Pharmacokinetic profile analyses for inhaled drugs in humans using the lung delivery and disposition model.
The kinetic clarification of lung disposition for inhaled drugs in humans via pharmacokinetic (PK) modeling aids in their development and regulation for systemic and local delivery, but remains challenging due to its multiplex nature. This study exercised our lung delivery and disposition kinetic model to derive the kinetic descriptors for the lung disposition of four drugs [calcitonin, tobramycin, ciprofloxacin and fluticasone propionate (FP)] inhaled via different inhalers from the published PK profile data. With the drug dose delivered to the lung (DTL) estimated from the corresponding γ-scintigraphy or in vivo predictive cascade impactor data, the model-based curve-fitting and statistical moment analyses derived the rate constants of lung absorption (ka ) and non-absorptive disposition (knad ). The ka values differed substantially between the drugs (0.05-1.00 h-1 ), but conformed to the lung partition-based membrane diffusion except for FP, and were inhaler/delivery/deposition-independent. The knad values also varied widely (0.03-2.32 h-1 ), yet appeared to be explained by the presence or absence of non-absorptive disposition in the lung via mucociliary clearance, local tissue degradation, binding/sequestration and/or phagocytosis, and to be sensitive to differences in lung deposition. For FP, its ka value of 0.2 h-1 was unusually low, suggesting solubility/dissolution-limited slow lung absorption, but was comparable between two inhaler products. Thus, the difference in the PK profile was attributed to differences in the DTL and the knad value, the latter likely originating from different aerosol sizes and regional deposition in the lung. Overall, this empirical, rather simpler model-based analysis provided a quantitative kinetic understanding of lung absorption and non-absorptive disposition for four inhaled drugs from PK profiles in humans.


Investigation of Host-Microbe-Parasite Interactions in an In Vitro 3D Model of the Vertebrate Gut.
In vitro models of the gut-microbiome axis are in high demand. Conventionally, intestinal monolayers grown on Transwell setups are used to test the effects of commensals/pathogens on the barrier integrity, both under homeostatic and pathophysiological conditions. While such models remain valuable for deepening the understanding of host-microbe interactions, often, they lack key biological components that mediate this intricate crosstalk. Here, a 3D in vitro model of the vertebrate intestinal epithelium, interfaced with immune cells surviving in culture for over 3 weeks, is developed and applied to proof-of-concept studies of host-microbe interactions. More specifically, the establishment of stable host-microbe cocultures is described and functional and morphological changes in the intestinal barrier induced by the presence of commensal bacteria are shown. Finally, evidence is provided that the 3D vertebrate gut models can be used as platforms to test host-microbe-parasite interactions. Exposure of gut-immune-bacteria cocultures to helminth "excretory/secretory products" induces in vivo-like up-/down-regulation of certain cytokines. These findings support the robustness of the modular in vitro cell systems for investigating the dynamics of host-microbe crosstalk and pave the way toward new approaches for systems biology studies of pathogens that cannot be maintained in vitro, including parasitic helminths.


Examination of the relationship between iron status and cognitive function among healthy young women with and without a recent history of blood donation.
With growing awareness of the prevalence of nonanemic iron deficiency among blood donors, there is a need to explore the extent of potential negative consequences. This study examined the relationship between various measures of iron status, blood donation history, and neuropsychological and psychosocial functioning in healthy young women. Using a cross-sectional design, 160 female undergraduates completed neuropsychology tests and measures of sleep, fatigue, quality of life, and depression before providing a blood sample. Correlational analyses examined the relationship between iron status (ferritin, iron, hemoglobin, and zinc protoporphyrin) and cognitive and psychosocial functioning. Performance on these measures was also examined as a function of recent blood donation history (zero, one, more than one donation in the past year). Iron status (low ferritin, iron, or hemoglobin or high zinc protoporphyrin) was not associated with poorer performance on the cognitive tasks. Further, participants who reported donating once in the previous year performed better, rather than worse, than those with no recent donation history on several measures of executive function, even when controlling for ferritin levels. Although there was some evidence of greater fatigue among those who had donated more than once in the past year, this effect was not accounted for by ferritin levels. The present findings are consistent with prior evidence that nonanemic iron deficiency is not associated with cognitive impairment or psychosocial dysfunction in healthy young females. Because these results are based on cross-sectional evidence, further study using longitudinal research is needed to confirm these findings.


Rationally designed tetra (4-carboxyphenyl) porphyrin/graphene quantum dots/bismuth molybdate Z-scheme heterojunction for tetracycline degradation and Cr(VI) reduction: Performance, mechanism, intermediate toxicity appraisement.
Constructing novel Z-scheme heterojunctions is an effective strategy for obtaining high-performance photocatalysts. Herein, tetra (4-carboxyphenyl) porphyrin (TCPP) and graphene quantum dots (GQDs) were loaded on the surface of Bi2MoO6 (BMO) to fabricate novel Z-scheme heterojunctions of TCPP/G/BMO. Especially, TCPP/G/BMO-2 showed an exceptional visible-light photoactivity for tetracycline (TC) degradation (81.0%, 40 min) and Cr(VI) reduction (90.7%, 60 min), respectively by 2.38 folds and 2.96 folds enhancement compared to sole Bi2MoO6. The substantial enhancement of activity is attributed to the synergy effect of the Z-scheme charge transfer mechanism and the improved light absorption. The degradation pathways of TC were inferred by determining the generated intermediates using high performance liquid chromatography-mass spectrometry (HPLC-MS), and the toxicity of the transformation products was assessed by Toxicity Estimation Software Tool (T.E.S.T). Overall, on the basis of trapping experiments and electron spin resonance spectra (ESR) analysis, the photocatalytic mechanisms of Cr(VI) reduction and TC degradation by the TCPP/G/BMO Z-scheme heterojunction was proposed. This work indicates TCPP/G/BMO could be a promising photocatalyst for wastewater treatment.


Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer.
Treatment of stage IV metastatic breast cancer patients is limited to palliative options and represents an unmet clinical need. Here, we demonstrate that pharmacological inhibition of miRNA-10b - a master regulator of metastatic cell viability - leads to elimination of distant metastases in a mouse model of metastatic breast cancer. This was achieved using the miRNA-10b inhibitory nanodrug, MN-anti-miR10b, which consists of magnetic nanoparticles, conjugated to LNA-based miR-10b antagomirs. Intravenous injection of MN-anti-miR10b into mice bearing lung, bone, and brain metastases from breast cancer resulted in selective accumulation of the nanodrug in metastatic tumor cells. Weekly treatments of mice with MN-anti-miR-10b and low-dose doxorubicin resulted in complete regression of pre-existing distant metastases in 65% of the animals and a significant reduction in cancer mortality. These observations were supported by dramatic reduction in proliferation and increase in apoptosis in metastatic sites. On a molecular level, we observed a significant increase in the expression of HOXD10, which is a known target of miRNA-10b. These results represent first steps into the uncharted territory of therapy targeted to the metastatic niche.


Detectable Blood Lead Level and Body Size in Early Childhood.
Rates of childhood obesity have risen at the same time rates of high blood lead levels (BLLs) have fallen. Recent studies suggest that higher BLL is inversely associated with body size in older children (ages 3-19 years). No contemporaneous studies have examined if having a detectable BLL is associated with body size in very early childhood. We examined if detectable BLL is associated with body size in early childhood. A total of 299 birth cohort participants completed a study visit at ages 2-3 years with weight and height measurements; prior to this clinic visit, a BLL was drawn as part of routine clinical care. Body mass index (BMI) percentile and Z-score were calculated; children with BMI ≥85th percentile were considered overweight/obese at age of 2 years. Detectable BLL was defined as BLL ≥1 μg/dL. A total of 131 (43.8 %) children had a detectable BLL measured at mean aged 15.4 ± 5.5 months. Mean age at body size assessment was 2.2 ± 0.3 years (53.2 % male, 68.6 % African-American). After adjusting for race, sex, and birth weight, children with a detectable BLL had a 43 % lower risk of BMI ≥85th percentile (P = 0.041) and a 0.35-unit lower BMI Z-score (P = 0.008) compared to children without a detectable BLL. Neither race nor sex modified this association (all interactions P > 0.21). Consistent with recent studies in older children, having a detectable BLL was associated with smaller body size at ages 2-3 years. Additional research on the mechanism of this association is needed but may include mechanisms of appetite suppression via lead.


Inflammation-responsive nanoparticles suppress lymphatic clearance for prolonged arthritis therapy.
The clearance of nanomedicine in inflamed joints has been accelerated due to the increased lymph angiogenesis and lymph flow in arthritic sites. To maximize the therapeutic efficacy for rheumatoid arthritis (RA), it is necessary to facilitate targeted delivery and extended drug retention in inflamed synovium simultaneously. In general, nanosized particles are more likely to achieve prolonged circulation and targeted delivery. While drug carriers with larger dimension might be more beneficial for extending drug retention. To balance the conflicting requirements, an inflammation-responsive shape transformable nanoparticle, comprised of amyloid β-derived KLVFF peptide and polysialic acid (PSA), coupled with therapeutic agent dexamethasone (Dex) via an acid-sensitive linker, was fabricated and termed as Dex-KLVFF-PSA (DKPNPs). Under physiological condition, DKPNPs can keep stable nanosized morphology, and PSA shell could endow DKPNPs with long circulation and active targeting to arthritic sites. While in inflamed joints, acidic pH-triggered Dex dissociation or macrophages-induced specific binding with PSA would induce the re-assembly of DKPNPs from nanoparticles to nanofibers. Our results reveal that intravenously injected DKPNPs display prolonged in vivo circulation and preferential distribution in inflamed joints, where DKPNPs undergo shape transition to fibrous structures, leading to declined lymphatic clearance and prolonged efficacy. Overall, our dual-stimulus responsive transformable nanoparticle offers an intelligent solution to achieve enhanced therapeutic efficacy in RA.


Moderate transmission but high prevalence of malaria in Madagascar.
Malaria transmission remains poorly documented in areas of low transmission. A study has been carried out over two consecutive years in Analamiranga, a village located at an altitude of 885m on the western edge of the Malagasy highlands, with the aim of generating and updating malariometric indexes for both mosquitoes and schoolchildren. In this village, no vector control measures were performed during the study period nor during previous decades. Mosquitoes were collected monthly when landing on human volunteers and in various resting-places. Blood samples were taken every 3 months from schoolchildren aged 6-12 years and microscopically examined. Of 7,480 mosquitoes collected on human subjects, 5,790 were anophelines. Ten anopheline species were represented and three of these, Anopheles funestus, Anopheles arabiensis and Anopheles mascarensis, accounted for 59.2% of the collection. Of these three species 4,640 were also collected in resting places. The proportion of mosquitoes fed on bovids was high; conversely, the anthropophilic rate (mosquitoes fed on human beings) was especially low: 31%, 7% and 1%, respectively, for A. funestus, A. arabiensis and A. mascarensis. The only confirmed malaria vector was A. funestus with a low sporozoite index (of 6,830 A. funestus, five were positive for Plasmodium falciparum and four for Plasmodium vivax). The annual entomological inoculation rate (number of bites of infected anophelines per adult person) was estimated at 2.49 with low variation over the 2 years. Overall, 909 thick blood smears were tested from blood samples taken from schoolchildren with 30.3% being malaria-positive. The four Plasmodium species infecting human subjects were detected in the following proportions: P. falciparum 78.9%, P. vivax 19.4%, Plasmodium malariae 1.0% and Plasmodium ovale 0.7%. The proportions of children who were infected with any Plasmodium ranged from 10.7% in February to 51.0% in September. Parasitemic children with fever (axillary temperature >37.5 degrees C) accounted for 16.4% of the children sampled. This study demonstrates that there are substantial parasitological consequences of even a relatively low entomological transmission and also recommends including exterior resting-places of mosquitoes in future spraying campaigns in the highlands of Madagascar.


A perspective on psychophysical testing in children.
In this paper, we show that the development of acuity in infancy is not due solely to foveal maturation, since there is a clear development of acuity in the peripheral visual field. The development of peripheral acuity, and the naso-temporal asymmetry during early development reinforce the idea that the visual loss in adult strabismic amblyopes is not due to an arrest of development, but rather to the chronic interocular suppression of the deviated eye. The Teller Acuity Card Test does not reliably detect strabismic amblyopia, and therefore should not be recommended as a screening test. However, the test is adequate for diagnosing visual losses in children with organic eye disorders and possibly anisometropia.


After haemin treatment intracellular non-haem iron increases prior to haem oxygenase-1 induction: A study in human monocytic cell line THP-1.
Iron overload is a major health concern for transfusion-dependent patients. Repeated transfusions result in the loading of large amounts of haem-derived iron on macrophages, in turn, inducing cell death. We previously demonstrated that haemin-induced cell death in human monocytic THP-1 cells is consistent with ferroptosis, an iron-dependent cell death regulation mechanism. However, direct measurement of iron after haemin treatment has not yet been conducted. In this study, we measured intracellular non-haem iron concentration and haem oxygenase levels after haemin treatment. Human monocytic THP-1 cells were treated with haemin, and the cell lysate was prepared. Non-haem iron concentration of the cell lysate was measured using the Nitroso-PSAP method. Expression of haem oxygenase-1 (HO-1) and haem oxygenase-2 (HO-2) was quantified by western blotting. We measured intracellular non-haem iron and the expression of haem oxygenases post-haemin treatment. Concentration of non-haem iron post-haemin treatment increased dependently with time and dose. HO-1 expression was detected 4 h after haemin treatment, whereas HO-2 expression was constitutive. Increase in non-haem iron prior to induction of HO-1 expression suggests the involvement of HO-2 in haem-induced cytotoxicity. (184 words).


Effect of age and gender on pharmacokinetics and pharmacodynamics of a single ticagrelor dose in healthy individuals.
The aim of this study was to assess age and gender effects on ticagrelor pharmacokinetics and pharmacodynamics (PK/PD). Forty healthy individuals [18-45 years (young); ≥ 65 years (elderly); ten men, ten women per age group) received 200 mg ticagrelor. Ticagrelor was rapidly absorbed [time to maximum concentration (C(max)) (t(max)) 2.5-3.0 h], and its major active metabolite, AR-C124910XX rapidly formed (t(max) 3.0-3.5 h) in all groups. Ticagrelor exposure was higher in elderly vs. the young [area under the curve from time 0 to infinity (AUC(0-∞)) 52%; C(max) 63% higher] and women vs. men (AUC(0-∞) 37%; C(max) 52% higher). Mean terminal elimination half-life was slightly longer in women vs. men but was unaffected by age. Similar results were observed for AR-C124910XX (elderly vs. young, AUC(0-∞) 48%; C(max) 61% higher), and in women vs. men (AUC(0-∞) 55%; C(max) 56% higher). Across all groups, ticagrelor produced substantial final-extent inhibition of platelet aggregation (IPA): >90% at 4 and 8 h postdose. Individuals with highest ticagrelor exposure (i.e., elderly) had the lowest IPA, indicating an age-related platelet sensitivity effect. In young individuals, platelet sensitivity was greater in men vs. women. Ticagrelor tolerability was not affected by age or gender. Systemic exposures to ticagrelor and AR-C124910XX were higher in elderly vs. young and in women vs. men. Age- and gender-related changes in IPA were apparent, but substantial IPA was achieved in all groups. No adjustment in ticagrelor dose should be considered necessary based on age and gender.


Eight-Year Review of Bordetella pertussis Testing Reveals Seasonal Pattern in the United States.
Review of Bordetella pertussis polymerase chain reaction testing from 2007 through 2014 revealed a yearly spike in positivity rates during the summer throughout the United States. Paradoxically, the highest test volumes occurred outside of this time frame, which provides an opportunity for improved test utilization.


A substance resembling somatomedin C in the American cockroach.
Material antigenically resembling somatomedin C (type I insulin-like growth factor, IGF-I) is demonstrated in the American cockroach Periplaneta americana by means of a monoclonal antibody immunoperoxidase technique. It was localized histochemically in neuronal cell somata and axonal fibers (probably interneurons) of the central nervous/neuroendocrine system and in 'endocrine-type' cells lining the midgut epithelium. The IGF-I-like substance is different from vertebrate insulin and also distinct from materials immunostained by different insulin antibodies in the brain and neurohaemal complex of this insect species. These findings are viewed in the light of recent reports on the presence and action of insulin-like chemicals in insects, and with respect to the existence of an insect brain-midgut system similar to the mammalian brain-gastroenteropancreatic system.


Neoadjuvant chemotherapy in advanced gastric cancer with non-curative factors: a Phase II study with 5-fluorouracil, leucovorin, and cisplatin.
BACKGROUND: Neoadjuvant chemotherapy (NAC) has recently received increasing attention in an attempt to increase the rate of complete tumor resections, reduce systemic metastases, and prolong survival in patients with advanced gastric cancer.METHODS: Since 1993, 21 patients with unresectable or non-curative resectable gastric cancer received NAC, consisting of 5-fluorouracil, leucovorin, and cisplatin (FLP) with at least two cycles before surgery.RESULTS: All except 2 patients underwent surgical treatment, and resection was performed in 18 (85.7%). There were no deaths and no major morbidity following operation. There was no complete response (CR), but 12 patients (57.1%) had a partial response (PR), the response rate was 47.6% for the primary region, 64.7% for abdominal para-aortic (No.16) lymph node metastasis, 40.0% for liver metastasis, and 11.1% for peritoneal dissemination. One-year survival of the 21 patients was 40.5%, and median survival time (MST) was 322 days. MST in the responders was 571 days, and that in non-responders was 199 days ( P < 0.01). MST was 835 days in patients who underwent curative resection and 310 days in those who underwent non-curative surgery ( P < 0.01). There was no grade 4 toxicity, but grade 3 leukopenia occurred in 4 patients (19.0%), grade 3 anemia occurred in 3 patients (14.3%), and grade 3 stomatitis in 2 patients (9.5%). There were no serious renal disorders and no treatment-related death.CONCLUSIONS: The combination of FLP for NAC was feasible and useful for tumor reduction, especially for No.16 lymph node metastasis. There was a survival benefit in patients whose tumor had PR or who had had curative resection. We should confirm the effect and survival benefit of FLP for NAC by a prospectively randomized clinical controlled study.


Carbon monoxide inhibits endothelin-1 release by human pulmonary artery smooth muscle cells.
Endothelin-1 is a potent vasoconstrictor with mitogenic properties. This 21-amino-acid protein, released in the vasculature by endothelial and smooth muscle cells, has been implicated in pulmonary hypertension. More recently, evidence has accumulated for a role of the heme oxygenase system in pulmonary hypertension. Heme oxygenase catalyses the breakdown of heme to produce carbon monoxide, biliverdin and free iron. Here we show that a carbon monoxide-releasing molecule, but not biliverdin, inhibits endothelin-1 release from serum-stimulated human pulmonary artery smooth muscle cells. Under certain conditions, carbon monoxide appears to act as an endogenous break on endothelin-1 release.


The occurrence of intraoperative complications during partial nephrectomy and their impact on postoperative outcome: results from the RECORd1 project.
The aim of this study was to analyze the predictive factors of intraoperative complications in patients submitted to PN and the impact of intraoperative complications on postoperative outcomes. Data of 1055 patients who underwent PN for cortical renal masses were recorded from a multicenter prospective observational study (RECORd1 project). Overall, 48 (5%) patients experienced 49 intraoperative complications (four medical, 45 surgical). At multivariable analysis, age (OR=1.02, 95% CI: 1.00-1.08, P=0.03), imperative versus elective surgical indication (OR=2.55, 95% CI: 1.12-5.85, P=0.03), open (OR=5.76, 95% CI: 1.05-9.21, P=0.01) and laparoscopic (OR=2.35, 95% CI: 1.11-4.95, P=0.03) versus robotic approaches resulted independent predictive factors of intraoperative complications. Patients experiencing intraoperative complications had a significantly higher rate of overall postoperative complications (41.6% vs. 17.3%, P<0.0001), surgical postoperative complications (29.2% vs. 12.6%, P<0.0001), Clavien 2 surgical postoperative complications (14.6% vs. 7.2%, P=0.05) and a significantly longer length of stay (8 [6-9] vs. 7 [5-8] days, P<0.0001) than those with an uneventful intraoperative course. Efforts should be made to minimize the risk of intraoperative complications during PN, and, in that case, patients should be carefully monitored.


Developing 'Smart' Dairy Farming Responsive to Farmers and Consumer-Citizens: A Review.
Innovation has resulted in more dairy products being produced with less inputs than ever before. It has also affected how animals are raised, the structure of the sector and the nature of products produced. Not all impacts have been positive. As disruptive technologies-such as precision farming and robotics-herald significant change, it is timely to reflect on the perspectives of different actors on innovations within the sector. Drawing on a review of academic literature, this paper considers farmers' and consumer-citizens' perspectives; as expected, their diverse knowledge, interests and values surface a range of perspectives. To provide focus to the study, it examines technologies across three stages of the dairy production cycle: breeding, feeding and milking. It finds that consumer-citizen and farmer perspectives have been examined by researchers in several countries, using a variety of methods, across a range of technologies. It finds both areas of agreement and tension within and between consumer-citizen and producer cohorts. While differences in knowledge account for some variation, differences in values are also significant. The extent to which efforts can and should be put into addressing differences is raised as a point for reflection.


Comparison of Perioperative Morbidity of Radical Cystectomy With Neobladder Versus Ileal Conduit: A Matched Pair Analysis of 170 Patients.
The objective of this study was to evaluate if use of an ileal conduit (IC) versus a neobladder (NB) during radical cystectomy (RC) can play a role in the morbidity of the surgical procedure. Since 2001 our institution has prospectively maintained a database of more than 500 patients who have undergone RC. The records of 258 patients who received an RC and IC and 121 who received an RC and NB were reviewed for the present study. Using a binary logistic regression model a propensity score was generated for the following factors: sex, age, smoking habit, Charlson score, American Society of Anesthesiology score, preoperative hydronephrosis, and pathologic T stage. Two groups of patients with similar propensity scores were created with a ratio of 1:1, one group who received an IC and another who received an NB. The following features were compared between the 2 groups: blood loss, intraoperative complication rate, time to oral intake resumption, postoperative complication rate (overall, Clavien classification 1-2, Clavien classification 3-5, related to RC, related to urinary reconstruction). In total, 170 patients were selected; 85 with NB, 85 with IC, and the 2 groups were well matched according to the desired features. No differences were noted for all of the compared features. The morbidity of RC does not seem to be affected by the choice of IC versus NB.


Key dimer interface residues impact the catalytic activity of 3CLpro, the main protease of SARS-CoV-2.
3C-like protease (3CLpro) processes and liberates functional viral proteins essential for the maturation and infectivity of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19. It has been suggested that 3CLpro is catalytically active as a dimer, making the dimerization interface a target for antiviral development. Guided by structural analysis, here we introduced single amino acid substitutions at nine residues at three key sites of the dimer interface to assess their impact on dimerization and activity. We show that at site 1, alanine substitution of S1 or E166 increased by twofold or reduced relative activity, respectively. At site 2, alanine substitution of S10 or E14 eliminated activity, whereas K12A exhibited ∼60% relative activity. At site 3, alanine substitution of R4, E290, or Q299 eliminated activity, whereas S139A exhibited 46% relative activity. We further found that the oligomerization states of the dimer interface mutants varied; the inactive mutants R4A, R4Q, S10A/C, E14A/D/Q/S, E290A, and Q299A/E were present as dimers, demonstrating that dimerization is not an indication of catalytically active 3CLpro. In addition, present mostly as monomers, K12A displayed residual activity, which could be attributed to the conspicuous amount of dimer present. Finally, differential scanning calorimetry did not reveal a direct relationship between the thermodynamic stability of mutants with oligomerization or catalytic activity. These results provide insights on two allosteric sites, R4/E290 and S10/E14, that may promote the design of antiviral compounds that target the dimer interface rather than the active site of severe acute respiratory syndrome coronavirus 2 3CLpro.


The extraction and re-implantation of teeth for the difficult laryngoscopy.
We describe two cases where it was necessary to remove teeth to biopsy the larynx for malignant disease. Immediate reimplantation of the teeth proved successful.


Effects of growth conditions on the lipid composition of Bifidobacterium bifidum subsp. pennsylvanicum.
Lipid-phosphorus and lipid-galactose content and phospholipid and fatty acid composition of Bifidobacterium bifidum subsp. pennsylvanicum were examined under a wide variety of growth conditions. Cells from 29-C cultures contained less lipid-phosphorus than did cells from 37-C cultures, but their lipid-galactose content and phospholipid composition did not differ. At both temperatures, the growth phase influenced the lipid composition similarly. Phosphate, Mg2+ and K+ concentrations in the medium did neither significantly change the cellular lipid-phosphorus content nor the phospholipid composition. Only Mg2+-deficiency markedly reduced growth and lowered the content of cellular lipid-galactose. Omission of Tween 80 from the medium did not affect growth, but lowered the content of lipid-galactose and augmented those of lipid-phosphorus and diphosphatidylglycerol in the cell. Increased osmolarity and substitution of other Tween for Tween 80 caused the same changes in lipid composition, and besides inhibited growth. Omitting Tween 80 and replacing it by other Tweens dramatically reduced the percentage of unsaturated fatty acids. C12- and C14-fatty acids made up about 50% of total fatty acids in cells from Tween 20 cultures and 12-14% in cells from Tween 40 and Tween 60 cultures. The differences in the decline of unsaturated fatty acids and in the degree of replacement of these acids by C12- and C14-fatty acids may be related to the variations in growth in cultures with various Tweens by way of changes in the physical state of the membrane lipids.


Analysis of the gene expression profile of Schistosoma japonicum cercariae by a strategy based on expressed sequence tags.
We present an analysis of the expression profile of Schistosoma japonicum cercariae by a strategy based on expressed sequence tags (ESTs). A cDNA library from S. japoniucm cercariae was constructed and was used to generate ESTs. In total, 201 clones randomly selected from the library were sequenced; 136 ESTs were successfully obtained and sent to the BLAST server for homology searching. Among the 136 ESTs, 85 (62.50%) did not match any protein or gene sequence published in the BLAST databases; these comprised 75 (55.15%) ESTs matched (or partly matched) S. japonicum and Schistosoma mansoni ESTs, 4 (2.94%) matched human ESTs and 6 (4.41%) that did not match any sequence. Fifty-one (37.50%) ESTs were identified by the BLAST server; these consisted of 8 (5.88%), 9 (6.62%) and 34 (25.00%) that showed high homology with genes or proteins reported from S. japonicum, S. mansoni and other organisms, respectively. These identified ESTs can be grouped into nine categories: transporters (1.96%), secretory proteins (1.96%), kinases (3.92%), proteases (5.88%), structural and cytoskeletal proteins (13.73%), metabolism-related proteins (9.80%), regulatory and signaling proteins (11.76%), transcription and translation machinery (25.50%), and others (25.50%). Several interesting new genes cloned from this cDNA library are discussed here. These findings will be valuable for the understanding of the biology of this parasite.


Selective labeling of vagal sensory nerve fibers in the lower esophageal sphincter with anterogradely transported WGA-HRP.
Wheat germ agglutinin-horseradish peroxidase conjugate (WGA-HRP) injected into the nodose ganglion was anterogradely transported into the vagal sensory terminal fibers that were further visualized in the lower esophageal sphincter (LES) of the cat. The distribution pattern of the labeled fibers in the LES wall was investigated. All the labeled fibers came from the serosa and penetrated between the bundles of longitudinal muscle fibers. Then the labeled fibers took two different pathways: they either ran, and probably ended, between the longitudinal and circular muscle layers, or they ran directly from the longitudinal to the circular muscle layer. Between the longitudinal and circular muscle layers, they followed a sinuous pathway. In contrast, when they crossed the circular muscle layer toward the mucosa, they ran perpendicular to the orientation of the muscle fibers. After having entered the mucosa, they became twisted and penetrated deeply into the epithelium. These two populations of vagal sensory labeled fibers might correspond respectively to the muscular and mucosal receptors classically described in previous electrophysiological studies.


Prediction of Surgical Outcome by Modeling Based on Risk Factors of Morbidity After Pulmonary Resection for Lung Cancer in Older Adults.
Surgical treatment for older patients with lung cancer presents more challenges compared with general population. The aim of the study was to predict surgical outcome after pulmonary resection in older patients with lung cancer by developing a clinical model. Clinical records of 525 patients who were older than 70 years of age and who underwent pulmonary resection for lung cancer in a single center were reviewed. Patients were divided into three ordered categories of surgical outcome according to the Clavien-Dindo classification. By using a development cohort of 401 patients, an ordinal logistic regression was performed to develop a prediction model for surgical outcome. The model was internally validated by the bootstrap method and was externally validated by another cohort of 124 patients. Two previous models were tested as benchmarks of our model. The model was developed based on five risk factors of morbidity: American Society of Anesthesiologists classification (p < 0.001), pulmonary disease (p = 0.001), tumor size (p = 0.011), tumor location (p = 0.015), and surgical approach (p = 0.036). The c-statistic of the model was 0.75 (95% confidence interval: 0.69 to 0.80), which was similar to the bootstrapping one (0.75; 95% confidence interval: 0.68 to 0.80). The Hosmer-Lemeshow test showed a strong goodness of fit of the model (p = 0.674). In external validation, the performance of our model was superior to that of the two previous models. Our model displayed an acceptable ability to predict surgical outcome in older patients undergoing pulmonary resection for lung cancer. Use of the model can be helpful in decision making about surgical treatment in this special population.


Acetylation mimic of lysine 280 exacerbates human Tau neurotoxicity in vivo.
Dysfunction and accumulation of the microtubule-associated human Tau (hTau) protein into intraneuronal aggregates is observed in many neurodegenerative disorders including Alzheimer's disease (AD). Reversible lysine acetylation has recently emerged as a post-translational modification that may play an important role in the modulation of hTau pathology. Acetylated hTau species have been observed within hTau aggregates in human AD brains and multi-acetylation of hTau in vitro regulates its propensity to aggregate. However, whether lysine acetylation at position 280 (K280) modulates hTau-induced toxicity in vivo is unknown. We generated new Drosophila transgenic models of hTau pathology to evaluate the contribution of K280 acetylation to hTau toxicity, by analysing the respective toxicity of pseudo-acetylated (K280Q) and pseudo-de-acetylated (K280R) mutant forms of hTau. We observed that mis-expression of pseudo-acetylated K280Q-hTau in the adult fly nervous system potently exacerbated fly locomotion defects and photoreceptor neurodegeneration. In addition, modulation of K280 influenced total hTau levels and phosphorylation without changing hTau solubility. Altogether, our results indicate that pseudo-acetylation of the single K280 residue is sufficient to exacerbate hTau neurotoxicity in vivo, suggesting that acetylated K280-hTau species contribute to the pathological events leading to neurodegeneration in AD.


Prognostic value of rCBF measurements and CT in focal cerebral ischemia.
CT is the most effective examination technique for studying the evolution of ischemic attacks, but if performed within the first 3 weeks it does not allow prognosis of possible evolution towards necrosis. CBF measurement and vasoreactivity tests under Althesin do allow this prognosis. Thirty patients whose evolution was checked clinically and by repeated CT examinations (89 in all) underwent CBF measurements (intra-arterial xenon 133) and vasoreactivity tests. In all cases (17 patients) where vasoreactivity had completely disappeared (inverse steal), the infarct evolved towards necrosis.


An analysis of Con A-mediated agglutination in a Chinese hamster ovary subclone which responds morphologically to growth in dibutyryl cyclic AMP. III. The role of microvilli in the agglutination process.
We have used the H-7w subclone of a Chinese hamster ovary cell line (K1) to investigate the role of cell surface architecture (specifically microvilli, blebs, and sheets) in determining the relative agglutinability of a cell line with Con A. Our evidence clearly demonstrates that no specific, immediately recognizable surface architecture is associated with the agglutinable or non-agglutinable phenotype. Our data suggest that the expression of microvilli on the cell surface is neither necessary to nor sufficient for the phenotype described by enhanced agglutinability with Con A. Furthermore our work demonstrates that cells covered with blebs are as agglutinable as cells covered with microvilli thereby suggesting that the intertwining of microvilli may not be an essential facet of the agglutination phenomenon.


Assessment of late treatment-related symptoms using patient-reported outcomes and various factors affecting return to work in survivors of breast cancer.
Breast cancer is the most common cancer in women worldwide. Survival in these patients has increased because of early diagnosis and multimodality treatment methods. Return to premorbid functional status after treatment is essential for rehabilitation and good quality of life. Many patients suffer from late treatment-related symptoms which affect their return to premorbid status. Various health-related and work-related variables also affect the return to premorbid status. This is a cross-sectional study in which 98 patients with breast carcinoma who received curative treatment were included 6-12 months post-radiotherapy completion. Patients were interviewed to assess their type of work and hours of work prior to diagnosis and at the time of the study. The extent to which they are able to return to their pre-diagnosis level of work was noted and various factors that were hindering them were documented. Treatment-related symptoms were assessed using selected questions from NCI PRO-CTCAE (version 1.0) questionnaire. The median age of diagnosis of patients included in the study was 49-50 years. The most common symptoms experienced by patients were fatigue (55%), pain (34%) and oedema (27%). 57% of patients were employed before diagnosis, of which only 20% were able to return to their employment post-treatment. All patients were involved in household work prior to diagnosis and 93% were able to get back to their routine household work, with 20% of patients requiring frequent work breaks. About 40% of patients reported social stigma as a factor that hindered them from returning to work. Most patients return to household work post-treatment. Fatigue, pain and social stigma were the most common barriers to return to employment. Patient-reported outcomes and functional assessments can enable better survivorship care.


Pelvic Gastrointestinal Stromal Tumor With Pulmonary Metastasis.
Extragastrointestinal stromal tumors (EGISTs) comprise a small portion of gastrointestinal stromal tumors. Metastasis normally occurs to nearby organs. However, metastasis to the lungs is uncommon in EGISTs. Furthermore, recurrence of the EGIST in a new location years later has not been documented. We present this case to highlight this behavior of EGISTs in hopes to better understand this rare type of neoplasm.


Post-traumatic dizziness.
Following an episode of syncope, a 42-year-old woman was referred to exclude a cardiac cause. This primary event was determined to be a straightforward case of vasovagal syncope, resulting in mild head trauma. Following this, the patient was left with symptoms of dizziness and a subjective "muzzy" sensation. Initially assumed to be a form of "post-concussive symptom", she was referred to a neurologist who employed neurovestibular manoeuvres to both determine the cause of these symptoms and satisfactorily resolve them.


Benign Pediatric Salivary Gland Lesions.
Salivary gland lesions are rare in pediatric patients. In addition, the types of salivary gland tumors are different in their distribution in specific sites in the major and minor salivary glands in children compared with adults. This article reviews benign neoplastic and nonneoplastic salivary gland disorders in pediatric patients to help clinicians to develop an orderly differential diagnosis that will lead to expedient treatment of pediatric patients with salivary gland lesions.


Cutaneous leishmaniasis in the central provinces of Hama and Edlib in Syria: Vector identification and parasite typing.
Cutaneous leishmaniasis is a disease transmitted by sand fly bites. This disease is highly prevalent in Syria where Leishmania major and Leishmania tropica are the known aetiological agents. In 2011, more than 58,000 cases were reported in the country by the Ministry of Health. The central region of the country harbors 20 % of the reported cases. However, the epidemiology of the disease in this area is not well understood. An epidemiological survey was conducted in 2010 to identity the circulating parasite and the sand fly vector in the central provinces of Edlib and Hama. Sand fly specimens were collected using CDC light traps and identified morphologically. Total DNA was extracted from the abdomens of female specimens and from Giemsa-stained skin lesion smears of 80 patients. Leishmania parasites were first identified by sequencing the ITS1 gene amplicons. Then polymorphism analysis was performed using the RFLP technique. A total of 2142 sand flies were collected. They belonged to eight species, among which Phlebotomus sergenti and Phlebotomus papatasi were the most predominant. L. tropica ITS1 gene was amplified from two pools of P. sergenti specimens and from skin smears of cutaneous leishmaniasis patients. This suggests that P. sergenti is the potential vector species in the study area. The digestion profiles of the obtained amplicons by TaqI restriction enzyme were identical for all analysed L. tropica parasites. Moreover, L. infantum ITS1 gene was amplified from two pools of Phlebotomus tobbi in the relatively humid zone of Edlib. L. tropica is confirmed to be the aetiological agent of cutaneous leishmaniasis cases in the central provinces. RFLP technique failed to show any genetic heterogeneity in the ITS1 gene among the tested parasites. The molecular detection of this parasite in human skin smears and in P. sergenti supports the vector status of this species in the study area. The detection of L. infantum in P. tobbi specimens indicates a potential circulation of this parasite in the humid zone of Edlib. Further epidemiological studies are needed to evaluate the burden of this visceral parasite in the study region.


[Shoulder arthroplasty for treatment of the sequelae of proximal humerus fractures].
The sequelae of fractures of the proximal humerus can be of considerable clinical significance. Careful classification of the sequelae allows precise determination of whether correction osteotomy, reconstruction, or implantation of one of the various prostheses available is indicated. The integrity of the greater tuberosity, its position and continuous osseous integration to the metaphysis of the proximal humerus is the most important predictive factor for a good outcome following implantation of an anatomical shoulder prosthesis. When there is some incongruence of the glenohumeral joint while the greater tuberosity remains intact, shoulder arthroplasty can give a better clinical outcome than is seen after arthroplasty for a primary fracture. In the case of nonunion of subcapital fractures the results achieved by reconstruction, i.e. bone grafting and internal fixation using plates with fixed-angle blades, are superior to those possible with an anatomical prosthesis. Reverse shoulder arthroplasty gives better results than anatomical prostheses in the treatment of severe tuberosity malunion. The results of reverse shoulder arthroplasty for the sequelae of fractures are also influenced by the integrity of or damage to the soft tissues, the muscles of the rotator cuff (teres minor muscle), and bone. Secondary interventions for the sequelae of fractures of the proximal humerus are complex and involve high rates of complications and revisions.


Syncope in the athletic patient.
Syncope is a common but concerning event in athletic patients. As such, efforts must be made to distinguish presyncope from syncope with a critical distinction of syncope during exercise and postexercise syncope. Syncope most often occurs just after exercise and is usually benign; however, syncope during exercise may be a sign of pathologic structural or electrical cardiac issues. Solving this diagnostic puzzle mandates a detailed history and examination frequently augmented with diagnostic testing and imaging studies. Recommendations for treatment and potential restriction from activity also present challenging decisions to the health care provider.


Thrombospondin 2 expression is correlated with inhibition of angiogenesis and metastasis of colon cancer.
Two subtypes of thrombospondin (TSP-1 and TSP-2) have inhibitory roles in angiogenesis in vitro, although the biological significance of these TSP isoforms has not been determined in vivo. We examined TSP-1 and TSP-2 gene expression by reverse transcription polymerase chain reaction (RT-PCR) analysis in 61 colon cancers. Thirty-eight of these 61 colon cancers were positive for TSP-2 expression and showed hepatic metastasis at a significantly lower incidence than those without TSP-2 expression (P = 0.02). TSP-2 expression was significantly associated with M0 stage in these colon cancers (P = 0.03), whereas TSP-1 expression showed no apparent correlation with these factors. The colon cancer patients with TSP-2 expression showed a significantly low frequency of liver metastasis correlated with the cell-associated isoform of vascular endothelial growth factor (VEGF-189) (P = 0.0006). Vascularity was estimated by CD34 staining, and TSP-2(-)/VEGF-189(+) colon cancers showed significantly increased vessel counts and density in the stroma (P < 0.0001). TSP-2(-)/VEGF-189(+) colon cancer patients also showed significantly poorer prognosis compared with those with TSP-2(+)/VEGF-189(-) (P = 0.0014). These results suggest that colon cancer metastasis is critically determined by angiogenesis resulting from the balance between the angioinhibitory factor TSP-2 and angiogenic factor VEGF-189.


Application of an Iterative Fragment Selection (IFS) Method to Estimate Entropies of Fusion and Melting Points of Organic Chemicals.
The main objective of this study is to develop and evaluate novel Quantitative Structure-Property Relationships (QSPRs) for predicting entropy of fusion (ΔSM ) and melting point (TM ) of organic chemicals from chemical structure. The QSPRs are developed using the Iterative Fragment Selection (IFS) method that requires only 2D structural information from the user (SMILES codes) for property prediction. The QSPRs also provide information on the applicability domain for each calculation and uncertainty estimates for the predictions. The root mean square error (RMSE) for the external validation sets are 11.8 J mol-1 K-1 and 46.9 K for the ΔSM and TM QSPRs, respectively. The performance of the new QSPRs is comparable to other predictive methods but has advantages with respect to availability and ease of use as well as the guidance on applicability domain for each prediction. Limitations of the new QSPRs are discussed. The QSPRs are coded as a user-friendly, freely available tool.


Theranostic lyotropic liquid crystalline nanostructures for selective breast cancer imaging and therapy.
Herein, we report the development of theranostic lyotropic liquid crystalline nanostructures (LCN's) loaded with unique MnO nanoparticles (MNPs) for selective cancer imaging and therapy. MNPs serves as a fluorescent agent as well as a source of manganese (Mn2+) and enables localized oxidative stress under the hallmarks of cancer (acidosis, high H2O2 level). In pursuit of synergistic amplification of Mn2+ antitumor activity, betulinic acid (BA) is loaded in LCN's. In this investigation, nano-architecture of LCN's phase interface is established via SAXS, Cryo-TEM and Cryo-FESEM. Intriguing in vitro studies showed that the LCN's triggered hydroxyl radical production and exhibited greater selective cytotoxicity in cancer cells, ensuring the safety of normal cells. Significant tumor ablation is realized by the 96.5 % of tumor growth inhibition index of LCN's as compared to control group. Key insights into on-site drug release, local anti-cancer response, and tumor location are gained through precise guidance of fluorescent MNPs. In addition, comprehensive assessment of the safety, pharmacokinetics and tumor distribution behavior of LCN's is performed in vivo or ex vivo. This work emphasizes the promise of modulating tumor microenvironment with smart endogenous stimuli sensitive nano systems to achieve advanced comprehensive cancer nano-theranostics without any external stimulus. STATEMENT OF SIGNIFICANCE: Effective diagnosis and treatment approaches with maximum anti-cancer activity and minimal side-effects are critical to ameliorate cancer therapy. Compared to radiation, photodynamic and photothermal therapy, the specific and selective activation of tumor microenvironmental endogenous stimuli for the logical generation of cytotoxic OH· free radicals serves as an efficient therapeutic strategy for chemodynamic-cancer treatment. In this investigation, MnO nanoparticles fulfill two needs (fluorescence-based optical imaging and a source of Mn2+ based chemodynamic therapy) in one unit. This approach also ensures the safety of normal cells, as the toxic OH· free radical activity is substantially suppressed under the mild alkaline/H2O2 conditions in normal cell microenvironment.


Comparing self-reported vs. parent/caregiver reported levels of social participation for young adults with intellectual disabilities: A pilot study.
This study focused on the level of satisfaction of social participation reported by young adults with intellectual disabilities, and the comparison of these levels to those reported by their caregivers. Fifteen young adults with intellectual disabilities and their parents/caregivers completed the Patient-Reported Outcomes Measurement Information System Satisfaction with Participation in Discretionary Social Activities-Calibrated Items (PROMIS SF-Social Sat DSA) and the Satisfaction with Social Roles and Activities-Short Form (Neuro-QoL SF). Reports from these young adults were compatible to that of the general population. There was general agreement on the Social Sat DSA between the individuals and their caregivers, but there were differences between groups on the Neuro-QoL SF, with the caregivers typically giving higher scores (p = .025). This pilot study demonstrates the importance of involving both the individuals with intellectual disabilities, and their parents/caregivers when conducting survey research. Further research is encouraged.


Relationship between glucose transporter and changes in the absorptive system in small intestinal absorptive cells during the weaning process.
In the present study, we investigated the changes in the localization of the glucose transporter GLUT2 and the fructose transporter GLUT5 in small intestinal absorptive cells during postnatal development, especially during the weaning period, using immunohistochemistry and confocal laser scanning microscopy. In the jejunum, GLUT2 was observed within the apical and basolateral membrane domain of absorptive cells, especially in the middle part of the villi. In the suckling rat ileum, GLUT2 was found within the apical and basolateral membrane domain of absorptive cells, but after 18 or 19 days after birth, GLUT2 was found mainly within the apical membrane domain. GLUT5 was observed within the apical membrane domain of absorptive cells in the suckling rat jejunum. In the 18- or 19-day-old rat jejunum, GLUT5 was localized within the apical and basolateral membrane domain of absorptive cells in the lower part of the villi, but after weaning, GLUT5 was found within the apical and basolateral membrane domain of absorptive cells throughout the entire villi. In the suckling rat ileum, there was little GLUT5 in the absorptive cells. In the 18- or 19-day-old rat ileum, GLUT5 was localized within the apical membrane domain of absorptive cells in the lower part of the villi, but after weaning, GLUT5 was observed mainly within the apical membrane domain of absorptive cells throughout the entire villi. These results suggest that the localization of glucose transporters corresponds with a shift from neonatal-suckling to weaned absorptive cells during postnatal development.


Identification of two differentially expressed forms of progranulin mRNA in the teleost fish Paralichthys olivaceus.
Two forms of progranulin mRNA were isolated from kidney and spleen cDNA libraries of the olive flounder, Paralichthys olivaceus. The 3'-untranslated regions (3'-UTRs) of these flounder progranulin (f-pgrn) mRNAs differed in a 20-nucleotide sequence element (5'-AACTGATTACGTTCAACAAC-3') that was present in one mRNA (designated f-pgrn type II) and not in the other (designated f-pgrn type I). Both mRNA sequences contained an open reading frame encoding a 289-amino-acid polypeptide of approximately 33 kDa. Southern blot analysis of the P. olivaceus flounder genome using an f-pgrn cDNA probe and a PCR-based approach identified a single copy of f-pgrn corresponding to the type II mRNA. The expression profiles of the two types of f-pgrn mRNA differed from each other and were tissue- and condition-dependent. The type II mRNA was detected abundantly in studied tissues (gill, kidney, spleen, and intestine) of non-stimulated healthy flounders. The type I mRNA was rarely expressed in any tissues of healthy flounders, but it was continuously increased in the examined tissues of flounders after the intraperitoneal injection of lipopolysaccharide. On the other hand, the expression of type II mRNA was decreased in inverse proportion to the type I mRNA in the LSP-stimulated flounders. These results suggest that type I and type II f-pgrn mRNA are translated into different proteins with different activities in the immune system of flounder.


Rheological characterisation of dextran-concanavalin A mixtures as a basis for a self-regulated drug delivery device.
The rheological characterisation of glucose sensitive mixtures containing dextran and concanavalin A (con A) with and without glucose, was undertaken using oscillatory rheometry at 20 and 37 degrees C so that comparative data could be gathered in the linear viscoelastic (LVE) range. Measurements for a series of mixtures showed that complex viscosity is a function not only of the con A concentration but of the content and molecular weight of the dextran used. The extent of liquefaction on addition of glucose also depended on these factors. The tan delta profiles confirmed the change from semi-solid towards fluid behaviour. This occurs when glucose effects dismantling of the three-dimensional structure of the dextran-con A system by competitive binding to the glucose receptors in the protein. For the mixtures studied, the changes occurred between contents of 0 and 1% (w/w) glucose at 20 and 37 degrees C and form a useful basis for the formulation of a self-regulating delivery device for the control of hyper-and hypoglycaemia in diabetes.


Abnormal vergence with upper brainstem infarcts: pseudoabducens palsy.
Infarcts of the rostral brainstem often cause vertical gaze palsies but may also produce inappropriate convergence that manifests as pseudoabducens palsy and convergence-retraction nystagmus (CRN). Although the substrate for vergence has been defined in the monkey as lying dorsal and lateral to the oculomotor nucleus, the human homologue is unknown. - The authors reviewed the clinical features, ocular findings, and CT or MR lesions in seven patients with pseudoabducens palsy and "top-of-the-basilar" infarction. They reviewed the literature for infarcts causing pseudoabducens palsy or CRN with precise autopsy localization. The authors then mapped the location of the infarcts on anatomic templates. The smallest MR infarct produced an ipsilateral pseudoabducens palsy and CRN, and was located just rostral to the oculomotor nucleus, near the midbrain-diencephalic junction. Two patients with only contralateral pseudoabducens palsy had both subthalamic and thalamic infarction. Four patients with bilateral pseudoabducens palsy had larger infarcts involving the midbrain. All patients with pseudoabducens palsy had upgaze palsy. Two patients with CRN from the literature had small infarcts near the midbrain-diencephalic junction at autopsy. Lesions near the midbrain-diencephalic junction are important for the development of pseudoabducens palsy. Pseudoabducens palsy and CRN are probably both manifestations of abnormal vergence activity. Inhibitory descending pathways for convergence may pass through the thalamus and decussate in the subthalamic region.


Who cares about care in nursing education?
Many sources indicate that nurses have a negative view of work with ageing patients. Wide-spread stereotypes concerning old age no doubt exercise influences in the formation of nurses' attitudes. The research reported here suggests that nurses' negative attitudes towards the elderly are consolidated rather than dissolved in the course of their training. The reasons for this may not, in fact, lie in the nature of the gerontology components (small as they usually are) of the curriculum. Rather, the course (or the "professional socialisation" process) as a whole appears to carry messages that devalue personal care duties--contra the prestige of activities attached to all levels of medical technology. The ageing patient, often requiring much hands-on (the body) care is thus located well outside areas of work which are perceived by nurses to include clearly focused professional pathways.


Chemochromatography: its use for the separation of nikkomycins X and Z.
A novel mode of reversed-phase high-performance liquid chromatography in which the mobile phase reacts chemically with the compounds to be separated was developed. Nikkomycin X and nikkomycin Z, two natural isomeric nucleoside peptide antibiotics, move as a single peak on a C18 reversed-phase column using an aqueous trifluoroacetic acid mobile phase. Addition of sodium bisulfite (1.0%) to the mobile phase results in the formation of a polar bisulfite addition product with nikkomycin X, but not with nikkomycin Z, inside the HPLC column. This type of reactive chromatography, or chemochromatography, led to the analytical and preparative separation of nikkomycins X and Z which are normally very intractable to separation by conventional chromatographic techniques.


Simultaneous determination of ethylene glycol, propylene glycol, 1,3-butylene glycol and 2,3-butylene glycol in human serum and urine by wide-bore column gas chromatography.
A method has been developed for the separation and measurement of ethylene glycol and three other glycols (propylene glycol, 1,3-butylene glycol and 2,3-butylene glycol) in biological samples by wide-bore column gas chromatography with a flame ionization detector. The method used 1,3-propylene glycol (1,3-propanediol) as an internal standard. The method was linear at least from 2 to 1000 micrograms/ml, with a detection limit of 1 microgram/ml. Analytical recoveries were 89-98% for the different concentrations. Precision studies showed coefficients of variation of 1.5-7.7% for the different concentrations. The assay was applied to the analysis of biological samples from two patients who had ingested ethylene glycol and/or other glycols in a suicide attempt.


Mechanisms of NF-κB deregulation in lymphoid malignancies.
Deregulations promoting constitutive activation of canonical and non-canonical NF-κB signaling are a common feature of many lymphoid malignancies. Due to their cellular origin and the pivotal role of NF-κB for the normal function of B lymphocytes, B-cell malignancies are particularly prone to genetic aberrations that affect the pathway. Key positive regulators of NF-κB signaling can act as oncogenes that are often prone to chromosomal translocation, amplifications or activating mutations. Negative regulators of NF-κB have tumor suppressor functions and are frequently inactivated either by genomic deletions or point mutations. Whereas some aberrations are found in a variety of different lymphoid malignancies, some oncogenic alterations are very restricted to distinct lymphoma subsets, reflecting the clonal and cellular origin of specific lymphoma entities. NF-κB activation in many lymphoma cells is also driven by the microenvironment or chronic signaling that does not rely on genetic alterations. A number of drugs that target the NF-κB pathway are in preclinical or clinical development, revealing that there will be new options for therapies in the future. Since each lymphoma entity utilizes distinct mechanisms to activate NF-κB, a major challenge is to elucidate the exact pathological processes in order to faithfully predict clinical responses to the different therapeutic approaches.


HMGB1 induced inflammatory effect is blocked by CRISPLD2 via MiR155 in hepatic fibrogenesis.
A number of studies have showed that High mobility group box-1 (HMGB1), which played key role in inflammation activation by triggering the toll like receptor 4 (TLR4) signaling axis in hepatic fibrogenesis, may share similar inflammation stimulating mechanism with LPS. Herein, we introduced a recently established anti-LPS protein cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2) to investigate endogenous protection mechanism of HMGB1 induced inflammatory response. Our results shows that stromal cells and monocytes showed an evaluated pattern for CRISPLD2 expression after HMGB1 treatment, which was dependent on the integrity of TLR4 function. Pro-inflammatory Cytokines levels were significantly elevated after CRISPLD2 silencing despite the HMGB1 status. Soluble CRISPLD2 administration relieve the HMGB1 dependent pro-inflammatory cytokines release. Interestingly, we found that miRNA 155 play a key role in the process. Our data suggest that CRISPLD2 may have a unique anti-HMGB1 effect via miRNA and play an important role in immune balance.


Unexpected diagnosis of superficial neurofibroma in a lesion with imaging features of a vascular malformation.
Plexiform neurofibroma is a pathognomonic, often disabling feature of neurofibromatosis type I. Although the target-like appearance of deep plexiform neurofibroma on T2-weighted MRI has been well-described, a second superficial form of plexiform neurofibroma has differing imaging features. We report a 15-year-old boy who presented with multiple cutaneous lesions exhibiting clinical and imaging characteristics of a venolymphatic malformation. These lesions were histologically proved to represent superficial plexiform neurofibromas. We wish to emphasize the unique MR findings of superficial plexiform neurofibromas; these findings are different from the imaging characteristics of the deep form and can be confused with a low-flow vascular malformation.


A practical approach to assess inhalation toxicity of metal oxide nanoparticles in vitro.
Exposure of humans to metal oxide nanoparticles (NPs) occurs mainly via air, and inhaled metal oxide NPs may generate inflammation. The aim of this study was to investigate the proinflammatory potential of six metal oxide NPs (CeO2 , Mn2 O3 , CuO, ZnO, Co3 O4 and WO3 ; 27-108 μg ml-1 ) using human primary 3-dimensional airway epithelium (MucilAir™) and dendritic cell (DC) models. Metal oxide NPs were mainly aggregated/agglomerated in the cell media, as determined by dynamic light scattering, scanning electron microscopy and differential centrifugal sedimentation. WO3 and ZnO were highly soluble, both with and without respiratory mucus. Proinflammatory signalling by the epithelium was evaluated after a 24 hour exposure by increased interleukin-6 and -8 and monocyte chemoattractant protein 1 cytokine release, which occurred only for CuO. Moreover, maturation of immature human DCs, which play a key role in the lung immune system, were evaluated by expression of surface markers HLA-DR, CD80, CD83 and CD86 after a 48 hour exposure. Only Mn2 O3 consistently upregulated DC maturation markers. Furthermore, by addition of medium from metal oxide NP-exposed 3-dimensional airway cultures to metal oxide NP-exposed DC cultures, the interplay between lung epithelium and DCs was studied. Such an interplay was again only observed for Mn2 O3 and in one of five DC donors. Our results show that, even when using dosages that represent very high in vivo exposure levels, up to 27 hours of constant human airway exposure, metal oxide NPs cause minimal proinflammatory effects and that epithelial cells not necessarily interfere with DC maturation upon metal oxide NP exposure. The present approach exemplifies a relevant translation towards human safety assessment.


Implementing market-based reforms in the English NHS: bureaucratic coping strategies and social embeddedness.
This paper reports findings from an ethnographic study that explored how market-based policies were implemented in one local health economy in England. We identified a number of coping strategies employed by local agents in response to multiple, rapidly changing and often contradictory central policies. These included prioritising the most pressing concern, relabelling existing initiatives as new policy and using new policies as a lever to realise local objectives. These coping strategies diluted the impact of market-based reforms. The impact of market-based policies was also tempered by the persistence of local social relationships in the form of 'sticky' referral patterns and agreements between organisations not to compete. Where national market-based policies disrupted local relationships they produced unintended consequences by creating an adversarial environment that prevented collaboration.


Emerging Concepts in the Treatment of Diabetic Retinopathy.
Diabetic retinopathy (DR) is the leading cause of vision loss in working-age adults in the developed world. This review discusses the current approach to managing the disease, such as glycemic and blood pressure control, as well as laser photocoagulation, as well as emerging concepts and controversies on novel therapies. In recent years, the rise of intraocular anti-angiogenesis treatments is changing the paradigm of classic laser photocoagulation in the management of DR, but its long-term benefits remain an area of controversy. We also discuss new targets including anti-inflammation, neuroprotection, and novel laser technologies. Finally, we discuss new advances in retinal imaging that has vastly improved the diagnosis and management of DR. Diagnosis and management of diabetic retinopathy is a rapidly progressing field. Emerging concepts in ophthalmic imaging, medical treatments, and surgical approaches provide insights into how DR management will evolve in the near future.


Inherited metabolic diseases mimicking hereditary spastic paraplegia (HSP): a chance for treatment.
The syndromic group of hereditary spastic paraplegias has a heterogeneous clinical profile and a broad differential diagnosis, including neurometabolic disorders that are potentially treatable. This group includes 5,10-methylenetetrahydrofolate reductase deficiency, cobalamin C deficiency disease, dopamine responsive dystonia, cerebrotendinous xanthomatosis, biotinidase deficiency, GLUT1 deficiency syndrome, delta-e-pyrroline-carboxylase-synthetase deficiency, hyperonithinemia-hyperammonemia-homocitrullinuria syndrome, arginase deficiency, multiple carboxylase deficiency, and X-linked adrenoleukodystrophy. This review describes these diseases in detail, highlighting the importance of early diagnosis and effective treatment aiming at preserving functionality and quality of life in these patients. For the purpose of this study, we carried a non-systematic review on PUBMED, finding an initial sample of 122 papers; upon refining, 41 articles were found relevant to this review. Subsequently, we added review articles and works with historical relevance, totalizing 76 references. An adequate diagnostic workup in patients presenting with spastic paraplegia phenotype should include screening for these rare conditions, followed by parsimonious ancillary investigation.


Relationship of early acute complications and insertion site in push method percutaneous endoscopic gastrostomy.
Percutaneous endoscopic gastrostomy (PEG), which is frequently used for nutrition management in patients having difficulty with oral intake, is considered a safe procedure. However, serious complications may occur depending on site of the puncture. This study aimed to clarify whether push method PEG construction at the posterior wall (PW) of the greater curvature (GC) had a higher risk of complications. We retrospectively investigated the relationship between puncture site at the PW of the GC and early acute complications in 540 patients receiving PEG. Early acute complications were defined as bleeding or perforation within 30 days after the PEG procedure. PEG-related complications were observed in 80 patients in total, with early acute complications detected in 42 patients. PEG construction at the PW of the GC in 12 cases exhibited a significantly higher occurrence of early acute complications versus PEG at other sites (41.7% vs. 7.0%, p = 0.001). Further, multivariate analysis revealed PW at the GC to be independently associated with early acute complications (OR 9.59, 95% CI 2.82-32.61; p = 0.0003). It may be desirable to avoid PEG at the PW of the GC. If performed, clinicians should pay careful attention to early acute complications.


shRNA-targeted hTERT suppress cell proliferation of bladder cancer by inhibiting telomerase activity.
RNA interference (RNAi) has demonstrated profound prospect in human gene research. hTERT, the rate-limiting component of telomerase activity, is highly expressed in bladder cancer cells. Here, we investigated the anti-proliferation effects of small hairpin interfering RNA (shRNA)-targeted hTERT gene on bladder cancer in vitro and in vivo. The results showed that ph2-shRNA, the most-effective vector carrying shRNA-targeted hTERT, could significantly inhibit the cell proliferation by down-regulating hTERT expression, decreasing telomerase activity, decreasing cell number of S phase, increasing the cell number of G0/G1 phase in T24 cells and xenograft tumor tissues, and attenuate the tumor growth of xenograft mice model compared with controls. Our results demonstrate that hTERT-directed shRNAs are potent inhibitors of bladder cancer.


A rapid spectrophotometric method for the determination of mefloquine hydrochloride.
A simple ultraviolet spectrophotometric method for the estimation of mefloquine hydrochloride in methanol (ME(2)) has been developed and has been compared with the reported ultraviolet spectrophotometric method in 0.1 N hydrochloric acid (ME(1)). Analytical parameters such as stability, selectivity, accuracy and precision have been established for both the methods and evaluated statistically to assess the application of the individual methods. Both the methods were compared with the existing pharmacopoeial method for estimation of the drug. Both the methods were found to have the advantages for simplicity, stability, sensitivity, reproducibility and accuracy for using as an alternate to the existing non-spectrophotometric methods for the routine analysis of the drug in pharmaceutical formulations and also in pharmaceutical investigations involving mefloquine hydrochloride.


Ashbya gossypii beyond industrial riboflavin production: A historical perspective and emerging biotechnological applications.
The filamentous fungus Ashbya gossypii has been safely and successfully used for more than two decades in the commercial production of riboflavin (vitamin B2). Its industrial relevance combined with its high genetic similarity with Saccharomyces cerevisiae together promoted the accumulation of fundamental knowledge that has been efficiently converted into a significant molecular and in silico toolbox for its genetic engineering. This synergy has enabled a directed and sustained exploitation of A. gossypii as an industrial riboflavin producer. Although there is still room for optimizing riboflavin production, the recent years have seen an abundant advance in the exploration of A. gossypii for other biotechnological applications, such as the production of recombinant proteins, single cell oil and flavour compounds. Here, we will address the biotechnological potential of A. gossypii beyond riboflavin production by presenting (a) a physiological and metabolic perspective over this fungus; (b) the molecular toolbox available for its manipulation; and (c) commercial and emerging biotechnological applications for this industrially important fungus, together with the approaches adopted for its engineering.


Patient participation in pulmonary interventions to reduce postoperative pulmonary complications following cardiac surgery.
Clinical interventions aimed at reducing the incidence of postoperative pulmonary complications necessitate patient engagement and participation in care. Patients' ability and willingness to participate in care to reduce postoperative complications is unclear. Further, nurses' facilitation of patient participation in pulmonary interventions has not been explored. To explore patients' ability and willingness to participate in pulmonary interventions and nurses' facilitation of pulmonary interventions. Single institution, case study design. Multiple methods of data collection were used including preadmission (n=130) and pre-discharge (n=98) patient interviews, naturalistic observations (n=48) and nursing focus group interviews (n=2). A cardiac surgical ward of a major metropolitan, tertiary referral hospital in Melbourne, Australia. One hundred and thirty patients admitted for cardiac surgery via the preadmission clinic during a 1-year period and 40 registered nurses who were part of the permanent workforce on the cardiac surgical ward. Patients' understanding of their role in pulmonary interventions and patients' preference for and reported involvement in pulmonary management. Nurses' facilitation of patients to participate in pulmonary interventions. Patients displayed a greater understanding of their role in pulmonary interventions after their surgical admission than they did at preadmission. While 55% of patients preferred to make decisions about deep breathing and coughing exercises, three-quarters of patients (75%) reported they made decisions about deep breathing and coughing during their surgical admission. Nurses missed opportunities to engage patients in this aspect of pulmonary management. Patients appear willing to take responsibility for pulmonary management in the postoperative period. Nurses could enhance patient participation in pulmonary interventions by ensuring adequate information and education is provided. Facilitation of patients' participation in their recovery is a fundamental aspect of care delivery in this context.


Influence of lipophilicity of anthracyclines on the interactions with cholesterol in the model cell membranes - Langmuir monolayer and SEIRAS studies.
The interactions of anthracyclines with biological membranes strongly depend on the drug lipophilicity, which might also determine the specific affinity to cholesterol molecules. Therefore, in this work we show the studies concerning the effect of two selected anthracyclines, daunorubicin (DNR) and idarubicin (IDA) on simple models of healthy (DMPC:Chol 7:3) and cancer cells membranes with increased level of cholesterol (DMPC:Chol 3:7) as well as pure cholesterol monolayers prepared at the air-water interface and supported on gold surface. It has been shown that more lipophilic IDA is able to penetrate cholesterol monolayers more effectively than DNR due to the formation of IDA-cholesterol arrangements at the interface, as proved by the thermodynamic analysis of compression-expansion cycles. The increased interactions of IDA were also confirmed by the time measurements of pre-compressed monolayers exposed to drug solutions as well as grazing incidence X-ray diffraction studies demonstrating differences in the 2D organization of cholesterol monolayers. Langmuir studies of mixed DMPC:Chol membranes revealed the reorganization of molecules in the cancer cell models at the air-water interface at higher surface pressures due to the removal of DNR, while increased affinity of IDA towards cholesterol allowed this drug to penetrate the layer more efficiently without its removal. The SEIRAS spectra obtained for supported DMPC:Chol bilayers proved that IDA locates both in the ester group and in the acyl chain region of the bilayer, while DNR does not penetrate the membranes as deeply as IDA. The increased penetration of the mixed phospholipid layers by idarubicin might be attributed to the higher lipophilicity caused by the lack of methoxy group and resulting in a specific affinity towards cholesterol.


Xerophthalmia and acquired night blindness in a patient with a history of gastrointestinal neoplasia and normal serum vitamin A levels.
A 69-year-old male patient presented to our department with a 3-month history of nyctalopia. Reviewing of his general health revealed a history of gastrointestinal tumor treated with a modified WHIPPLE operation. Ocular findings at presentation included mild xerophthalmic features and nonspecific pigmentary retinal changes. A standard full-field electroretinogram (ERG) was obtained that showed normal photopic function and extinguished scotopic function. The ocular symptoms, the history and the ERG findings suggested vitamin A deficiency as a possible cause for his complaints. Serum vitamin A levels were subsequently requested, but the results were within normal limits. Despite the normal serum vitamin A levels, the patient was instructed to commence treatment with high doses of oral vitamin A supplements. One month after the onset of the treatment, the patient reported that his visual function has significantly improved, while repeat ERG testing revealed that scotopic function has improved to normal levels. This case highlights that in patients with acquired night blindness due to vitamin A deficiency, the ERG responses possibly represent a more sensitive marker compared to the serum levels of vitamin A.


Evaluation of anterior segment structures with Scheimpflug camera in patients undergoing sutureless scleral fixation by modified Yamane technique.
To evaluate anterior segment parameters in patients undergoing sutureless scleral fixation intraocular lens implantation with the modified Yamane technique (SSF-IOL-MY) by using Scheimpflug camera system. Each group of 25 patients was included for aphakia undergoing SSF-IOL-MY and for senile cataract undergoing uneventful phacoemulsification and intraocular lens implantation (Phaco+IOL). Anterior chamber depth (ACD), iridocorneal angle (ICA), anterior chamber volume (ACV) and keratometric values were evaluated by Scheimpflug camera (Sirius, CSO, Italy) system. It was seen that the ACD, ICA and ACV display wider structures in patients with SSF-IOL-MY group compared to Phaco+IOL group. However, the ACD (p = 0.828) and ICA (p = 0.219) have not a statistically significant difference, while ACV (p = 0.007) has a statistically significant difference. In terms of keratometric values of the patients, there was no statistically difference in K1, K2 and Kmax values (p = 0.348, p = 0.106, p =0.269, respectively). Although there was no statistically significant difference between the groups in terms of anterior corneal astigmatism, posterior corneal astigmatism was statistically higher in the Phaco+IOL group (p = 0.192, p = 0.031, respectively). SSF-IOL-MY surgery affects anterior segment parameters similar to the Phaco+IOL method, which is the gold standard in cataract surgery. In this surgery, it was approached to the gold standard method in terms of IOL position with the ACD, ACV and ICA values and the results of the corneal incision with the keratometric values.


Okadaic acid inhibits the release of TSH in response to TRH and K+ from rat anterior pituitaries.
The effects of okadaic acid, a non-phorbol-12-tetradecanoate-13-acetate (non-TPA)-type tumor promoter and a potent inhibitor of protein phosphatases, on thyroid-stimulating hormone (TSH) secretion from the rat anterior pituitary were examined. Preincubation of anterior pituitaries with okadaic acid caused a time- and concentration-related decrease in a subsequent thyrotropin-releasing hormone (TRH)-stimulated TSH secretion, whereas it did not cause any changes in basal secretion of TSH. In addition, okadaic acid inhibited a subsequent high K(+)-induced TSH secretion. In contrast, ionomycin-induced TSH secretion was not inhibited by pretreatment with okadaic acid. The present results suggest that okadaic acid may block the release of TSH by inhibition of Ca2+ influx through voltage-sensitive and/or receptor-operated Ca2+ channels.


Quality of life and associated factors among family caregivers of individuals with psychiatric illness at DRH, South Wollo, Ethiopia, 2020.
Mental illness results in an enormous social and economic burden not only on patients, but also on their families and communities. Many caregivers of patients with mental illnesses suffer from an extremely poor quality of life. In Sub-Saharan Africa, approximately 71% caregivers suffer from economic burden of severe mental illness. To our knowledge, no study has been conducted on quality of life of caregivers in Ethiopia. Therefore, this study aimed to assess the quality of life of family caregivers of patients with mental illness at Dessie Referral Hospital. The institution-based cross-sectional study was conducted among 398 caregivers selected using a consecutive sampling technique. The World Health Organization Quality of Life BREF was used to assess the quality of life. Logistic regression was performed and statistical significance was declared at a p-value < 0.05. 189 (47.5%) of family caregivers had poor quality of life. Being divorced, unable to read and write, primary education, being spouse, sibling and children of the patient, poor social support and high perceived stigma were significantly associated with the outcome variable. Because the magnitude of poor quality of life among family caregivers was high, family intervention programs are highly recommended to improve quality of life among caregivers.


Vertical location of the ear, assessed by the Leiber test, in healthy North American Caucasians 6--19 years of age.
A method of assessing the level of the ears, slightly modified from that devised by Leiber (1972), and the instrument developed for the measurements, are described. In a study of 1312 healthy North American Caucasians of both sexes aged 6--19 years, dystopic ears were found in 15 (1.2%). The ears were low-set in 13 (5 bilateral and 8 unilateral), in more males (8) than females (5), and were high-set in 2 (bilateral in a girl and unilateral in a boy). The level of normally located ears changed with age, from low-normal location in early school age to middle-normal in young adulthood. Almost 10% of "normally" located ears were situated asymmetrically, but these asymmetries could not be detected visually.


Molecular neurobiology of loss: a role for basolateral amygdala extracellular matrix.
Psychological loss is a common experience that erodes well-being and negatively impacts quality of life. The molecular underpinnings of loss are poorly understood. Here, we investigate the mechanisms of loss using an environmental enrichment removal (ER) paradigm in male rats. The basolateral amygdala (BLA) was identified as a region of interest, demonstrating differential Fos responsivity to ER and having an established role in stress processing and adaptation. A comprehensive multi-omics investigation of the BLA, spanning multiple cohorts, platforms, and analyses, revealed alterations in microglia and the extracellular matrix (ECM). Follow-up studies indicated that ER decreased microglia size, complexity, and phagocytosis, suggesting reduced immune surveillance. Loss also substantially increased ECM coverage, specifically targeting perineuronal nets surrounding parvalbumin interneurons, suggesting decreased plasticity and increased inhibition within the BLA following loss. Behavioral analyses suggest that these molecular effects are linked to impaired BLA salience evaluation, leading to a mismatch between stimulus and reaction intensity. These loss-like behaviors could be rescued by depleting BLA ECM during the removal period, helping us understand the mechanisms underlying loss and revealing novel molecular targets to ameliorate its impact.


Relationship between brain stem volume and aggression in children diagnosed with autism spectrum disorder.
Aggressive behaviors are common in individuals diagnosed with autism spectrum disorder (ASD) and may be phenotypic indicators of different subtypes within ASD. In current research literature for non-ASD samples, aggression has been linked to several brain structures associated with emotion and behavioral control. However, few if any studies exist investigating brain volume differences in individuals with ASD who have comorbid aggression as indicated by standardized diagnostic and behavioral measures. We examined neuroimaging data from individuals rigorously diagnosed with ASD versus typically developing (TD) controls. We began with data from brain volume regions of interest (ROI) taken from previous literature on aggression including the brainstem, amygdala, orbitofrontal cortex, anterior cingulate cortex, and dorsolateral prefrontal cortex. We defined aggression status using the Irritability subscale of the Aberrant Behavior Checklist and used lasso logistic regression to select among these predictor variables. Brainstem volume was the only variable shown to be a predictor of aggression status. We found that smaller brainstem volumes are associated with higher odds of being in the high aggression group. Understanding brain differences in individuals with ASD who engage in aggressive behavior from those with ASD who do not can inform treatment approaches. Future research should investigate brainstem structure and function in ASD to identify possible mechanisms related to arousal and aggression.


Magnetic resonance imaging evaluation of spontaneous portosystemic collaterals.
Three patients, two of whom had histories of episodic hepatic encephalopathy, were shown by magnetic resonance imaging (MRI) to have occult spontaneous portosystemic shunts. The multiplanar imaging capabilities of MRI provided an optimal, noninvasive method of visualization of collateral anatomy in each case.


Comparison of spinal accessory nerve transfer to supra-scapular nerve vs. shoulder arthrodesis in adults with brachial plexus injury.
Restoring shoulder mobility, stability, and strength is a key goal in patients with brachial plexus injuries. Shoulder arthrodesis is chiefly used as an adjunct to, or after failure of, initial direct nerve surgery. The objective of this study was to compare clinical and functional shoulder outcomes after direct nerve transfer vs. shoulder arthrodesis in adults with supra-clavicular brachial plexus injuries. Shoulder arthrodesis, currently used as a salvage procedure in brachial palsy injuries, deserves to be viewed to a valid alternative to direct nerve transfer. A retrospective study was conducted in 58 patients with a follow-up of at least 2 years. Among them, 20 were managed by transfer of a spinal accessory nerve fascicle to the supra-scapular nerve and 38 by shoulder arthrodesis. Outcome measures were shoulder range-of-motion, isometric shoulder strength, and the Disabilities of the Arm, Shoulder, and Hand (DASH) score. Mean age at surgery was 24 years and mean follow-up was 46 months (range, 24-156 months). Motion ranges of the shoulder were not significantly different between the two treatment groups. Data variance was significantly greater in the nerve transfer group than in the shoulder arthrodesis group for scapular antepulsion (p=0.0011), abduction (p<0.001), and external rotation (p=0.0066). Strength was significantly greater in the arthrodesis group in all directions of motion. The DASH scores showed no significant between-group differences. The results of this study conflict with the widely help opinion that nerve transfer to the supra-scapularis nerve produces better clinical outcomes compared to shoulder arthrodesis. Nerve transfer was not better than shoulder arthrodesis in our patients. The data variance heterogeneity suggests poor predictability and reliability of nerve transfer, in contrast to the modest but predictable and uniform results of shoulder arthrodesis. IV, retrospective observational comparative study.


An aptamer-capture based chromogenic assay for thrombin.
A simple chromogenic assay for human alpha thrombin is developed through aptamer affinity capture and a subsequent enzyme reaction. Thrombin is captured on the aptamer-modified magnetic beads, and catalyzes the conversion of chromogenic substrates to optically measured products. The measurement of the generated products by an absorbance spectrometer allows for the final quantification of thrombin. This assay shows high sensitivity by taking advantage of sample enrichment and enzyme amplification, and exhibits good specificity by involving the selective aptamer binding and the specific enzyme reaction. A concentration detection limit of 40 fM can be reached when the tripeptide substrate of tosyl-Gly-Pro-Arg-p-nitroanilide is used in a 24 h enzyme reaction, and the use of 2h enzyme reaction in the assay enables the detection of 400 fM thrombin for a rapid analysis. This assay can be applied to detect thrombin in dilute human serum.


The protein kinase Kin4 inhibits exit from mitosis in response to spindle position defects.
Accurate nuclear position is essential for each daughter cell to receive one DNA complement. In budding yeast, a surveillance mechanism known as the spindle position checkpoint ensures that exit from mitosis only occurs when the anaphase nucleus is positioned along the mother-bud axis. We identified the protein kinase Kin4 as a component of the spindle position checkpoint. KIN4 prevents exit from mitosis in cells with mispositioned nuclei by inhibiting the mitotic exit network (MEN), a GTPase signaling cascade that promotes exit from mitosis. Kin4 is active in cells with mispositioned nuclei and predominantly localizes to mother cells, where it is ideally situated to inhibit MEN signaling at spindle pole bodies (SPBs) when anaphase spindle elongation occurs within the mother cell.


The production and characterisation of antisera to 17-hydroxyprogesterone.
Sheep were immunised with 11-deoxycortisol-21-hemisuccinate-bovine serum albumin (11-deoxycortisol-21-HS-BSA) or with 17-hydroxyprogesterone-7 alpha-carboxyethyl thioether-keyhole limpet haemocyanin (17-OHP-7 alpha-CETE-KLH) or with 17-OHP-3-(O-carboxymethyl)oxime-KLH (17-OHP-3-CMO-KLH). The resultant antisera were assessed using [3H]17-OHP and dextran-coated charcoal to separate the antibody bound and free fractions. All sheep produced antisera with an apparent affinity constant of from 1.4 to 6.6 X 10(9) 1/mol. Those raised against 11-deoxycortisol-21-HS-BSA had titres ranging from 1:12,000 to 1:78,000 but showed significant cross-reactivity with many of the steroids tested. Sheep immunised with 17-OHP-7 alpha-CETE-KLH had antisera titres of from 1:102,000 to 1:180,000 and only 17-hydroxypregnenolone cross-reacted significantly (10-20%). The best antisera were raised in sheep immunised with 17-OHP-3-CMO-KLH. Titres ranged from 1:168,000 to 1:390,000 and there were about 8 g/l of specific antibodies which cross-reacted 5.7% or less with 17-hydroxypregnenolone, and less than 0.5% with progesterone, 11-deoxycortisol and the other steroids studied. The antisera to 17-OHP-3-CMO-KLH were further assessed using [125I]17-OHP; titres ranged from 1:5,700,000 to 1:18,000,000 with affinity constants of from 1.67 to 2.5 X 10(10) 1/mol. They showed minimal or no cross-reactivity with the steroids studied. Reimmunisation after an 8-month interval produced antisera with a higher affinity constant and even lower cross-reactivity with other steroids.


Dynamics of a tightly coupled mechanism for flagellar rotation. Bacterial motility, chemiosmotic coupling, protonmotive force.
The bacterial flagellar motor is a molecular engine that couples the flow of protons across the cytoplasmic membrane to rotation of the flagellar filament. We analyze the steady-state behavior of an explicit mechanical model in which a fixed number of protons carries the filament through one revolution. Predictions of this model are compared with experimentally determined relationships between protonmotive force, proton flux, torque, and speed. All such tightly coupled mechanisms produce the same torque when the motor is stalled but vary greatly in their behavior at high speed. The speed at zero load predicted by our model is limited by the rates of association and dissociation of protons at binding sites on the rotor and by the mobility of force generators containing transmembrane channels that interact with these sites. Our analysis suggests that more could be learned about the motor if it were driven by an externally applied torque backwards (at negative speed) or forwards at speeds greater than the zero-load speed.


Metabolic changes in first-episode early-onset schizophrenia with second-generation antipsychotics.
Individuals with a diagnosis of schizophrenia have a reduced life expectancy compared with the general population and cardiovascular disease is the major contributor to this early mortality. The use of second-generation antipsychotic (SGA) medications is associated with significant weight gain and metabolic side effects; however, there is limited knowledge in certain diagnostic groups, specifically early-onset schizophrenia (EOS). This study aimed to investigate the metabolic side effects of SGAs, specifically olanzapine, risperidone and quetiapine, in a cohort of drug-naïve children and adolescents with first-episode EOS. Body mass index (BMI), serum cholesterol and triglycerides were measured at baseline and a median of 7 months of follow up in drug-naïve children and adolescents with EOS. A total of 49 children and adolescents received a diagnosis of first-episode EOS and we had complete follow-up data for 74% (N = 36). A significant increase in BMI, serum triglycerides and cholesterol was observed in the unselected cohort after commencement of SGAs. One-third of children and adolescents had abnormal serum triglycerides and cholesterol; however, a dose-response was not demonstrated. Olanzapine and quetiapine had a greater increase in serum triglycerides. In addition to highlighting the need for routine screening for metabolic side effects in EOS, interventions to prevent and treat obesity and the metabolic syndrome are indicated.


The association between metabolic syndrome and bone mineral density: a meta-analysis.
Previous researches demonstrate uncertainty about the effect of metabolic syndrome (MS) on bone. We performed a meta-analysis to investigate the association of MS with bone mineral density (BMD) of spine and femoral neck (FN). In this meta-analysis, searches of Medline, Embase, Cochrane Library, Chinese biological medical database and China national knowledge infrastructure were undertaken to identify studies in humans of the association between MS and BMD. Random effects model was used for this meta-analysis. The results of our research were reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 11 studies (including an outlier study) with 13,122 subjects were included in our research. We detected a significant overall association of MS with increased BMD of spine (weighted mean difference, WMD = 0.027, 95 % confidence interval, CI [0.011, 0.042]) and no significant overall association of MS with BMD of FN (WMD = 0.008, CI [-0.011, 0.026]). Subgroup analyses indicated significant association between MS and increased BMD of spine in subjects whose BMD was measured by dual-energy X-ray absorptiometry (DXA) scanner manufactured by Hologic Inc., subjects diagnosed by International Diabetes Federation criteria and subjects diagnosed by National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) criteria. And significant association between MS and increased BMD of FN in Caucasian subjects, subjects whose BMD was measured by DXA scanner manufactured by Hologic Inc. and subjects diagnosed by NCEP-ATP III criteria was also found. Our meta-analysis suggests that MS has no clear influence on BMD, or its influence maybe beneficial.