequence corresponds to antigenic type. Enteroviruses were identified in 37 of 56 specimens (66%), 30 of 40 rhesus macaques, 5 of 11 pigtail macaques, 2 of 4 sooty mangabeys, and 0 of 1 chimpanzee. No previously known human viruses were detected. Three previously known simian enterovirus serotypes--SV6, SV19, and SV46--were among the viruses identified, but more than half of the identified viruses were previously unknown; these have been assigned as new types: EV92 and EV103.


Restraint stress and anti-tumor immune response in mice.
Psychological stress modulates the immune system through the hypothalamic-pituitary-adrenal axis, the sympatho-adrenomedullary axis and the opioid system. According to literature data, restraint stress increases the immune cell apoptosis, decreases the spleen and thymus cell content, the natural killer (NK) activity in the spleen, and it compromises the anti-tumor immune response in mice. We immobilized mice in two consecutive nights, and then determined the cell number, apoptosis, NK cell content, NK activity and the level of cytokine mRNAs (TNF-beta, TNF-alpha, IL-4, IL-5, IL-1alpha, IFN-gamma, IL-2, IL-6, IL-1beta and IL-3) in the thymus and spleen. No consistent changes were detected in any of the immune parameters either in C57Bl/6 or in DBA/2 mice. Stressed or control B6 mice were injected with B16 melanoma cells immediately after the immobilization or one week later. No significant differences were found in the growth of primary tumors and lung metastases in stressed and control animals. Taken together, our mice, kept in a general-purpose non-SPF animal house, seemed to be refractory to the stress-induced immunomodulation. Our interpretation is that stress-induced immunomodulation can occur only in mice isolated from any background stressors, or rather natural stimuli, throughout their life.


Secretory-defect distal renal tubular acidosis is associated with transporter defect in H(+)-ATPase and anion exchanger-1.
Recent progress in molecular physiology has permitted us to understand pathophysiology of various channelopathies at a molecular level. The secretion of H(+) from alpha-intercalated cells is mediated by apical plasma membrane H(+)-ATPase and basolateral plasma membrane anion exchanger-1 (AE1). Studies have demonstrated the lack of H(+)-ATPase immunostaining in the intercalated cells in a few patients with distal renal tubular acidosis (dRTA). Mutations in H(+)-ATPase and AE1 gene have recently been reported to cause dRTA. This study extends the investigation of the role of transporter defect in dRTA by using immunohistochemical methods. Eleven patients with hyperchloremic metabolic acidosis were diagnosed functionally to have secretory-defect dRTA: urine pH >5.5 during acidemia, normokalemia or hypokalemia, and urine-to-blood pCO(2) <25 mmHg during bicarbonaturia. Renal biopsy tissue was obtained from each patient, and immunohistochemistry was carried out using antibodies to H(+)-ATPase and AE1. For comparison, renal tissues from the patients who had no evidences of distal acidification defect by functional studies were used: four with glomerulopathy or tubulointerstitial nephritis (disease controls) and three from nephrectomized kidneys for renal cell carcinoma (normal controls). The H(+)-ATPase immunoreactivity in alpha-intercalated cells was almost absent in all of the 11 patients with secretory-defect dRTA. In addition, 7 of 11 patients with secretory-defect dRTA were accompanied by negative AE1 immunoreactivity. In both disease controls and normal controls, the immunoreactivity of H(+)-ATPase and AE1 was strong in alpha-intercalated cells. In conclusion, significant defect in acid-base transporters is the major cause of secretory-defect dRTA.


IL12Rβ1ΔTM is a secreted product of il12rb1 that promotes control of extrapulmonary tuberculosis.
IL12RB1 is a human gene that is important for resistance to Mycobacterium tuberculosis infection. IL12RB1 is expressed by multiple leukocyte lineages, and encodes a type I transmembrane protein (IL12Rβ1) that associates with IL12p40 and promotes the development of host-protective T(H)1 cells. Recently, we observed that il12rb1—the mouse homolog of IL12RB1—is alternatively spliced by leukocytes to produce a second isoform (IL12Rβ1ΔTM) that has biological properties distinct from IL12Rβ1. Although the expression of IL12Rβ1ΔTM is elicited by M. tuberculosis in vivo, and its overexpression enhances IL12p40 responsiveness in vitro, the contribution of IL12Rβ1ΔTM to controlling M. tuberculosis infection has not been tested. Here, we demonstrate that IL12Rβ1ΔTM represents a secreted product of il12rb1 that, when absent from mice, compromises their ability to control M. tuberculosis infection in extrapulmonary organs. Furthermore, elevated M. tuberculosis burdens in IL12Rβ1ΔTM-deficient animals are associated with decreased lymph node cellularity and a decline in TH1 development. Collectively, these data support a model wherein IL12Rβ1ΔTM is a secreted product of il12rb1 that promotes resistance to M. tuberculosis infection by potentiating T(H) cells response to IL-12.


Small versus large volume dilute surfactant lavage for meconium aspiration syndrome.
Surfactant lavage has been used to treat neonatal meconium aspiration syndrome (MAS). To assess the effects of lavage with a small volume of dilute surfactant in neonates with MAS, and compare the results with those of historical controls treated with larger volumes. From August 2002 to June 2005, we treated 11 newborns with MAS using 20 ml of dilute surfactant at a phospholipid concentration of 10 mg/ml (SVL group). We compared the results with those of 9 infants previously treated with large-volume lavage (LVL group), using 40 ml of dilute surfactant, 5 mg/ml. Both groups were similar at baseline except for a higher mean birth weight in the LVL group (3.29+/-0.36 vs 2.92+/-0.4 kg, P = 0.04). The lavage procedure was longer in the LVL than the SVL group (48.89 +/-7.41 vs. 30.91+/-5.83 mins, P <0.001). Measures of oxygenation, including mean PaO2, oxygenation index, and arterial/alveolar 02 ratio, showed no significant difference between the two groups. Adverse events in the LVL group included transient hypoxemia in 3 infants and white- out on chest x-ray in 5 cases. None of the patients in the SVL group had these findings. The peak mean airway pressure in.the LVL group was higher than that in the SVL group (16.0+/-2. 65 vs 13.3+/-3.01 cmH2O, P = 0.046). SVL has the same benefits in neonatal MAS as LVL. However, SVL appears to be associated with fewer adverse events.


Purification of large cytosolic proteases for in vitro assays: 20S and 26S proteasomes.
Proteasomes are the main cytosolic proteases responsible for generating peptides for antigen processing and presentation in the MHC (major histocompatibility complex) class-I pathway. Purified 20S and 26S proteasomes have been widely used to study both specificity and efficiency of antigen processing. Here, we describe the purification of active human 20S and 26S proteasomes from human erythrocytes by DEAE-ion exchange chromatography, ammonium sulfate precipitation, glycerol density gradient centrifugation, and Superose-6 size exclusion chromatography and their characterization using fluorogenic substrates and specific inhibitors.


Pioglitazone-Loaded Nanostructured Hybrid Material for Skin Ulcer Treatment.
Pioglitazone, a popular antidiabetic drug, which was recently shown to be effective in the treatment of skin ulcers, was successfully encapsulated in polysaccharide nanoparticles and used as a bioactive component of the wound-dressing material based on modified bacterial nanocellulose. Alginate and hydroxypropyl cellulose were used as a matrix for the nanoparticulate drug-delivery system. The matrix composition and particles' size, as well as drug encapsulation efficiency and loading, were optimized. Pioglitazone hydrochloride (PIO) loaded particles were coated with chitosan introduced into the crosslinking medium, and covalently attached to the surface of bacterial nanocellulose functionalized with carboxyl groups. PIO was released from the surface of the hybrid material in a controlled manner for 5 days. Preliminary cytotoxicity studies confirmed safety of the system at PIO concentrations as high as 20 mg/mL. The obtained hybrid system may have potential application in the treatment of skin ulcers e.g., in diabetic foot.


Infrared analysis in clinical chemistry: its use in the laboratory and in non-invasive near patient testing.
Laboratory based NIR analysers have been available for some time. The recent development of more portable equipment such as the commercially available Futrex-9000 NIR transmittance blood chemistry analyser, which can be used to analyse relatively opaque samples for a mixture of components, shows promise but requires further evaluation for routine clinical use. NIR equipment for general use has only recently become available and is therefore relatively expensive. However, as the development of new applications occurs the instrumentation will become more widely used, which will inevitably result in reduced capital cost. The advantages of NIR systems are speed, portability, lack of consumables, dry chemistry, non-invasive, modest running costs, virtually no moving parts and almost infinite applications in clinical biochemical analysis. It is likely that the first applications of NIR will be where there is a requirement for multiple assays such as glucose, urea and bilirubin and where sample size is a limitation. Thus non-invasive near patient testing may become common in the future in settings such as neonatal units, renal units, diabetic clinics and intensive care units.


The structure of the pelvis in the immature human kidney.
Examination of the renal pelvis of late fetal and neonatal kidneys shows that in about one quarter of the calyces examined the arrangement is similat to that in the rat, the outer medulla being separated from the calyceal cavity by a very thin epithelium. It is suggested that this presents a vulnerable area through which intrarenal damage can occur as a result of vesico-ureteric reflux in the immature kidney.


A case of atypical canine lymphoma with oral mass and multiple osteolysis.
An 8-year-old female Golden Retriever had an oral mass and lameness. Multiple osteolysis of the systemic skeleton without monoclonal gammopathy was shown on electrophoresis of serum and urine samples. Cytological and histopathological examinations of the oral mass revealed atypical polymorphic cells similar to myeloid cells, and bone marrow aspiration indicated that these abnormal cells also might have invaded the bone marrow. These cells were negative to peroxidase and non-specific esterase staining, and clonal expansion of B lymphocytes could be detected by polymerase chain reaction (PCR) assay for antigen receptor gene rearrangement. The case was diagnosed as atypical lymphoma and treated by multi-drug chemotherapy. On the 142nd day after the first admission, the case had remission and the oral mass and multiple osteolysis were improved.


Care for people with dementia in Slovenia.
The number of patients with dementia in Slovenia will increase 33% in the next ten years. Unfortunately, networks offering different activities for demented patients are still insufficiently developed, although in the last ten years a significant improvement has been observed in all areas of care (diagnosis, treatment, day care centres, nursing homes, and non-governmental organizations). The article provides a short overview of developing care for persons with dementia in Slovenia.


The human antibody response to uropathogenic Escherichia coli: a review.
Urinary tract infections caused by Escherichia coli are associated with a local and systemic antibody response. We have studied the serum and urine antibody responses to Escherichia coli in men and women with pyelonephritis, cystitis, and asymptomatic bacteriuria. Protein immunoblots consistently demonstrated serum antibody response to lipopolysaccharide (LPS). Anti-LPS antibody titres rose significantly and progressively when comparing acute with convalescent sera in those who have had their first urinary infection. For those with repeated infections, high titre LPS antibodies were present and did not change significantly between acute and convalescent sera. Antibody responses to the major outer membrane proteins were present but did not differ significantly when compared with normal human serum. A specific anti-P pilus antibody response was demonstrated by immunoblotting. Anti-P pilus antibody was quantitated using ELISA and the titres were found to be very low. Three other techniques were also used to demonstrate the presence of serum antibody. Antibody was detectable by immunofluorescence, but the antigenic specificity of the antibody was more difficult to ascertain. Immunoprecipitation was more specific for determining the nature of the antibody response. Lastly, immunoelectron microscopy was valuable in demonstrating antipilus and antiflagellar antibodies. Immunoelectron microscopy and immunoblotting provided evidence that human antiserum to P pili was modestly cross-reactive and could bind heterologous P pili. These studies indicated that the major antibody response in humans occurs after pyelonephritis and is directed against LPS. An anti-P pilus response is frequently present and is cross-reactive to some extent with other P pili.


Indocyanine green clearance following single and chronic cimetidine doses.
Twenty-five indocyanine green (ICG) clearance determinations were performed in four subjects in the presence of quinidine or propranolol before and after one week of treatment with cimetidine, 1200 mg/day, and following a single 600 mg cimetidine dose. There was no significant difference between the mean ICG clearance before cimetidine treatment and that after one week of therapy with cimetidine, while the mean ICG clearance was 25% lower following single cimetidine doses (p greater than 0.05). It is concluded that cimetidine has only a transient hepatic blood flow lowering effect.


Surgical outcomes after cochlear implantation in children with incomplete partition type I: comparison with deaf children with a normal inner ear structure.
To compare audiologic performance after cochlear implantation (CI) in children with incomplete partition (IP) Type I and age-matched children with normal cochleae. Retrospective chart review. Academic center. Twenty-three children (25 ears) with IP Type I and 230 age-matched deaf children (230 ears) with nonsyndromic normal inner ears who underwent CI between January 2000 and June 2013. The Categories of Auditory Performance (CAP) Scale score and the Meaningful Auditory Integration Scale (MAIS) score. The mean age of IP Type I patients at the time of CI was 5.3 years (standard deviation, 5.4 yr; range, 0.9-17.7 yr). The mean duration of follow-up was 4.7 years (standard deviation, 3.5 yr; range, 1.1-11.2 yr). Fourteen of the 25 IP Type I ears (56%) had cerebrospinal fluid gusher during the cochleostomy. In the IP type ears, the number of inserted electrodes was 16.3 ± 3.2 (range, 11-22), and the insertion angle was 236.5 ± 41.2 degrees (range, 180-305 degrees). The cochlear nerve was assessed in 17 of the 25 IP type ears, and hypoplasia was present in nine (53%). Facial nerve stimulation occurred in 15 of the 25 IP type ears. IP Type I patients younger than 3 years at CI had significantly lower CAP Scale and MAIS scores than age-matched controls at 12 and 24 months after CI, but similar CAP Scale and MAIS scores as age-matched controls at 42 and 72 months after CI. IP Type I patients aged 3 to 18 years at CI had similar CAP Scale and MAIS scores as age-matched controls at all post-CI time points. Children with IP Type I who underwent CI performed as well as children with normal cochlea in the long-term.


hERG stereoselective modulation by mexiletine-derived ureas: Molecular docking study, synthesis, and biological evaluation.
Long QT syndrome (LQTS) is a disorder of cardiac electrophysiology resulting in life-threatening arrhythmias; nowadays, only a few drugs are available for the management of LQTS. Focusing our attention on LQT2, one of the most common subtypes of LQTS caused by mutations in the human ether-à-go-go-related gene (hERG), in the present work, the stereoselectivity of the recently discovered mexiletine-derived urea 8 was investigated on the hERG potassium channel. According to preliminary in silico predictions, in vitro studies revealed a stereoselective behavior, with the meso form showing the greatest hERG opening activity. In addition, functional studies on guinea pig isolated left atria, aorta, and ileum demonstrated that 8 does not present any cardiac or intestinal liability in our ex vivo studies. Due to its overall profile, (R,S)-8 paves the way for the design and development of a new series of compounds potentially useful in the treatment of both congenital and drug-induced forms of LQTS.


Carboranes as Aryl Mimetics in Catalysis: A Highly Active Zwitterionic NHC-Precatalyst.
Modern catalysis takes advantage of aryl-based interactions to tune and control reactions. In the design of N-heterocyclic-carbene catalysts, both the electronic and steric nature of the nitrogen substituents play a crucial role. Although hydrocarbon-based systems and especially aryl residues have contributed considerably to overcome multifaceted catalytic challenges, the unique properties of carborane moieties, including delocalized charge, potential planar chirality, and well-known thermodynamic stability, offer unprecedented opportunities to develop new catalysts while being employed as aryl mimetics. We report a straightforward synthetic route to a novel zwitterionic triazolium-based N-heterocyclic carbene (NHC) precatalyst bearing a 7,8-dicarba-nido-undecaboranyl substituent. The catalyst's excellent activity and its broad applicability are demonstrated in a wide range of organocatalytic transformations. Comparison of the performance with known N-aryl NHC catalysts offers preliminary insights into the stereoelectronic nature of this nido-carboranyl substituent.


The "cruel radiance of what is": helping couples live with chronic illness.
The threat of no longer being the person one wants to be hovers over each ill person and plays out relationally. The dynamic interplay of this experience of self-loss and other-loss (Roos, 2002; Weingarten, 2012) has a significant impact on couples, both of whom may come to have both experiences. In this article, I focus on the couples' experience of self- and other-loss in the context of chronic illness, in which one person's experience flows into and informs the other's. In particular, I describe how asymmetric acknowledgment of self-loss and other-loss adds to the misery of couples who are already challenged by poor health. Physical pain also makes dealing with self- and other-loss harder. Therapists can serve couples better if they take a fully collaborative stance; appreciate the dilemmas of witnessing; help couples distinguish new trauma from retraumatization and fear; work with the weaver's dilemma and the boatman's plight (Weingarten, 2012); and are comfortable with discussion of end of life issues.


Racemic Vinylallenes in Catalytic Enantioselective Multicomponent Processes: Rapid Generation of Complexity through 1,6-Conjugate Additions.
Racemic vinylallenes are shown to be effective substrates for catalytic multicomponent diastereo- and enantioselective 1,6-conjugate addition of multifunctional allyl moieties to easily accessible α,β,γ,δ-unsaturated diesters. Reactions may be catalyzed by 5.0 mol % of a readily accessible NHC-Cu complex at ambient temperature, and other than a vinylallene, involve B2 (pin)2 and an α,β,γ,δ-unsaturated diester. A variety of vinylallenes were converted to products bearing a Z-trisubstituted alkenyl-B(pin) moiety, a vinyl group, a β,γ-unsaturated diester unit, and vicinal stereogenic centers in up to 67 % yield, 87:13 Z/E ratio, >98:2 d.r., and 98:2 e.r. Chemoselective modifications involving the alkenyl-B(pin), the vinyl, or the 1,2-disubstituted olefin moieties were carried out to demonstrate versatility and utility. Stereochemical models, based on mechanistic and DFT studies, demonstrate the dynamic behavior of intermediated Cu-allyl species and account for various selectivity profiles.


2,4-Dithiothymine as a potent UVA chemotherapeutic agent.
Substitution of both oxygen atoms in the exocyclic carbonyl groups of the thymine chromophore by sulfur atoms results in a remarkable redshift of its absorption spectrum from an absorption maximum at 267 nm in thymidine to 363 nm in 2,4-dithiothymine (ΔE = 9905 cm(-1)). A single sulfur substitution of a carbonyl group in the thymine chromophore at position 2 or 4 results in a significantly smaller redshift in the absorption maximum, which depends sensitively on the position at which the sulfur atom is substituted, varying from 275 nm in 2-thiothymine to 335 nm in 4-thiothymidine. Femtosecond transient absorption spectroscopy reveals that excitation of 2,4-dithiothymine at 335 or 360 nm leads to the ultrafast population of the triplet state, with an intersystem crossing lifetime of 180 ± 40 fs—the shortest intersystem crossing lifetime of any DNA base derivative studied so far in aqueous solution. Surprisingly, the degree and position at which the sulfur atom is substituted have important effects on the magnitude of the intersystem crossing rate constant, showing a 1.2-, 3.2-, and 4.2-fold rate increases for 2-thiothymine, 4-thiothymidine, and 2,4-dithiothymine, respectively, relative to that of thymidine, whereas the triplet yield increases 60-fold to near unity, independent of the site of sulfur atom substitution. While the natural thymine monomers owe their high degree of photostability to ultrafast internal conversion to the ground state and low triplet yields, the near-unity triplet yields in the thiothymine series account for their potent photosensitization properties. Nanosecond time-resolved luminescence spectroscopy shows that 4-thiothymidine and 2,4-dithiothymine are efficient singlet oxygen generators, with singlet oxygen quantum yields of 0.42 ± 0.02 and 0.46 ± 0.02, respectively, in O2-saturated acetonitrile solution. Taken together, these photophysical measurements strongly suggest that 2,4-dithiothymine can act as a more effective UVA chemotherapeutic agent than the currently used 4-thiothymidine, especially in deeper-tissue chemotherapeutic applications.


Pneumocystis is not a direct cause of sudden infant death syndrome.
We compared the frequency of Pneumocystis in 126 sudden infant death syndrome (SIDS) cases with a control group of 24 infants from the San Diego SIDS/SUDC Research Project who died of accidental or inflicted injuries. Cysts were identified in 33% of SIDS cases and 29% of controls. We conclude that Pneumocystis is not a direct cause of SIDS.


V79 Fibroblasts Are Protected Against Reactive Oxygen Species by Flax Fabric.
Chinese hamster pulmonary fibroblasts (V79 cells) pre-treated with flax fabrics derived from non-modified or genetically engineered flax fibres and treated with H2O2 revealed a markedly lower level of intracellular reactive oxygen species (ROS) than control, non-pre-treated cells. The fabrics were prepared from fibres derived from two kinds of transgenic plants: W92 plants, which overproduce flavonoids, and M type plants, which produce hydroxybutyrate polymer in their vascular bundles and thus in fibres. Incubating the V79 cells with the flax fabrics prior to H2O2 treatment also reduced the amount of DNA damage, as established using the comet assay (also known as alkaline single-cell gel electrophoresis) and pulsed-field electrophoresis of intact cellular DNA. Selected gene expression analysis revealed the activator impact of fabrics on the apoptotic (BCL2 family, caspases) gene expression. This promoting activity was also detected for histone acetyltransferase (HAT; MYST2) gene expression. The flax fabric derived from both GM flax plants exhibited a protective effect against oxidative stress and ROS-mediated genotoxic damage, but the W92 fabric was the strongest. It is thus suggested that these fabrics might be useful as a basis for new biomedical products (e.g. wound dressings) that actively protect cells against inflammation and degeneration.


Copper(I)-Catalyzed Asymmetric Desymmetrization through Inverse-Electron-Demand aza-Diels-Alder Reaction: Efficient Access to Tetrahydropyridazines Bearing a Unique α-Chiral Silane Moiety.
An unprecedented copper(I)-catalyzed asymmetric desymmetrization of 5-silylcyclopentadienes with in situ formed azoalkene was realized through an inverse-electron-demand aza-Diels-Alder reaction (IEDDA) pathway, in which 5-silylcyclopentadienes served as efficient enophiles. This new protocol provides a facile access to the biologically important heterocyclic tetrahydropyridazines containing a unique α-chiral silane motif and three adjoining stereogenic centers in generally good yield (up to 92 %) with exclusive regioselectivity, high diastereoselectivity (>20:1 diastereomeric ratio), and excellent enantioselectivity (up to 98 % enantiomeric excess). DFT calculations and control experiments further confirmed the proposed reaction mechanism.


Base pair fluctuations in helical models for nucleic acids.
A statistical method is developed to estimate the maximum amplitude of the base pair fluctuations in a three dimensional mesoscopic model for nucleic acids. The base pair thermal vibrations around the helix diameter are viewed as a Brownian motion for a particle embedded in a stable helical structure. The probability to return to the initial position is computed, as a function of time, by integrating over the particle paths consistent with the physical properties of the model potential. The zero time condition for the first-passage probability defines the constraint to select the integral cutoff for various macroscopic helical conformations, obtained by tuning the twist, bending, and slide motion between adjacent base pairs along the molecule stack. Applying the method to a short homogeneous chain at room temperature, we obtain meaningful estimates for the maximum fluctuations in the twist conformation with ∼10.5 base pairs per helix turn, typical of double stranded DNA helices. Untwisting the double helix, the base pair fluctuations broaden and the integral cutoff increases. The cutoff is found to increase also in the presence of a sliding motion, which shortens the helix contour length, a situation peculiar of dsRNA molecules.


Unresponsiveness of GH and cortisol to insulin-hypoglycemia in a patient with sub-total pancreatectomy.
Responses of plasma growth hormone (GH) and cortisol to insulin-induced hypoglycemia were repeatedly examined during a therapy of diabetes mellitus in a sub-totally pancreatectomized patient. During a mild control period of diabetes mellitus without any hypoglycemic attacks, insulin-induced hypoglycemia evoked a remarkable increase in plasma GH as well as cortisol while neither GH nor cortisol responded to insulin hypoglycemia during the strict control period with frequent episodes of hypoglycemia. On the other hand, plasma GH and cortisol responses to all other endocrinological stimuli were normal. The mechanism of such impaired hormone secretion during the strict control period of diabetes mellitus in this patient remains unclear.


Echistatin: the refined structure of a disintegrin in solution by 1H NMR and restrained molecular dynamics.
The structure of the disintegrin echistatin has been determined by 1H NMR, distance geometry calculations and restrained molecular dynamics simulations. The structure has been refined from the preliminary distance geometry calculations with the inclusion of additional 1H NMR data and hydrogen bonds identified in early stages of the molecular dynamics calculations. The calculations reported here allow a distinction to be made between the two possible disulfide bridging patterns-echistatin is crosslinked as follows: Cys2-Cys11, Cys7-Cys32, Cys8-Cys37, Cys20-Cys39. The final set of structures gives an average pairwise root mean square distance of 0.100 nm (calculated over the backbone atoms of residues Ser4-Cys20 and Asp30-Pro40). The core of echistatin is a well defined though irregular structure, composed of a series of non-classical turns crosslinked by the disulfide bridges and stabilised by hydrogen bonds. The RGD sequence is located in a protruding loop whose stem is formed by two rigid, hydrogen-bonded strands (Thr18-Cys20, Asp30-Cys32). The RGD sequence is connected to this structure by short, flexible segments. High (but not unlimited) mobility is probably necessary for fast recognition and fitting to the integrin receptors. Sequence variability among the disintegrins is found in the segments flanking the RGD sequence, suggesting that these may be important in conferring specificity for the receptors.


The CD44+ ALDH+ population of human keratinocytes is enriched for epidermal stem cells with long-term repopulating ability.
Like for other somatic tissues, isolation of a pure population of stem cells has been a primary goal in epidermal biology. We isolated discrete populations of freshly obtained human neonatal keratinocytes (HNKs) using previously untested candidate stem cell markers aldehyde dehydrogenase (ALDH) and CD44 as well as the previously studied combination of integrin α6 and CD71. An in vivo transplantation assay combined with limiting dilution analysis was used to quantify enrichment for long-term repopulating cells in the isolated populations. The ALDH(+) CD44(+) population was enriched 12.6-fold for long-term repopulating epidermal stem cells (EpiSCs) and the integrin α6(hi) CD71(lo) population was enriched 5.6-fold, over unfractionated cells. In addition to long-term repopulation, CD44(+) ALDH(+) keratinocytes exhibited other stem cell properties. CD44(+) ALDH(+) keratinocytes had self-renewal ability, demonstrated by increased numbers of cells expressing nuclear Bmi-1, serial transplantation of CD44(+) ALDH(+) cells, and holoclone formation in vitro. CD44(+) ALDH(+) cells were multipotent, producing greater numbers of hair follicle-like structures than CD44(-) ALDH(-) cells. Furthermore, 58% ± 7% of CD44(+) ALDH(+) cells exhibited label-retention. In vitro, CD44(+) ALDH(+) cells showed enhanced colony formation, in both keratinocyte and embryonic stem cell growth media. In summary, the CD44(+) ALDH(+) population exhibits stem cell properties including long-term epidermal regeneration, multipotency, label retention, and holoclone formation. This study shows that it is possible to quantify the relative number of EpiSCs in human keratinocyte populations using long-term repopulation as a functional test of stem cell nature. Future studies will combine isolation strategies as dictated by the results of quantitative transplantation assays, in order to achieve a nearly pure population of EpiSCs.


Ethical consumerism, human rights, and Global Health Impact.
In this paper, I raise some doubts about Nicole Hassoun's account of the obligations of states, pharmaceutical firms, and consumers with regard to global health, presented in Global Health Impact. I argue that it is not necessarily the case, as Hassoun claims, that if states are just, and therefore satisfy all of their obligations, then consumers will not have strong moral reasons, and perhaps obligations, to make consumption choices that are informed by principles and requirements of justice. This is because there may be justice-based limits on what states can permissibly and feasibly do both to promote access to existing drugs for all of those who need them, and to promote research and development for new drugs that could treat diseases that primarily affect the global poor. One important upshot of my argument is that there can be reasons for organizations like the Global Health Impact Organization to exist, and to do the kind of work that Hassoun argues is potentially valuable in our deeply unjust world, even in much less unjust worlds in which states and firms largely, or even entirely, comply with their obligations.


Cisplatin, vindesine, and bleomycin (DVB) combination chemotherapy for esophageal carcinoma.
Forty-six patients with epidermoid carcinoma of the esophagus have been treated with a three-drug combination of cisplatin, vindesine, and bleomycin. Of the 40 patients currently evaluable for response, 21 have had partial remissions (52%). At least four of these responses were almost complete, with only microscopic disease found on endoscopy or review of the resected specimen. Toxic effects have, in general, been manageable. The major toxic effects included nausea and vomiting, nephrotoxicity, and myelosuppression. There were two drug-related deaths: one due to renal failure and one due to sepsis. The three-drug combination appears to be substantially more effective than either the two-drug combination of cisplatin and bleomycin or vindesine alone. Effects on survival cannot yet be evaluated.


Interrelation of Proctodrilus species (Oligochaeta: Lumbricidae) with lessivage and layering in European soil profiles.
The objective of this paper is to relate species occurrences of the earthworm genus Proctodrilus to soil properties, in particular the horizons and layers in the soil profile. Data on the occurrence in the soil profile of the earthworm species Proctodrilus antipai (Michaelsen, 1891), P. opisthoductus Zicsi, 1985, P. thaleri Höser Zicsi 2009, and P. tuberculatus (Černosvitov, 1935) were collected in central Germany, northern Bohemia, Hungary, and Romania. Species of Proctodrilus were collected from 138 sites in total, P. antipai from 48, P. opisthoductus from 24, P. thaleri from 4, and P. tuberculatus from 97 sites. The field data show that species inhabiting the same site do not form communities but rather inhabit different soil layers. Furthermore, species of Proctodrilus prefer to live close to the boundaries between layers, a feature that can be regarded as a taxonomic characteristic of the genus and that is probably connected with their enteronephric excretory system. The habitats of the different species differ in the degree of soil leaching. P. thaleri and P. opisthoductus are restricted to the region of recent lessivage in warm-humid parts of Europe. Occurrence of the four Proctodrilus species is therefore not related to soil type but rather to soil stratification and soil leaching. Differences in the ecological behaviour of the species can be understood as taxonomic characters.


Applying a Social Justice Lens to Youth Mentoring: A Review of the Literature and Recommendations for Practice.
Youth mentoring interventions are often designed with the intention of promoting improved outcomes among marginalized youth. Despite their promise to reduce inequality through the provision of novel opportunities and increased social capital to marginalized youth, youth mentoring interventions hold the potential to reproduce rather than reduce inequality. In the current review, we explore literature on youth mentoring that has incorporated a social justice lens. We conclude that there is a need for greater attention to principles of social justice in the design, implementation, and evaluation of youth mentoring interventions. After reviewing the literature, we make recommendations for research and practice based on a social justice perspective and explore alternatives to traditional youth mentoring that may allow for better alignment with social justice principles.


[Correlation of hormone-metabolic status in breast cancer and effectiveness of adjuvant hormone therapy].
Hormono-metabolic status was assayed before and after month 6, 12, 24, 36, 48, 54 and 60 of therapy in 72 patients with receptor-positive tumors of the breast who completed 5 years of adjuvant tamoxifen (20 mg/24 hrs) or letrozole (2.5 mg/24 hrs). Eleven patients were not followed up, 11 relapsed and had metastases while 50 completed therapy. Significant fall in body mass (Ketle's index), in C-peptide concentration after an insignificant rise and C-peptide/insulin ratio 129 min after glucose loading, low basal blood level of estradiol as well as stable estradiolemia throughout treatment were characteristic of cases of pre-treatment recurrence and metastastic spread. Insulin resistance status, basal serum-estradiol level and fasting its course of development during hormonotherapy should be the subject of further research in criteria for adjuvant hormonotherapy efficacy.


DNA Methylation in Cancer and Aging.
DNA methylation is known to be abnormal in all forms of cancer, but it is not really understood how this occurs and what is its role in tumorigenesis. In this review, we take a wide view of this problem by analyzing the strategies involved in setting up normal DNA methylation patterns and understanding how this stable epigenetic mark works to prevent gene activation during development. Aberrant DNA methylation in cancer can be generated either prior to or following cell transformation through mutations. Increasing evidence suggests, however, that most methylation changes are generated in a programmed manner and occur in a subpopulation of tissue cells during normal aging, probably predisposing them for tumorigenesis. It is likely that this methylation contributes to the tumor state by inhibiting the plasticity of cell differentiation processes. Cancer Res; 76(12); 3446-50. ©2016 AACR.


Combined use of alcohol and energy drinks: Dose relationship with self-reported physiological stimulation and sedation side effects.
Negative physiological stimulation and sedation side effects are experienced by a significant proportion of consumers who consume alcohol mixed with energy drinks (AmED). Few studies have compared the frequency of side effects between sessions of AmED and sessions of alcohol only within-subject, and none have explored a dose relationship. Explore the occurrence of self-reported physiological stimulant and sedative side effects between sessions of AmED and alcohol only, and at varying ED dosage levels within AmED sessions. A convenience sample of 2953 residents of New South Wales, Australia completed an online survey. N=731 AmED users reported daily caffeine intake, typical alcohol and AmED consumption, and past 12-month experience of physiological stimulation and sedation side effects during AmED and alcohol only sessions. Within-subject analyses compared occurrence of side effects between session types. Hierarchical binary logistic regression analyses explored the association of ED dose during AmED sessions with the experience of physiological side effects. There were greater odds of most stimulant side effects, and lower odds of sedation side effects, during AmED sessions compared to alcohol only sessions. Compared to one ED, consumption of three or more EDs was significantly associated with the majority of both stimulant and alcohol intoxication side effects after controlling for demographics and consumption covariates. AmED is associated with perceived changes in physiological stimulant and sedation side effects of alcohol. Experience of side effects is positively associated with ED dosage. Future research should account for varying ED dosage, and reflect real world consumption levels.


Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia.
Renal hypouricemia is an inherited disorder characterized by impaired renal urate (uric acid) reabsorption and subsequent low serum urate levels, with severe complications such as exercise-induced acute renal failure and nephrolithiasis. We previously identified SLC22A12, also known as URAT1, as a causative gene of renal hypouricemia. However, hypouricemic patients without URAT1 mutations, as well as genome-wide association studies between urate and SLC2A9 (also called GLUT9), imply that GLUT9 could be another causative gene of renal hypouricemia. With a large human database, we identified two loss-of-function heterozygous mutations in GLUT9, which occur in the highly conserved "sugar transport proteins signatures 1/2." Both mutations result in loss of positive charges, one of which is reported to be an important membrane topology determinant. The oocyte expression study revealed that both GLUT9 isoforms showed high urate transport activities, whereas the mutated GLUT9 isoforms markedly reduced them. Our findings, together with previous reports on GLUT9 localization, suggest that these GLUT9 mutations cause renal hypouricemia by their decreased urate reabsorption on both sides of the renal proximal tubules. These findings also enable us to propose a physiological model of the renal urate reabsorption in which GLUT9 regulates serum urate levels in humans and can be a promising therapeutic target for gout and related cardiovascular diseases.


Swallow-induced syncope and carotid sinus hypersensitivity: Coincident or associated conditions?
Swallow induced syncope is a rare clinical condition which is thought to result from an abnormal vagal reflex leading to bradycardia and cerebral hypoperfusion. It mostly occurs in patients with organic or functional disorders of the esophagus, and often requires permanent pacemaker implantation, along with treatment of the underlying esophageal pathology. In the following case, we report of a 71-year-old male with achalasia post per oral endoscopic myectomy, who presented with syncope and documented AV-block while eating solid food. In addition, long sinus pauses were noted during carotid sinus massage, suggesting that the two distinct entities may be associated, and further supporting the mechanism of neurally mediated syncope in the pathophysiology of swallow-induced syncope.


Effect of urea denaturation on tryptophan fluorescence and nucleotide binding on tubulin studied by fluorescence and NMR spectroscopic methods.
Tubulin, the major protein of microtubules, has been shown to be an example of protein undergoing multistep unfolding. Local unfolding and stepwise loss of a number of characteristic functions were demonstrated. In order to understand urea induced effects on tryptophan fluorescence and nucleotide binding on tubulin, both fluorescence and NMR techniques were used. Tubulin was denatured by different urea concentrations. The present experiments were carried out at concentrations of tubulin (to approximately 10 microM) at which most of the protein will be in the dimeric state. Quenching studies in the presence of KI suggest that all the tryptophans are fairly solvent exposed. Similar studies using acrylamide as quencher, suggest unfolding of tubulin at these protein concentrations to be an apparent two state process between the native and the completely unfolded states unlike at low concentrations where a partially folded intermediate was observed. No observable effects of the nucleotide or the metal ion on tryptophan fluorescence were observed. An attempt was made using NMR to monitor the changes in the nucleotide interaction with tubulin as the protein is unfolded by urea denaturation. No significant effects were observed in the binding of the nucleotide to tubulin by urea denaturation.


Clinical Characteristics and Visual Outcomes of Patients Hospitalized for Ocular Trauma in Shandong Province, China.
To analyze the clinical characteristics and visual prognoses of patients with ocular trauma treated in Shandong Eye Hospital. The inpatient data of patients with eye injuries hospitalized in our institution from January 2014 to December 2018 were retrospectively reviewed, including demographic information, types of trauma, causes of injury, treatment, and initial and final visual acuities. A total of 1,425 patients (1,622 eyes), aged 39.5 ± 18.5 years, were included. The ratio of male to female was 5.3 : 1. Of the mechanical eye injuries, there were 490 (34.4%) open-globe injuries and 454 (31.9%) closed-globe injuries. Nonmechanical eye injuries had 426 patients (29.9%), while 55 patients (3.9%) had adnexal injuries. Over a half of the traumas were work-related (51.1%, 728 patients). Most patients were treated with surgical intervention (1,404 eyes, 87.9%). There were significant differences in the final visual acuities between open-globe injuries and closed-globe injuries (P < 0.001), as well as between mechanical injuries and nonmechanical injuries (P < 0.001). The final visual acuity was closely correlated with the initial visual acuity (Spearman's correlation coefficient = 0.618, P < 0.001) and the OTS score (Spearman's correlation coefficient = 0.691, P < 0.001). Ocular trauma usually occurs in young and middle-aged men and in the workplace in Shandong Province. The proportion of nonmechanical injuries is high, and the prognosis is poor. A comprehensive understanding of the characteristics of ocular trauma is useful for blindness prevention and treatment.


Elaborative feedback in clinical dental teaching-An assessment from the students' perspective.
The aim of this prospective learning research study is to examine the impact of structured elaborative feedback in clinical dental skills teaching from the students' perspective. A total of 60 dental students participated in the study. The mean average age was 23 years (20-40 years), of which 37 were female (61.7%) and 23 male (38.3%). The participants were randomly divided into a study and control group (n=30 each). The curriculum for clinical tooth-shade differentiation is a complete educational module. Recording of shade taking was carried out on the phantom patient using clinically simulated settings with elaborative feedback in the study group. Pre-test (begin of module T1) and post-test (end of module T2) questionnaires were used to assess knowledge and interest in connection with elaborative feedback. Subjective learning success from the students' perspective and the acceptance of the learning environment were recorded using a questionnaire at the end of the module. The responses corresponded to a Likert scale. The STATA program (Stata/MP 12, StataCorp, CollegeStation, USA) was used for statistical analyses (p<0.05). A clear improvement in the quality of response in both groups was observed for questions regarding knowledge of the content and interest (p<0.001). The highest values were achieved at reference time T2 for "Practical steps with digital tooth-shade measurement devices" in the study group. Subjective success in terms of learning and the acceptance of the learning environment tended to be rated more highly in the study group. These results corresponded with the reduction of errors during the practical exercises. All participants (100%) in the study group found individual feedback to be helpful.


'Why didn't they see my scars?' Critical thematic analysis of simulated participants' perceived tensions surrounding objective structured clinical examinations.
Simulated participants (SPs) play an important role in simulated assessments of clinical encounters between medical students and patients, most notably in objective structured clinical examinations (OSCEs). SP contributions to OSCEs are invaluable, taking the role of a patient or carer. While SPs in some settings/contexts may rate students, their role has been problematized in the literature for their lack of agency within a standardised format of OSCEs that promotes reliability, objectivity and accountability. In this study, we explored SP experiences for tensions that result from simulated assessments and their potential implications for education. Semi-structured interviews were conducted with seven SPs who were also tasked with providing a global mark for students. They were purposively selected to include women and men of different ages, occupation, education and experience as an SP. The interviews were analysed using a critical thematic analysis using a phenomenological approach. SP experiences directly addressed tensions and contradictions around OSCEs. SP participants described their experiences under four themes: industrialising, reducing, performativity and patient safety. OSCEs were compared to an industrial process that promoted efficiency but which bore no resemblance to real-life doctor-patient encounters. They were perceived to have a power and agency that reduced SPs to verbalising scripts to ensure that students were exposed to a standardised simulated experience that also underlined the performative role of SPs as props. These performative and reductionist experiences extended to students, for whom the mark sheet acted as a checklist, promoting standardised responses that lacked genuineness. All of this created a tension for SPs in promoting patient safety by ensuring that those medical students who passed were clinically competent. OSCEs often form part of high-stakes exams. As such, they are governed by processes of industrialisation, accountability and standardisation. OSCEs possess a power and agency that can have unintended negative consequences. These include 'conditioning' students to adopt behaviours that are not suited to real-life clinical encounters and are not person-centred.


[Iron and copper in Plagioscion squamosissimus (Piscis: Sciaenidae) from the Orinoco river, Venezuela].
Bauxite explotation of the Orinoco River in recent years is an important source of heavy metals discharge in the ecosystem, changing the natural biochemical flow of these elements and their concentrations in water, sediment and organisms. Iron and copper concentrations were measured in the fish Plagioscion squamosissimus in the Orinoco river, by sampling the fish population for three months (September-November 1998) in the main channel of the middle Orinoco (07 degrees 38' 21.2" N; 66 degrees 19' 10.9" W) and in Castillero lagoon (7 degrees 39' 09" N; 66 degrees 09' 00" W) with 2 and 4 cm mesh sizes. The internal organs of 30 fishes per month and site were stove-dried at 80 degrees C, pulverized and dried in disecator for 30 min to use as indicators with the acid digestion method for predicting the effect of heavy metals. We found relatively high values of iron and copper concentrations in fishes of the lagoon, and high seasonal variations in the iron concentration.


Dynamic control of protein folding pathway with a polymer of tunable hydrophobicity.
While the knowledge of protein folding in a dilute solution is now well-advanced, little is known of the influence of surrounding conditions on the folding kinetics, in particular when the protein is in a dynamically responsive environment. Here we report a new procedure to control the pathways of protein folding by using a thermally responsive polymer that varies its hydrophobicity concomitant with the protein structural changes. The advantages of folding in a dynamic environment have been demonstrated first by Langevin dynamics simulations on the basis of coarse-grained models for both the protein and polymer and then by experiments for lysozyme refolding in the presence of poly(N-isopropylacrylamide-co-N-tert-butylacrylamide), a thermal responsive polymer that varies its hydrophobicity in response to temperature. The simulation suggests that decreasing the polymer hydrophobicity during the folding process may result in an optimized free-energy landscape that enhances both the folding yield and kinetics. The experiments affirm that an optimal folding condition can be identified when structural transitions of the protein collaborate with the polymer hydrophobicity tuned by variation of temperature.


Radiographic absorptiometry for pre-screening of osteoporosis in patients with low energy fractures.
Dual energy X-ray absorptiometry (DEXA) is the most accurate method and thus the method of choice for diagnosing osteoporosis. Due to the limited access to DEXA-scanners, screening of patients with low energy fractures (LEF) for osteoporosis is not routinely performed in Denmark. Pre-screening with a simple, less expensive device might be able to exclude patients with normal bone mineral density (BMD) from further DEXA-scans. We aimed to determine the frequency of osteoporosis in patients with LEF, and evaluate the diagnostic impact of a radiographic absorptiometry (RA) scanner in the casualty department of a major Danish county hospital. In a 5-month period, 136 adult patients with LEF were invited for BMD measurements. In 74 (54%) patients DEXA-scans (spine and femoral neck) and phalangeal RA-scans were performed. A total of 86% of the patients were female and 39% were suffering from osteoporosis (T-scores < or = -2.5) according to the DEXA results. RA-BMD and T-scores differed significantly between the two groups, with and without osteoporosis (p < 0.001). Comparing T-scores from RA with the lowest T-scores from DEXA, a highly significant correlation was found for women (R = 0.7, p < 0.001). Using a RA cut-off value (T-score < -1) for women ensuring 100% sensitivity for identifying women with osteoporosis, the positive predictive value was 46%. Up to 19% of DEXA-scans could be avoided in this setting. In our population the simple RA-BMD-method was cost-effective as a pre-screening tool for osteoporosis in women. However, the final diagnosis still relies on results from DEXA-scans.


[Potential applications of marijuana and cannabinoids in medicine].
Cannabinoids, psychoactive substances present in cannabis, have been known to mankind for hundreds of years. Apart from 9-tetrahydrocannabinol (THC) substances found in the cannabis herb with the highest toxicological value are cannabidiol (CBD) and cannabinol (CBN). The discovery of CB1 and CB2 receptors, located in various tissues (ranging from the brain to peripheral tissues), has defined the potential objective of these new chemical substances' effects. Many studies on the application of cannabinoids in the treatment of various diseases such as diabetes, neoplasms, inflammatory diseases, neurological conditions, pain and vomitting were conducted. Drugs containing e.g. THC appear on the pharmaceutical market. Substances affecting cannabinoid receptors may show beneficial effects, but they may also cause the risk of side effects related mainly to the inhibition of central nervous system. The purpose of this dissertation is the analysis, whether the substances responsible for the effects of marijuana, can find application in medicine. Original articles and reviews were used to summarize the results of studies connected to the topic.


Poliovirus detection in wastewater and stools following an immunization campaign in Havana, Cuba.
Recent outbreaks of poliomyelitis caused by vaccine-derived virus have raised concerns that vaccine-derived poliovirus may continue to circulate after eradication. In these outbreaks, the virus appears to have replicated for > or =2 years before detection. Early detection is critical for an effective response to these outbreaks. Although acute flaccid paralysis (AFP) surveillance will remain the standard for poliovirus detection, wastewater sampling could be a useful supplement. In this study, we evaluated the sensitivity of wastewater sampling by concurrently collecting stools from children aged < 3 years attending two neighbourhood clinics in Havana, Cuba, and wastewater from the same neighbourhoods. Sample collection was begun during the third week after the national immunization campaign, continued weekly through the seventh week, and was repeated during weeks 15 and 19. Virus detection and titration were performed using both cell culture and polymerase chain reaction techniques. Wastewater sampling was found to be at least as sensitive as stool sampling under these conditions. Poliovirus was isolated from children through week 7, suggesting that viral shedding reached undetectable levels between weeks 8 and 14. The last virus-positive wastewater sample was collected during week 15. Wastewater sampling under the conditions studied can be a sensitive supplement to AFP surveillance. Similar studies under different conditions are needed to determine the role of wastewater sampling in post-eradication surveillance.


Experimental demonstration of photon upconversion via cooperative energy pooling.
Photon upconversion is a fundamental interaction of light and matter that has applications in fields ranging from bioimaging to microfabrication. However, all photon upconversion methods demonstrated thus far involve challenging aspects, including requirements of high excitation intensities, degradation in ambient air, requirements of exotic materials or phases, or involvement of inherent energy loss processes. Here we experimentally demonstrate a mechanism of photon upconversion in a thin film, binary mixture of organic chromophores that provides a pathway to overcoming the aforementioned disadvantages. This singlet-based process, called Cooperative Energy Pooling (CEP), utilizes a sensitizer-acceptor design in which multiple photoexcited sensitizers resonantly and simultaneously transfer their energies to a higher-energy state on a single acceptor. Data from this proof-of-concept implementation is fit by a proposed model of the CEP process. Design guidelines are presented to facilitate further research and development of more optimized CEP systems.


GENETIC STRUCTURE AND EVOLUTION OF SPECIES IN THE MANGROVE GENUS AVICENNIA (AVICENNIACEAE) IN THE INDO-WEST PACIFIC.
Allozyme variation in species of the mangrove genus Avicennia was screened in 25 populations collected from 22 locations in the Indo-West Pacific and eastern North America using 11 loci. Several fixed gene differences supported the specific status of Avicennia alba, A. integra, A. marina, and A. rumphiana from the Indo-West Pacific, and A. germinans from the Atlantic-East Pacific. The three varieties of A. marina, var. marina, var. eucalyptifolia, and van australasica, had higher genetic similarities (Nei's I) and no fixed gene differences, confirming their conspecific status. Strong genetic structuring was observed in A. marina, with sharp changes in gene frequencies at the geographical margins of varietal distributions. The occurrence of alleles found otherwise in only one variety, in only immediately adjacent populations of another variety, provided evidence of introgession between varieties. The varieties appear to have diverged recently in the Pleistocene and are apparently not of ancient Cretaceous origin, as suggested earlier. Despite evidence of high degrees of outcrossing, gene flow among populations was relatively low (Ne m < 1-2), except where populations were geographically continuous, questioning assumptions that these widespread mangrove species achieve high levels of long-distance dispersal.


Mood enhancement persists for up to 12 hours following aerobic exercise: a pilot study.
The objective was to estimate the duration of the effects of aerobic exercise on mood. Healthy men (n = 13) and women (n = 35) ages 18 to 25 years (M = 20.2, SD = 3.4) were randomly assigned to either a control or exercise group. Participants completed the Profile of Mood States before, after, and at 1, 2, 4, 8, 12, and 24 hours following either exercise at 60% VO2 peak or quiet rest. Repeated-measures analysis of covariance was utilized with VO2 peak entered as a covariate. The exercise group showed significantly lower total mood disturbance immediately after and at 4, 8, and 12 hours following exercise.


Functional role of nerve-derived nitric oxide in isolated dog ophthalmic arteries.
To determine if nitric oxide (NO) is involved in the relaxant response to nerve stimulation by nicotine and electrical pulses in dog external ophthalmic arteries (EOA) and internal ophthalmic arteries (IOA). Changes in isometric tension were recorded in helical strips of the arteries, and the presence of perivascular nerve containing NADPH diaphorase was histochemically demonstrated. Nicotine (10(-4) M, EOA and IOA) and transmural electrical stimulation (5 Hz, EOA) produced a slight or no contraction followed by a moderate relaxation in the strips contracted with prostaglandin F2 alpha. The contraction was abolished by alpha-adrenoceptor antagonists. The relaxation was abolished and the contraction was potentiated by NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthase inhibitor; the relaxation was reversed by L-arginine. Contractile response in L-NA-treated EOA was greater than in the IOA, and the relaxation was less in nontreated EOA. NO-induced relaxation and norepinephrine-induced contraction were not influenced by L-NA. There were plenty of nerve fibers visualized by NADPH diaphorase staining method in the adventitia of EOA and IOA, indicating the presence of NO synthase-containing nerves. The neurogenic relaxation appears to be mediated by NO released from the vasodilator nerve in EOA and IOA. There is a reciprocal innervation in vasodilator nitroxidergic and vasoconstrictor noradrenergic nerves; functionally, the latter is more predominant in EOA than in IOA.


Changes in the Muscle Activity of Gymnasts During a Handstand on Various Apparatus.
Kochanowicz, A, Niespodziński, B, Mieszkowski, J, Marina, M, Kochanowicz, K, and Zasada, M. Changes in the muscle activity of gymnasts during a handstand on various apparatus. J Strength Cond Res 33(6): 1609-1618, 2019-Gymnasts perform handstands on various apparatus, both in stable and unstable conditions. Such performances require specific muscle activation, which should differ depending on the condition and expertise of the gymnast. Therefore, the aim of the study was to evaluate (a) the difference in electromyography (EMG) between handstands performed on 3 apparatus (floor, rings, and parallel bars); and (b) the difference between young and well-trained adult gymnasts. Ten adult (25 ± 3.94 years) and 15 young (13.9 ± 0.7 years) gymnasts participated in the study. We investigated EMG amplitude in 13 muscles normalized by arbitrary angle maximal isometric voluntary contraction (normalized root mean square [NRMS]). In comparison with the handstand on the floor (61 ± 28%), the wrist flexor muscles of gymnasts exhibited a decreased NRMS on the parallel bars (44 ± 25%; p = 0.017), and rings (46 ± 32%; p = 0.029), whereas no changes were observed in the triceps brachii. The rest of the investigated muscles showed a higher NRMS in rings. Differences between young and adult gymnasts were seen in the triceps brachii and anterior deltoid muscles, where more experienced gymnasts showed 19.1% (p = 0.014) and 17.6% (p = 0.048) lower NRMS, respectively. The different gymnastic apparatus led to specific muscle activation. This activation predominantly depended on hand support conditions, which alternated the primary wrist strategy of the handstand balance control, and in consequence, the activation of other muscles controlling balance. Training focused on the development of motor control and strength of the anterior deltoid, pectoralis major, latissimus dorsi, biceps brachii, and trapezius descendens muscles to improve handstand performance.


Economic evaluation of cancer therapies: more and better studies will lead to better choices in cancer care.
Randomised phase III trials are the ideal setting for prospective collection of economic and health related quality of life (HRQL) data. Many studies combine prospective clinical data with economic assumptions or data collected in separate costing studies. To extrapolate the trial outcomes to lifelong consequences, modelling approaches are often used. Also, in situations where no randomised trial data are available, modelling approaches are often applied. In this paper some methodological and practical issues are described. The aim of the economic evaluations is to support decision-making. As many new promising anti cancer drugs are forthcoming, the questions of how decision-makers will use the results of the economic evaluations and how patients can optimally benefit from these new drugs arise.


Serum protein electrophoresis abnormalities in adult solid organ transplant patients with post-transplant lymphoproliferative disorder.
Post-transplant lymphoproliferative disorder (PTLD) is an Epstein-Barr virus (EBV) associated malignancy that occurs in the setting of pharmacologic immunosuppression used after organ transplantation. The presence of monoclonal gammopathy (MG) after organ transplantation is a risk factor for the development of PTLD. We retrospectively explored the characteristics of serum protein electrophoresis (SPEP) in 38 adult solid organ transplant patients with biopsy proven PTLD and SPEP. Twenty-three (61%) had MG with nine (24%) showing multiple MG. Background gammaglobulin levels were abnormal in 13 (34%) patients with five (13%) and eight (21%) having polyclonal hypergammaglobulinemia or hypogammaglobulinemia, respectively. Hypogammaglobulinemia was correlated with the presence of MG (p = 0.01) and polymorphic B-cell hyperplasia histology (p = 0.01). No correlation between SPEP findings and overall survival were noted. With median follow-up of 116 wk (range 2-261 wk), 21 (55%) patients are alive with 20 (53%) in complete remission. Response to reduction in immunosuppression was correlated with improved overall survival (262 wk vs. 68 wk, p = 0.003). Persistence of MG after complete response of the PTLD did not predict relapse. There is a high incidence of MG and gammaglobulin abnormalities in patients with PTLD.


Myocardial Contraction during the Diastolic Isovolumetric Period: Analysis of Longitudinal Strain by Means of Speckle Tracking Echocardiography.
According to the ventricular myocardial band model, the diastolic isovolumetric period is a contraction phenomenon. Our objective was to employ speckle-tracking echocardiography (STE) to analyze myocardial deformation of the left ventricle (LV) and to confirm if it supports the myocardial band model. This was a prospective observational study in which 90 healthy volunteers were recruited. We evaluated different types of postsystolic shortening (PSS) from an LV longitudinal strain study. Duration of latest deformation (LD) was calculated as the time from the start of the QRS complex of the ECG to the latest longitudinal deformation peak in the 18 segments of the LV. The mean age of our subjects was 50.3 ± 11.1 years. PSS was observed in 48.4% of the 1620 LV segments studied (19.8%, 13.5%, and 15.1% in the basal, medial, and apical regions, respectively). PSS was more frequent in the basal, medial septal, and apical anteroseptal segments (>50%). LD peaked in the interventricular septum and in the basal segments of the LV. The pattern of PSS and LD revealed by STE suggests there is contraction in the postsystolic phase of the cardiac cycle. The anatomical location of the segments in which this contraction is most frequently observed corresponds to the main path of the ascending component of the myocardial band. This contraction can be attributed to the protodiastolic untwisting of the LV.


[The influence of Bazhen decoction on hematopoietic modulator in anaemic mice].
This study was designed to evaluate the effect of Bazhen decoction on bone marrow depression induced by cyclophosphamide (CY) in mice. An experimental model of mouse bone marrow injury was established through cyclophosphamide induced and the following phenomena were observed. The techniques of culture of hematopoietic progenitor cell and hematopoietic growth factor assay were used. Bazhen decoction could obviously promote the proliferation of bone marrow cells of anaemic mice. The culture media of spleen cell, macrophage, lung and skeletal muscle treated with Bazhen decoction had much stronger stimulating effects on hematopoietic cells. The bone marrow cells of the anaemic mice could yield TNF through Bazhen decoction treatment. It was suggested that Bazhen decoction is clinically a hopeful drug used to cure bone marrow depression and attenuate the side effects of CY.


Expression and localization of prolyl oligopeptidase in mouse testis and its possible involvement in sperm motility.
Prolyl oligopeptidase (POP) expression in mouse testis during sexual maturation was examined. Northern blot analysis showed that POP mRNA expression was highest at 2 weeks of age, and gradually reduced thereafter. However, enzyme activity was almost constant during the examined period. In situ hybridization study revealed a change in the expression site of POP mRNA in testis during sexual maturation. Positive signals were detected in all types of cells in the seminiferous tubules before maturation, and were restricted to spermatids at the spermatogenesis cycle stages I-VIII in adult mice. POP was detected in the insoluble fraction of sperm by Western blot analysis. Immunohistochemical analyses showed that POP is localized in the spermatids at steps 12-16 of spermiogenesis and in the midpiece of the sperm fragellum. It was also found that specific POP inhibitors, poststatin and benzyloxycarbonyl-proline-prolinal, suppressed sperm motility. These results suggest that POP may be involved in meiosis of spermatocytes, differentiation of spermatids, and sperm motility in the mouse.


The evaluation of five specialized support surfaces by use of a pressure-sensitive mat.
This study used two full-size pressure-sensitive mats to evaluate five patient support surfaces. The mats, containing 1,536 and 2,340 pressure measurement sites, respectively, made it possible to quantify the entire interface pressure distribution of each support surface. Measurements for groups of 64 and 32 subjects were obtained in supine positions of 0 degree, 30 degrees, at maximal head elevations (50 degrees-60 degrees), and at lateral recumbency. Several statistical descriptors were calculated to characterize the interface pressure distributions. The support surfaces tested included: a powered-air overlay (ACUCAIR Continuous-Air-flow System), a low-airloss bed (FLEXICAIR MC3 Low-Airloss Therapy), a continuous lateral-rotation low-airloss bed (RESTCUE Dynamic Air Therapy), an air-fluidized bed (CLINITRON II Air-Fluidized Therapy), and an integrated bed (prototype Advance 2000 Bed). An analysis of variance revealed that the interface pressure was significantly lower and weight-bearing area was significantly higher on the five surfaces, when compared to the standard hospital mattress.


Prediction of endoscopic disease activity in ulcerative colitis by two different assays for fecal calprotectin.
As mucosal healing is the goal of treatment in inflammatory bowel disease, defining a fecal [f-] calprotectin cut-off level for mucosal healing is crucial. Previous studies have presented different cut-off levels. The aim of this study was to investigate the ability of two f-calprotectin assays to differentiate mucosal healing from inflammation in ulcerative colitis. Sixty-two patients with ulcerative colitis underwent colonoscopy for classification of mucosal inflammation [Mayo endoscopic subscore]. The patients also submitted a fecal sample for f-calprotectin analysis using two different assays, Calpro ELISA and Buhlmann ELISA. The two assays correlated significantly, with a Spearman rank correlation coefficient of 0.86. Both assays showed significantly different f-calprotectin levels in patients with a Mayo endoscopic subscore of 0 [mucosal healing] and 1–3 [inflamed mucosa] [p <0.001]. Using ROC curve analyses, we selected the best cut-off levels for both assays with responding sensitivity and specificity [presented with 95% confidence intervals]; Calpro ELISA cut-off 61 μg/g, sensitivity 84.1% [75.0–93.2%], specificity 83.3 % [74.0–92.6%], and Buhlmann ELISA cut-off 96 μg/g, sensitivity 90.9 % [83.7–98.1%], specificity 83.3 % [74.0–92.6%]. Defining mucosal healing as a Mayo endoscopic subscore ≤1, cut-off levels increased: Calpro ELISA cut-off 110 μg/g, sensitivity 80.0%[70–90%], specificity 66.6 % [54.9–78.3%]; and Buhlmann ELISA cut-off 259 μg/g, sensitivity 83.3 %[74–92.6%], specificity 71.9 % [60.7–83.1%]. The study demonstrates the need for assay specific cut-off levels in clinical practice,as the f-calprotectin cut-off level for endoscopic disease activity differed in these two assays.


Role of Cross Sectional Imaging in Isolated Chest Wall Tuberculosis.
Isolated chest wall tuberculosis though a rare entity, the incidence of it has been on rise among immunocompromised population making it an important challenging diagnosis for the physicians. Its clinical presentation may resemble pyogenic chest wall abscess or chest wall soft tissue tumour. Sometimes it is difficult to detect clinically or on plain radiograph. The present study was conducted with an aim to evaluate the common sites and varying appearances of isolated chest wall tuberculosis. A hospital based cross-sectional retrospective study was conducted in Assam Medical College and Hospital, a tertiary care centre in North East India. The study group comprise of 21 patients (n=15 male and n=6 females) with isolated chest wall tuberculosis without associated pulmonary or spinal involvement who were subjected to Computed Tomography/Magnetic Resonance Imaging (CT/MRI) of the thorax following initial Ultrasonogram (USG) evaluation of the local site. Pathological correlation was done from imaging guided sampling of the aspirate or surgery. Variable sites of involvement were seen in the chest wall in our patients (n=21), with chest wall abscess formation being the most common presentation and rib being the most common bony site affected in the thoracic cage. Bony sclerosis was noted in 11 patients (52.4%), periosteal reaction in 10 patients (47.6%) and sequestration in five patients (23.8%). CT/MRI not only localized the exact site and extent of the abscesses which facilitated guided aspirations, but also helped in detecting typical bony lesions thereby, differentiating from pyogenic osteomyelitis besides ruling out associated pulmonary or pleural involvement in such patients. Cross-sectional imaging plays an important role by giving a wholesome picture of both soft tissue and bony pathology. It is important to have adequate understanding of the radiologic manifestations of the chest wall involvement and complications of tuberculosis to facilitate diagnosis and in assessing response to treatment on follow up in patients.


Triptycene End-Capped Benzothienobenzothiophene and Naphthothienobenzothiophene.
Previously it was demonstrated that triptycene end-capping can be used as a crystal engineering strategy to direct the packing of quinoxalinophenanthrophenazines (QPPs) towards cofacially stacked π dimers with large molecular overlap resulting in high charge transfer integrals. Remarkably, this packing motif was formed under different crystallization conditions and with a variety of derivatives bearing additional functional groups or aromatic substituents. Benzothienobenzothiophene (BTBT) and its derivatives are known as some of the best performing compounds for organic field-effect transistors. Here, the triptycene end-capping concept is introduced to this class of compounds and polymorphic crystal structures are investigated to evaluate the potential of triptycene end-caps as synthons for crystal engineering.


Routine complete capsular closure during hip arthroscopy.
The utility of hip arthroscopy has recently progressed beyond diagnostic to therapeutic purposes addressing central and peripheral compartment pathologies. Capsulotomy provides freedom of visualization and instrumentation. The contribution to hip stability of both dynamic and static hip structures is not fully understood. However, both basic science biomechanical and clinical outcome studies have exhibited a relevant role of the capsule in hip stability. Though rare, iatrogenic post-arthroscopy subluxation and dislocation have been reported. Therefore many surgeons have cautioned against aggressive capsulotomy or capsulectomy without repair, because of the potential for precipitation of iatrogenic hip instability. We typically perform a "T" capsulotomy and recommend complete capsular closure in conjunction with labral repair and osseous femoral and acetabular treatment. A safe, efficient, and effective method to accomplish complete capsular closure is presented to reduce iatrogenic postoperative hip instability.


A proof of concept trial of an online psychoeducational program for relatives of both veterans and civilians living with schizophrenia.
Family psychoeducation has been found to reduce relapse in schizophrenia but penetration rates are low. In this study, we evaluate the feasibility of an online multifamily group program for relatives of persons with schizophrenia that can be accessed from participants' homes. We explored participation rates and evaluations of a 12-month multimodal website intervention. Using a quasi-experimental design, we compared illness outcomes (factors on the Brief Psychiatric Rating Scale, hospitalizations) of persons with diagnosed schizophrenia, and relative distress outcomes (somatic concerns and anxiety/depression subscales on the Brief Symptom Inventory) from relatives participating in the intervention (n = 26) to archival data we had from comparable dyads who received customary care (n = 16). The majority of participants in the program attended more than half the core online support sessions, expressed high levels of satisfaction, and found the technology easy to access. There appeared to be little impact of online participation on clinical status of persons with schizophrenia or relatives' distress, although there was a trend for fewer hospitalizations in the online group. Small sample size is a factor in interpreting results. Online interventions for relatives of persons with schizophrenia, while feasible, present unique challenges. These include 1) assuring access to the intervention in populations who do not own a computer; 2) addressing privacy concerns; 3) overcoming the special challenges of conducting groups in real time; 4) managing emergent situations adequately; and 5) questions about efficacy.


Occipitoatlantal instability associated with articular tropism.
The authors report the case of a patient with rotatory posterior subluxation of the occiput on the atlas associated with tropism of the O-C1 articulations. Lateral flexion-extension plain films demonstrated 5 mm of posterior translation of the occiput on the atlas. Tomographs revealed tropism of the O-C1 articulations, and CT scans on extension demonstrated posterior rotatory subluxation of the occiput on the atlas. The patient had no osseous abnormality caudally below the atlantoaxial joint, and underwent posterior occipitoatlantal fusion by wiring. At the 4-year follow-up, the grafted bone had been incorporated, and the patient was completely free from preoperative symptoms. In the present patient, occipitoatlantal instability is presumed to have derived from articular tropism.


Determination of antimicrobial effect of protamine by transmission electron microscopy and SDS PAGE on Pseudomonas aeruginosa isolates from diabetic foot infection.
Diabetic foot infection is one of the major complications of diabetes leading to lower limb amputations. Isolation and identification of bacteria causing diabetic foot infection, determination of antibiotic resistance, antimicrobial potential of protamine by electron microscopy and SDS-PAGE analysis, arethe aims of this study. 285 pus samples from diabetic foot infection patients were collected from different hospitals of Karachi and Capital Health Hospital, Halifax, Canada. Clinical history of each patient was recorded. Bacterial isolates were cultured on appropriate media; identification was done by morphology, cultural and biochemical tests. Effect of protamine against multi drug resistant strains of Pseudomona aeruginosa was checked by minimum inhibitory concentration in 96 well micro-titer plates. The isolates were grown in bactericidal concentration of protamine on plates to isolate mutants. Effect of protamine on protein expression was checked by SDS- PAGE and ultra-structural morphological changes by transmission electron microscopy. Results indicated prevalence of foot infection as 92% in diabetic patients. Major bacterial isolates were Staphylococcus aureus 65 (23%), P. aeruginosa 80 (28.1%), Klebsiella spp. 37 (13%), Proteus mirabilis 79 (27.7%), and Escherichia coli 24 (12%). These isolates were highly resistant to different antibiotics. MIC value of protamine was 500 µg/ml against P. aeruginosa. SDS-PAGE analysis revealed that protamine can suppress expression of various virulence proteins and electron micrographs indicated condensation of cytoplasm and accumulation of protamine in cytoplasm without damaging the cell membrane. P. aeruginosa and S. aureus were the major isolates expressing multi-drug resistance and protamine sulfate represented good antimicrobial potential.


Hormonal and metabolic responses to cardiac surgery with sufentanil-oxygen anaesthesia.
The effects of sufentanil, 10 and 20 micrograms kg-1 on the hormonal and metabolic responses to coronary artery surgery were compared in 20 patients. The most important finding was that the changes in circulating beta-endorphin, ACTH, cortisol, GH, glucose, lactate and glycerol concentrations during and after cardiac surgery were similar with both doses of sufentanil. Although sufentanil prevented a significant increase in plasma beta-endorphin, ACTH and cortisol values until 6 h after cardiopulmonary bypass (CPB), a significant increase in GH secretion occurred with the onset of CPB. Plasma insulin concentrations declined significantly after 30 min CPB, but recovered after 60 min CPB with the restoration of normothermia. Blood glucose values did not change during surgery before CPB, but started to rise with the onset of CPB and continued to increase significantly in the postoperative period. Changes in blood lactate and plasma glycerol concentrations primarily reflected the load of CPB and the effects of heparin, respectively. The results show that increasing the dose of sufentanil up to 20 micrograms kg-1 does not result in better suppression of the endocrine and metabolic changes associated with cardiac surgery.


Cerebellar atrophy following diphenylhydantoin intoxication.
Seven epileptic patients with permanent ataxic dysfunction following DPH treatment are described. The ataxia correlates with cerebellar atrophy, though the extents of clinical and structural lesions are not necessarily proportional. Cerebellar atrophy is demonstrated by CT scans, the vermal region seems to be predominantly affected.--The tentatively increased susceptibility of female patients and of patients with pre-existing brain lesions, as well as the possible consequences pertaining to the course of the epilepsy are discussed.


Identification of ecologically significant habitats for urban nature conservation: a case study in Turkey.
Given the rapid urbanization of Turkey, sustained productivity of natural resources should be an integral part of any urban development policy. The biogeochemical cycles and ecosystem services link urban and rural ecosystems. It is, therefore, essential that ecologically significant habitats along urban-rural continuum be protected to secure public and environmental health. This necessitates their identification and the establishment of administrative and legal foundations for urban nature conservation in the management of urban habitats, should be established Ecological analysis of urban habitats of Karşiyaka led to the identification of 19 ecologically significant habitats. Nature conservation priority was rated, using rarity, species richness, stratification, site age, and area of the habitats. Ecologically significant habitats made up about 54 ha of the total urban green space of 289 ha in Karşiyaka. The total number of plant species was estimated to be 273.


Optimization of a mist chamber (Cofer scrubber) for sampling water-soluble organics in air.
While the atmospheric fate and transport of biogenic and anthropogenic hydrocarbons has been extensively studied, little is known about the behavior of first-, second-, and third generation photo-oxidation products that arise from OH radical oxidation of the parent species. The results of chamber experiments establish that *OH oxidation of biogenic and anthropogenic hydrocarbons yields carbonyls, dicarbonyls, hydroxycarbonyls, and keto-acids. However, little is known about the generation and fate of these products in the ambient atmospheric environment. This is changing because of the advent of methods that rely on 0-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBHA) derivatization of carbonyls in concert with gas chromatography/ion trap mass spectrometry. Such methods provide the means to identify and quantify water-soluble organics, which historically have been difficult to measure. A limitation of existing sampling methods, however, is the use of devices that require low flow rates (0.5-1 L min(-1)). Accordingly, long sampling times (3-4 h) are needed to obtain pptv-ppbv detection limits. The mist chamber is an attractive device because of the high flow rates (25-70 L min(-1)) compatible with its use. Herein, we evaluate a mist chamber using a flow rate of 25-30 L min(-1) to provide short (10 min) sampling times and pptv limits of detection. The results establish a relationship between the Henry's law constant (KH) and the collection efficiency and demonstrate the suitability of the method to measure analytes with KH > or = 10(3) M atm(-1). Adjusting the pH, adding quaternary ammonium salts, or decreasing the temperature of the collecting solution in the mist chamber did not significantly affect the collection efficiency. We tested the method by sampling photooxidation products of isoprene (glyoxal, methylglyoxal, hydroxyacetone, and glycolaldehyde) in the Blodgett Forest, CA. This is the first report of a study the employs the mist chamberto sample hydroxycarbonyls. The accuracy and the reproducibility of the method were evaluated by the analysis of duplicate samples and field spikes. The mean recovery of field spikes was > or =80%, and the relative standard deviation was < or =22% between duplicate measurements. The detection limits were 48, 15, 7.7, and 2.7 pptv for glycolaldehyde, hydroxyacetone, methylglyoxal, and glyoxal, respectively. This work demonstrates the power of the mist chamber in concert with PFBHA derivatization and mass spectrometry to measure pptv concentrations of water-soluble organics with a sampling time of 10 min.