Phacoemulsification with corneal astigmatism correction with the use of a toric intraocular lens in a case of megalocornea.
We report the case of a 49-year-old patient with megalocornea and coexisting corneal astigmatism. The corneal diameter in the right eye was 15.0 mm and in the left eye, 14.9 mm. In both eyes, a nuclear sclerotic cataract developed, with the tendency toward cortical mass swelling in the right eye. The aim of surgical treatment was to remove the cataract with simultaneous correction of corneal astigmatism by implanting an Acrysof toric intraocular lens (IOL). Intraocular lens stabilization was obtained by suturing it to an capsular tension ring (CTR) in the anterior chamber. The IOL-CTR complex was rotated into the lens capsule and aligned with the steep meridian of corneal astigmatism. The surgical technique provides a stable refractive and functional effect in patients with megalocornea and coexisting cataract and corneal astigmatism.


Comparison of methods to estimate glomerular filtration rate in paediatric oncology patients.
Glomerular filtration rate (GFR) is estimated daily in paediatric oncology patients; however, few equations, particularly ones that do not include serum creatinine, have been evaluated in this population. We aimed to compare the predictive performance of different equations available to estimate GFR in paediatric oncology patients. GFR was measured (mGFR) in paediatric oncology patients based on a chromium 51-labeled ethylene diamine tetraacetic acid excretion test. GFR was estimated (eGFR) in these same patients using equations identified from the literature. mGFR and eGFR values were compared, and the predictive performance of various eGFR equations was assessed in terms of their bias, precision and accuracy. In total, 124 mGFR values ranging from 7 to 146 mL/min were available for analysis from 73 children. Twenty-two equations were identified from the literature. The Flanders metadata equation displayed the lowest absolute bias (mean error of 0.9 mL/min) and the greatest precision (root mean square error of 13.1 mL/min). The univariate Schwartz equation predicted the highest percentage (81.5%) of eGFR values within 30% of mGFR values, and the Rhodin fat-free mass equation predicted the highest percentage (37.1%) of eGFR values within 10% of mGFR values. A number of equations were identified that could be used to estimate renal function in paediatric oncology patients; however, none was found to be highly accurate. The Flanders metadata equation and univariate Schwartz performed the best in this study, and we would suggest that these two equations may be used cautiously in paediatric oncology patients for clinical decision making, understanding their limitations.


Antifouling bastadin congeners target mussel phenoloxidase and complex copper(II) ions.
Synthetically prepared congeners of sponge-derived bastadin derivatives such as 5,5'-dibromohemibastadin-1 (DBHB) that suppress the settling of barnacle larvae were identified in this study as strong inhibitors of blue mussel phenoloxidase that is involved in the firm attachment of mussels to a given substrate. The IC₅₀ value of DBHB as the most active enzyme inhibitor encountered in this study amounts to 0.84 μM. Inhibition of phenoloxidase by DBHB is likely due to complexation of copper(II) ions from the catalytic centre of the enzyme by the α-oxo-oxime moiety of the compound as shown here for the first time by structure activity studies and by X-ray structure determination of a copper(II) complex of DBHB.


Molecular Medicine - CHI's 17th International Tri-Conference: Mastering Medicinal Chemistry - CHI's Seventh Annual Conference.
CHI's 17th International Tri-Conference on Molecular Medicine, held in San Francisco, included topics covering the drug discovery process, with an emphasis on lead optimization. This conference report highlights selected presentations on the development of several launched and investigational drugs, including Plerixafor, Trox-1 (CombinatoRX Inc), lorcaserin (Arena Pharmaceuticals Inc), vorapaxar (Merck & Co Inc) and ulimorelin (Tranzyme Pharma Inc).


A validated LC-MS/MS method for the quantification of climbazole metabolites in human urine.
Climbazole is a preservative and an anti-dandruff ingredient with applications in various cosmetic products. The general population is therefore exposed to this chemical, and exposure monitoring is desirable. We have postulated a pathway for the human metabolism of climbazole, leading to two specific metabolites which can be excreted via urine. An analytical method for the determination of these metabolites in human urine was developed and validated. The sample preparation includes an enzymatic hydrolysis protocol. The measurement as such is based on online solid phase extraction (SPE), coupled to ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Intra- and inter-series coefficients of variation (CV) were determined in the concentration range from 1 µg/l to 100 µg/l with spiked pooled urine samples, and they were consistently below 15%, mostly below 10%. The corresponding accuracies (mean relative recovery rates) in spiked pooled urine varied from 97% to 103%. The robustness of the method was estimated by spiking individual urine samples. At 1 µg/l, the robustness was rather limited due to interfering matrix peaks in several samples, but excellent results were obtained at 10 µg/l and 100 µg/l, with CVs between 7% and 14% and accuracies from 101% to 110%. Matrix interferences often seemed to be associated with higher creatinine contents (≥2.0 g/l) of the samples. We subsequently applied the method to urine specimens from a human metabolism study involving documented climbazole exposures. We were able to identify and quantify the postulated metabolites in those real samples, thus validating our metabolism hypothesis. We also investigated the precision and accuracy of the enzymatic deconjugation with the real samples. The deconjugation step was found to be highly repeatable and largely quantitative. Both metabolites formed glucuronides, though varying fractions were also excreted in unconjugated (free) forms. Phase II conjugates other than glucuronides did not seem to be produced in significant amounts. With our method, both climbazole metabolites can be reliably quantified in the range between about 1.5 µg/l (depending on matrix interferences in individual samples) and at least 500 µg/l.


The Madin-Darby canine kidney cell culture derived influenza A/H5N1 vaccine: a phase I trial in Taiwan.
Avian H5N1 influenza has caused human infections globally and has a high mortality rate. Rapid production of effective vaccines is needed. A phase 1, randomized, observer-blinded clinical trial was conducted to examine the safety and immunogenicity of an inactivated whole virion vaccine against the influenza A/H5N1 virus produced from the Madin-Darby canine kidney (MDCK) cell line. Participants were randomized to four groups and administered two intramuscular doses of vaccine containing 3 μg hemagglutinin (HA), 3 μg HA with 300 μg aluminum phosphate (AlPO4), 6 μg HA, and 6 μg HA with 300 μg AlPO4, respectively, at two visits, 21 days apart. Serum hemagglutination inhibition (HAI) and neutralizing antibody levels were determined at baseline and on Days 21 and 42. Sixty healthy individuals were enrolled. The neutralization assay showed a significant immune response in the 6 μg with ALPO4 group on Day 42 compared to pre-vaccination levels (11.32±9.77 vs. 4.00±0, p=0.02). The adjuvant effect in neutralization assay was also significant on Day 42 in the 6 μg group (4.52±1.94 without adjuvant vs. 11.32±9.77 with adjuvant, p=0.02). HAI assay also showed an aluminum adjuvant-induced increasing trend in HAI geometric mean titer on Day 42 in the 3 μg and 6 μg groups (6.02 versus 8.20, p=0.05 and 5.74 versus 8.21, p=0.14). The most frequent adverse event was local pain (20% to 60%). There were no vaccine-related severe adverse effects. MDCK cell line-derived H5N1 vaccine was well tolerated. It is necessary to investigate further the immunogenicity of higher antigen doses and the role of aluminum adjuvant in augmenting the effect of the vaccine.


Biological and biochemical consequences of the human ERCC-1 repair gene after transfection into a repair-deficient CHO cell line.
The consequences of the presence of the human gene ERCC1 in repair-deficient 43-3B cells were examined. The gene restores the sensitivity of this mutant not only to UV but also to 4NQO, N-Ac-AAF and alkylating agents to the normal level. Also, the frequency of mutation induction by UV at the Na+/K+-ATPase locus returns to the level of CHO wild-type cells. Additionally, the rate of cyclobutane pyrimidine dimer removal approaches that in wild-type CHO cells. The results obtained indicate that the human gene ERCC-1 restores the impaired functions in 43-3B, and that the gene is probably functionally homologous to the defective one in the 43-3B cell line. Some evidence was found for a difference between the human gene product and its rodent counterpart, as the restoration of normal sensitivity to 4NQO, ENU and N-Ac-AAF was complete whereas it was not for UV.


The primate median eminence. I. Correlative scanning-transmission electron microscopy.
A combined scanning/transmission electron microscopic (SEM/TEM) technique was used to analyze the third cerebral ventricle and underlying tissue of the median eminence of 6 mature rhesus monkeys. The same sample of the ventricular wall was subjected to both SEM and TEM. This technique demonstrates two basic subpopulations of supraependymal cells on the surface of the supraoptic, infundibular and mammillary recesses. Type 1 cells are definitely neuron-like in their surface configuration and internal fine structural organization. Type 2 cells are more similar to histiocytes and are not as numerous as type 1 cells. The functional capacity of type 1 cells is discussed in the context of their potential role as a neuronal network that may serve as a short loop autoregulatory mechanism controlling the synthesis of releasing hormones or biogenic amines.


Computed tomography in adult obliterative bronchiolitis.
Fifteen adults with obliterative bronchiolitis (OB) were investigated with computed tomography (CT). CT was considered to be abnormal in 13/15 patients (87%) showing widespread areas of increased attenuation of a patchy nature and variable proportion. CT revealed more extensive changes than the chest radiograph or bronchogram. It is a non-invasive well-tolerated and easily repeatable technique and may have an important role in the radiological evaluation of adults with OB.


Studies on aminopenicillin developments. Proceedings of a symposium. Concluding remarks.
This symposium has focused on the bacteriological, pharmacokinetic, therapeutic, and adverse effects of the aminopenicillins. The compounds which are currently being assessed are primarily amoxycillin, ampicillin, bacampicillin, pivampicillin, and talampicillin. The three last mentioned are prodrugs which upon gastrointestinal absorption are rapidly split to yield circulating ampicillin. Pharmacokinetics and side-effects are reasons why one may narrow the selection of most suitable compounds within this group down to three. Ampicillin and amoxycillin are primary choices for parenteral dosage, and amoxycillin and bacampicillin the most suitable for oral therapy.


Clinical outcomes and prognostic factors of robotic assisted rectal cancer resection alone versus robotic rectal cancer resection with natural orifice extraction: a matched analysis.
Robotic rectal cancer resection with natural orifice extraction is a recently developed minimally invasive surgery used in the treatment of patients with rectal cancer. However, its safety and feasibility remain undiscussed and controversial. This study reported the clinical outcomes and prognostic factors pertaining to traditional robotic assisted rectal cancer resection alone against that of robotic rectal cancer resection with natural orifice extraction to provide a discussion on this issue. 49 patients who underwent robotic rectal cancer resection with natural orifice extraction and 49 matched patients who underwent conventional robotic assisted rectal cancer resection were systematically analyzed in this study. Regarding the baseline characteristics, after matching, no significant differences were observed between the natural orifice specimen extraction (NOSE) group and the robotic assisted rectal cancer resection (RARC) group. Patients in the NOSE group had a reduced visual analog scale (p < 0.001), passed flatus more quickly (p = 0.002) and suffered less surgical stress than those in the RARC group. Moreover, 4 complications were observed in the NOSE group and 7 complications in the RARC group with no significant difference (p = 0.337) in terms of complications. The two groups had a similar survival outcomes, where the 3-year overall survival (p = 0.738) and 3-year progression-free survival (p = 0.986) were all comparable between the two groups. Histological differentiation and T stage could be regarded as independent prognostic factors for 3-year overall survival and 3-year progression-free survival. Robotic rectal cancer resection with natural orifice extraction is a safe and feasible minimally invasive surgery for patients suffering from rectal cancer as it encompasses considerable several advantages. Histological differentiation and T stage may serve as independent prognostic factors for 3-year overall survival and 3-year progression-free survival.


Bioprinting of radiopaque constructs for tissue engineering and understanding degradation behavior by use of Micro-CT.
Bioprinting has emerged as a potential technique to fabricate tissue engineering constructs and in vitro models directly using living cells as a raw material for fabrication, conforming to the heterogeneity and architectural complexity of the tissues. In several of tissue engineering and in vitro disease modelling or surgical planning applications, it is desirable to have radiopaque constructs for monitoring and evaluation. In the present work, enhanced radiopaque constructs are generated by substituting Calcium ions with Barium ions for crosslinking of alginate hydrogels. The constructs are characterized for their structural integrity and followed by cell culture studies to evaluate their biocompatibility. This was followed by the radiopacity evaluation. The radiological images obtained by micro-CT technique was further applied to investigate the degradation behavior of the scaffolds. In conclusion, it is observed that barium crosslinking can provide a convenient means to obtain radiopaque constructs with potential for multi-faceted applications.


Structural study of L-ascorbic acid 2-phosphate magnesium, a raw material in cell and tissue therapy.
L-ascorbic acid 2-phosphate magnesium (APMg) salt is a vitamin C derivative frequently used as a raw material in cell and tissue therapy. APMg is not only used as a replacement of the unstable ascorbate, but also shows additional cell-biological functionalities. However, its unknown structural characteristics hamper the mechanistic elucidation of its biological role. Therefore, different techniques were applied for APMg structure characterization. Firstly, the stoichiometric composition was characterized by its solvent, ligand and magnesium content. No crystals of APMg could be obtained; however, a single crystal of APNa, the sodium salt of l-ascorbic acid 2-phosphate, was successfully obtained and its crystal structure was elucidated. FT-IR was applied to further clarify the structure of solid APMg. Finally, the structure of APMg in aqueous solution was explored by potentiometric titration as well as FT-IR.


Hybrid membrane with controllable surface microroughness by micro-nano structure processing for diluted PM2.5 capture.
Tremendous efforts have been devoted by researchers on air particulate matter pollution for the increasing harm, however, the Air Pollution Index (API) from "good" to "excellent" is something hard to achieve. Here, halloysite nanotubes/polyvinyl alcohol (HNTs/PVA) hybrid membrane with surface micro-nano structure processing using a one-step method for efficient PM2.5 capture was prepared. The filtration efficiency is 45.35% and the pressure drop is 41.57 Pa of composite membrane with a 60 wt% halloysite dosage. Specially, it resulted in a relatively safer PM index value of about 16.54, which tends to be more stringent than the restriction by Government of China (PM2.5 < 35 μg/m3). The filtration performance was mainly attributed to the controllable microroughness surface as well as the hierarchical structure constructed by one-step method, which has a functional role in obstruction and adsorption for diluted PM2.5. The methodology can employ halloysite onto various polymers, like polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyacrylonitrile (PAN) and also polycaprolactone (PCL) to yield hybrid membranes with the similar modification of surface and structure. Such versatile membrane filters can be purposely designed and scaled up, which endows the existing hybrid membrane with great potentials in both residential and public areas pollution control to achieve a healthier living environment.


Myxozoan parasites vary in river herring according to life history stage and habitat.
Anadromous river herring have declined in many parts of their range, leading to fisheries management efforts to help repopulate this species by improving connectivity of rivers and restoring populations by fish transfers. With data lacking on parasites in these species, this study sought to better understand myxozoans across various life stages and habitats in river herring populations in New Jersey, USA. We compared fish from riverine habitats during early-life growth and adults returning to spawn, marine-phase fish, and landlocked Alewife populations. Three myxozoan species were identified in young-of-the-year (YOY) anadromous river herring, including Kudoa clupeidae in the skeletal musculature, Myxobolus mauriensis in the rib cartilage, and an uncharacterized coelozoic myxozoan within the lumen of mesonephric tubules. In YOY river herring, Blueback Herring were 2 times more likely to be infected by K. clupeidae than Alewife (p = 0.019) and in the Maurice River, fish were 4 times more likely to be infected with M. mauriensis than fish from Great Egg Harbor River (p = 0.000) and 11 times more likely than the Delaware River (p = 0.001). Spawning adult river herring were infected with a previously undescribed myxozoan parasite infecting the kidney. Sequencing the 18S rDNA indicated this species is closely related to Ortholinea species. Myxobolus mauriensis and the Ortholinea-like species were absent from marine-phase river herring indicating that infections were linked to river environments occurring during early-life growth and spawning, respectively. No myxozoans were present in landlocked Alewife, showing that similar infections occurring in rivers were absent in lake environments in the region.


'The art itself is nature': Darwin, domestic varieties and the scientific revolution.
Common to both the scientific and Darwinian revolutions were discussions challenging the distinction between art and nature. Was art a part of nature? Could art be used as a model for nature? This intellectual congruence, however, is more than just nominal. Charles Darwin and Asa Gray, for example, were well-aware of the 17th century debates which preceded them through the works of such revered English writers as William Shakespeare and Thomas Browne. Furthermore, they used their understandings of these debates to inform and express their own thinking about the relation between artificial and natural selection.


Advantages of totally laparoscopic distal gastrectomy over laparoscopically assisted distal gastrectomy for gastric cancer.
Laparoscopic gastrectomy for gastric cancer has become common due to improvement of the surgical techniques and devices for laparoscopic surgery. Although laparoscopically assisted distal gastrectomy (LADG) has several advantages over open distal gastrectomy, little has been reported about the safety and feasibility of totally laparoscopic distal gastrectomy (TLDG). Between October 2005 and June 2007, 80 laparoscopic distal gastrectomies with regional lymphadenectomies were performed for patients with gastric cancer. After 24 patients underwent LADG and 56 patients underwent TLDG, the clinical data were compared between the two groups. The groups were comparable in terms of age, gender, body mass index (BMI), tumor location, tumor size, macroscopic type, depth of invasion, histologic type, lymph node metastasis, and length of proximal margin. However, when only the patients with gastric cancer in the middle third of the stomach were compared between the two groups, the length of the proximal margin was significantly longer in the TLDG group (p < 0.05). The mean blood loss was significantly less in the TLDG group (p < 0.05). The patients in the TLDG group recovered earlier and thus had a significantly shorter postoperative hospital stay. Furthermore, the C-reactive protein level on postoperative day 7 was lower in the TLDG group than in the LADG group (p < 0.05). There was no significant difference in the postoperative complications between the two groups. This study demonstrated that TLDG has several advantages over LADG including smaller wounds, less invasiveness, and better feasibility of a secure ablation. The TLDG procedure yields safe anastomosis independently of the patient's constitution or the location of the cancer. Therefore, TLDG is considered to be a useful technique for patients with gastric cancer.


Transcervical needle biopsy for the differential diagnosis between uterine sarcoma and leiomyoma.
The clinical differential diagnosis between uterine sarcoma and benign leiomyoma is difficult even with magnetic resonance imaging (MRI). Therefore, a considerable number of patients have undergone hysterectomies due to an indication of "suspected malignancy" based on tumor size alone. However, approximately 80% of these hysterectomies have been judged to have been recommended inappropriately. In such situations, reliable preoperative diagnostic tests are required. The authors have evaluated the accuracy of needle biopsy for uterine myoma-like tumors, a procedure that to the authors' knowledge has been performed infrequently. Transcervical needle biopsy was performed in 435 patients with uterine myoma-like tumors. The biopsy specimens were scored for degree of malignancy according to the histopathologic criteria proposed by Bell et al. Histopathologic evaluation of surgical specimens and clinical outcome after 2 years of follow-up were used as the reference standards. Of 435 patients, 7 had uterine sarcomas, 4 of which were scored as > or = 4 points and were diagnosed as "sarcoma" by needle biopsy alone. No sarcoma cases were included in the group of patients with a score of 0. The cutoff score combining the highest sensitivity and specificity with respect to distinguishing uterine leiomyosarcoma from uterine leiomyoma was 2; sensitivity, specificity, and positive and negative predictive values were 100%, 98.6%, 58%, and 100.0%, respectively. Transcervical needle biopsy using histopathologic scoring is a reliable diagnostic test for the differential diagnosis between uterine sarcoma and leiomyoma. This diagnostic method, combined with MRI screening, could reduce the number of patients currently undergoing unnecessary surgery.


On the roles of Ca2+ diffusion, Ca2+ buffers, and the endoplasmic reticulum in IP3-induced Ca2+ waves.
We have investigated the effects of Ca2+ diffusion, mobile and stationary Ca2+ buffers in the cytosol, and Ca2+ handling by the endoplasmic reticulum on inositol 1,4,5-trisphosphate-induced Ca2+ wave propagation. Rapid equilibration of free and bound Ca2+ is used to describe Ca2+ sequestration by buffers in both the cytosol and endoplasmic reticulum (ER) lumen. Cytosolic Ca2+ regulation is based on a kinetic model of the inositol 1,4,5-trisphosphate (IP3) receptor of De Young and Keizer that includes activation and inhibition of the IP3 receptor Ca2+ channel in the ER membrane and SERCA Ca2+ pumps in the ER. Diffusion of Ca2+ in the cytosol and the ER and the breakdown and diffusion of IP3 are also included in our calculations. Although Ca2+ diffusion is severely limited because of buffering, when conditions are chosen just below the threshold for Ca2+ oscillations, a pulse of IP3 or Ca2+ results in a solitary trigger wave that requires diffusion of Ca2+ for its propagation. In the oscillatory regime repetitive wave trains are observed, but for this type of wave neither the wave shape nor the speed is strongly dependent on the diffusion of Ca2+. Local phase differences lead to waves that are predominately kinematic in nature, so that the wave speed (c) is related to the wavelength (lambda) and the period of the oscillations (tau) approximately by the formula c = lambda/tau. The period is determined by features that control the oscillations, including [IP3] and pump activity, which are related to recent experiments. Both solitary waves and wave trains are accompanied by a Ca2+ depletion wave in the ER lumen, similar to that observed in cortical preparations from sea urchin eggs. We explore the effect of endogenous and exogenous Ca2+ buffers on wave speed and wave shape, which can be explained in terms of three distinct effects of buffering, and show that exogenous buffers or Ca2+ dyes can have considerable influence on the amplitude and width of the waves.


Lung immunoreactivity and airway inflammation: their assessment after scorpion envenomation.
Release and activation of pro-inflammatory mediators are among the most important induced factors that are involved in the scorpion envenomation pathogenesis. Inflammatory response and lung reactivity were studied in mice following subcutaneous injection with Androctonus australis hector (Aah) venom. Venom immunodetection in lungs and sequestered cell population in the airways were determined. Cytokines, cellular peroxidase activities (eosinophil peroxidase, myeloperoxydase), and IgE antibodies were also assessed. Immunohistochemical study revealed a positive detection of the Aah venom in the alveolar wall, venule lumens, and inside inflammatory cells. Severe lung edema associated with rapid inflammatory response was observed after animal envenomation. Lung neutrophilia and eosinophilia were accompanied with IL-4, IL-5 release, and IgE synthesis. In conclusion, high cytokine levels, recruitment of inflammatory cells (eosinophils and neutrophils), and increased IgE concentration may contribute to the exacerbation and maintenance of the induced inflammatory response in lungs by scorpion venom. These results lead to the better understanding of this induced pathogenesis and could help the physicians to take care of envenomed patients.


Exploitation of the Herpes simplex virus translocating protein VP22 to carry influenza virus proteins into cells for studies of apoptosis: direct confirmation that neuraminidase induces apoptosis and indications that other proteins may have a role.
Previously, we have shown that apoptosis induced by influenza virus was inhibited by an anti-neuraminidase compound [4-guanidino-2, 3-dehydro-N-acetylneuraminic acid (GG167; Relenza; Zanamivir)], which does not enter cells, and acts at the attachment/entry phase of virus replication. Furthermore, a virulent virus, clone 7a, induced greater levels of apoptosis than the attenuated A/Fiji and had greater neuraminidase (NA) activity. To confirm more directly that NA induces apoptosis, the NA of clone 7a and A/Fiji was expressed fused to the Herpes simplex virus tegument coat protein VP22, transfected into HeLa cells and the level of apoptosis determined. VP22 translocates between cells via the medium thus allowing expressed proteins to transfer to a larger number of cells than those originally transfected. Clone 7a NA fused to VP22 induced a significant level of apoptosis whereas A/Fiji NA/VP22 did not, confirming that NA activity is an important determinant of apoptosis acting during fusion protein translocation between cells. Furthermore, the induction of apoptosis was abrogated by antibody to transforming growth factor-beta, which is activated by NA. This approach also showed that VP22/NS1 proteins of both clone 7a and A/Fiji induced apoptosis when expressed alone but inhibited double stranded RNA-induced apoptosis suggesting that this protein may have a dual mode of action. Also, the M1 and M2 proteins of both viruses induced apoptosis but their NP proteins did not.


Duration discrimination in the range of milliseconds and seconds in children with ADHD and their unaffected siblings.
Detecting genetic factors involved in attention deficit hyperactivity disorder (ADHD) is complicated because of their small effect sizes and complex interactions. The endophenotype approach eases this by coming closer to the relevant genes. Different aspects of temporal information processing are known to be affected in ADHD. Thus, some of these aspects could represent candidate endophenotypes for ADHD. Fifty-four sib-pairs with at least one child with ADHD and 40 control children aged 6-18 years were recruited and asked to perform two duration discrimination tasks, one with a base duration of 50 ms on automatic timing and one with a base duration of 1000 ms on cognitively controlled timing. Whereas children with ADHD, but not their unaffected siblings, were impaired in discrimination of longer intervals, both groups were impaired in discriminating brief intervals. Furthermore, a significant within-family correlation was found for discrimination of brief intervals. Task performances of subjects of the control group correlated with individual levels of hyperactivity/impulsivity for discrimination of brief intervals, but not of longer intervals. Cognitively controlled and also automatic processes of temporal information processing are impaired in children with ADHD. Discrimination of longer intervals appears as a typical 'disease marker' whereas discrimination of brief intervals shows up as a 'vulnerability marker'. Discrimination of brief intervals was found to be familial and linked to levels of hyperactivity/impulsivity. Taken together, discrimination of brief intervals represents a candidate endophenotype of ADHD.


A role for the Cockayne Syndrome B (CSB)-Elongin ubiquitin ligase complex in signal-dependent RNA polymerase II transcription.
The Elongin complex was originally identified as an RNA polymerase II (RNAPII) elongation factor and subsequently as the substrate recognition component of a Cullin-RING E3 ubiquitin ligase. More recent evidence indicates that the Elongin ubiquitin ligase assembles with the Cockayne syndrome B helicase (CSB) in response to DNA damage and can target stalled polymerases for ubiquitylation and removal from the genome. In this report, we present evidence that the CSB-Elongin ubiquitin ligase pathway has roles beyond the DNA damage response in the activation of RNAPII-mediated transcription. We observed that assembly of the CSB-Elongin ubiquitin ligase is induced not just by DNA damage, but also by a variety of signals that activate RNAPII-mediated transcription, including endoplasmic reticulum (ER) stress, amino acid starvation, retinoic acid, glucocorticoids, and doxycycline treatment of cells carrying several copies of a doxycycline-inducible reporter. Using glucocorticoid receptor (GR)-regulated genes as a model, we showed that glucocorticoid-induced transcription is accompanied by rapid recruitment of CSB and the Elongin ubiquitin ligase to target genes in a step that depends upon the presence of transcribing RNAPII on those genes. Consistent with the idea that the CSB-Elongin pathway plays a direct role in GR-regulated transcription, mouse cells lacking the Elongin subunit Elongin A exhibit delays in both RNAPII accumulation on and dismissal from target genes following glucocorticoid addition and withdrawal, respectively. Taken together, our findings bring to light a new role for the CSB-Elongin pathway in RNAPII-mediated transcription.


Bioresorbable Scaffolds: Clinical Outcomes and Considerations.
Bioresorbable scaffolds (BRS) have been engineered to eliminate the theoretic stimulus to late coronary events, a caveat of conventional metallic drug-eluting stents (DESs). Outcome benefits of BRSs over current-generation DESs are expected to accrue after complete bioresorption. Before this timeframe, BRSs need to prove at least similarly safe and effective compared with DESs. Several randomized studies of the Absorb BRS have been made available. Several manufacturers are at the beginning of their line of clinical development of competing BRSs. This article reviews the contemporary clinical outcomes of the Absorb scaffold, and provides an updated state of the art on the other players in the BRS arena.


Immunocytochemical localization of binding 'sites' for LH and hCG in preimplantation mouse embryos.
By using an immunoperoxidase antibody method, mouse blastocysts were found to bind specifically hCG and ovine LH but not FSH or the beta unit of hCG. Brown peroxidase reaction products were present in the morula and increased with the formation of the blastocoele. The LH/hCG binding 'sites' may be related to the initiation of steroidogenesis in the embryo.


Levels and patterns of polycyclic aromatic hydrocarbons and polychlorinated biphenyls in municipal waste incinerator bottom ash in Zhejiang province, China.
Polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) were analyzed in bottom ash from municipal solid waste (MSW) incineration in six cities in Zhejiang province, where one-fourth of the MSW incinerators of China are located. Total PAH contents varied from 2222.53 to 6883.91 microg/kg. The patterns of PAHs were found to be very similar in all the samples, dominated by three-ring and four-ring PAHs. Total PCB concentrations in bottom ash ranged from 1.00 to 1.31 microg/kg, while the coplanar PCBs in the bottom ash were in the range of 0.08-0.52 microg/kg. Among PCB congeners, low chlorinated PCBs contributed to the majority of total PCBs. Generally, PAH concentrations in cities with fluidized bed incinerator were less than those in cities with grate furnace incinerator. PAH and PCB levels were affected by both plastic content in MSW incinerator feed and combustion efficiency. However, further study is required to investigate the effect of these two variables deeply, as well as other influencing factors.


Is that your pager or mine: a survey of women academic family physicians in dual physician families.
This study explored the unique challenges and strategies of women in academic family medicine who are in dual physician families. An e-mail survey was sent to all female physician members of the Society of Teachers of Family Medicine (STFM) who were listed in the on-line database. The survey collected demographic information, details of job descriptions and family life, and included 3 open-ended questions about the experiences of dual physician families. Over 1200 surveys were sent to women physicians in academic family medicine. One hundred fifty-nine surveys were returned. Half of all women worked full time compared to 87% of their partners. Most women reported benefits of having a physician partner including support and having an understanding person at home, though scheduling conflicts and childcare responsibilities contributed to the need for job compromises. Women prioritized finding work-life balance and having supportive partners and mentors as most important to their success as academic family physicians. Dual physician relationships involve rewards and conflicts. More research should explore the competing demands of family life with success in academic medicine.


Mechanistic approaches for mixture risk assessments-present capabilities with simple mixtures and future directions.
Mechanistic studies with simple mixtures have provided insights into the nature of interactions among chemicals that lead to non-additive effects and have elucidated the exposure conditions under which interactions are likely to occur. This paper discusses studies on four mixtures: (1) 1,1-dichloroethylene and trichloroethylene, (2) carbon tetrachloride and Kepone, (3) hexane and methyl-n-butylketone, and (4) coplanar and non-coplanar polychlorinated biphenyls. These mechanistic studies show that interactions should be described at the level of target tissue dose and are best categorized as either pharmacokinetic (PK) or pharmacodynamic (PD) interactions. In PK interactions the presence of a second chemical alters the kinetics such that a unit of administered dose no longer produces a unit of dose at the target tissue. In PD interactions, the presence of other compounds alters the PDs such that a unit tissue dose no longer produces a unit of response. Physiologically based pharmacokinetic (PBPK) models for mixtures have become important tools for predicting conditions under which interactions are likely to alter the assumption of additivity and have permitted calculation of interaction thresholds with more confidence. New cumulative risk assessment approaches have provided opportunities to classify compounds on the basis of similar chemistry-based modes of action (cholinesterase inhibitors) or similar physiological modes of action (diverse chemicals that alter a common biological outcome, such as defeminization of the developing nervous system). The latter examples present challenges for expanding our risk assessment paradigm to focus on the biology of responses more than on the kinetics of the xenobiotics. Some of the future advances in mixture research will depend on progress in systems biology, a discipline that integrates information across multiple level of biological organization producing PD models of normal function and assessing conditions under which exposures to chemicals lead to the perturbations sufficiently great to produce toxicity and disease. We describe briefly the elements of a systems biology approach for assessing the interactions between various PCB congeners.


An insight to sequential ozone‑chlorine process for synergistic disinfection on reclaimed water: Experimental and modelling studies.
Water reclamation plants (WRPs) are facing the challenges of ensuring microbial safety and require efficient disinfection systems. Sequential ozone‑chlorine disinfection is supposed to be a favorable alternative for reclaimed water disinfection. This study compared the inactivation efficiency of E.coli by single ozone, single chlorine, and sequential ozone‑chlorine disinfection approaches. Notably, a single ozone or chlorine process could only achieve a log removal rate of up to 5 log, whereas the sequential ozone‑chlorine disinfection could completely inactivate microorganisms (7.3 log). For sequential ozone‑chlorine disinfection, the efficiency of chlorination was improved by 2.4%-18.5%. The synergistic effect mainly attributed to the elimination of chlorine consuming substances by ozone. Through the chlorine decay model (CRS) fitting and calculating the integral CT value, the enhancement ability of ozone to chlorine disinfection was quantified. By introducing an enhancement coefficient (β), a succinct and accurate model was established to estimate the inactivation rate of sequential ozone‑chlorine disinfection (mean absolute percentage error: 0.035). The results and methodology of this study are informative to optimize the disinfection units of WRPs.


Association of Hospital Interoperable Data Sharing With Alternative Payment Model Participation.
Interoperable patient data exchange across hospitals remains an important policy goal for reducing costs and improving the quality of care. Congress designated 2018 as the goal for nationwide interoperability, and policy makers hoped that aligning financial incentives via alternative payment models (APMs) would help achieve that goal. To measure interoperability progress since 2014, assess the association between alternative payment model participation and hospital engagement in interoperable data sharing from 2014 to 2018, and evaluate hospital-reported barriers to interoperability in 2018. This cohort study included nonfederal acute care hospitals in the US from January 2014 to December 2018 that responded to the American Hospital Association Annual Survey. Data were analyzed from October 2019 through March 2021. Participation in an APM, including accountable care organizations, bundled payments, or patient-centered medical homes. Hospital engagement in all 4 domains of interoperability: finding/querying for data, sending data electronically, receiving data electronically, and integrating electronic patient data from external care delivery organizations. The sample included 3928 hospitals in the US from January 2014 to December 2018. Progress across interoperability domains was uneven, 2430 (88.3%) hospitals sending and 2115 (76.9%) receiving patient data electronically in 2018. However, only 1249 (45.4%) hospitals engaged in all 4 domains of interoperability in 2018, and growth between 2014 and 2018 was slow. There was no evidence that participation in APMs was associated with interoperability, with multivariate models suggesting that participation in an APM was associated with only a non-statistically significant 1-percentage point increase in interoperability engagement (β = 0.01; 95% CI, -0.01 to 0.03). The most commonly cited barrier to interoperability was challenges associated with sharing data across different electronic health record vendors. In this cohort study of hospital interoperability, fewer than half of US hospitals were engaged in interoperable data exchange in 2018. There was no observable evidence that hospital APM participation was associated with interoperability engagement. Many hospitals report technical and governance challenges to data sharing that are unlikely to be addressed by the alignment of financial incentives alone.


Increasing mortality caused by chronic obstructive pulmonary disease (COPD) in relation with exposure to ambient fine particulate matters: an analysis in Southeastern China.
The objective of this study was to investigate the association between ambient particulate matters (PMs) and chronic obstructive pulmonary disease (COPD) mortality. generalized additive mixed model was employed to investigate the effects of ambient fine and coarse PMs on COPD mortality using 13,066 deaths from 2014 to 2016 among six cities in Zhejiang Province in Southeastern China. The daily average death count due to COPD was 3, varying from 1 to 7 among six cities. The daily 24-h mean concentrations were diverse among cities, from 29.7 to 56.8 μg/m3 for PM2.5, 16.7 to 30.3 μg/m3 for PM2.5-10, and 50.3 to 87.1 μg/m3 for PM10, respectively. The analysis showed that daily exposure to PM2.5 and PM10 was associated with increased mortality due to COPD and that weak effects were observed between PM2.5-10 and COPD mortality. Our results provided solid evidence that the fine particles in air pollution have stronger functions on adverse health effects other than coarser particles in Southeastern China, which may be considered as a potential clinic target in PM-associated COPD.


Troy/Tnfrsf19 marks epidermal cells that govern interfollicular epidermal renewal and cornification.
The skin epidermis is a highly compartmentalized tissue consisting of a cornifying epithelium called the interfollicular epidermis (IFE) and associated hair follicles (HFs). Several stem cell populations have been described that mark specific compartments in the skin but none of them is specific to the IFE. Here, we identify Troy as a marker of IFE and HF infundibulum basal layer cells in developing and adult human and mouse epidermis. Genetic lineage-tracing experiments demonstrate that Troy-expressing basal cells contribute to long-term renewal of all layers of the cornifying epithelium. Single-cell transcriptomics and organoid assays of Troy-expressing cells, as well as their progeny, confirmed stem cell identity as well as the ability to generate differentiating daughter cells. In conclusion, we define Troy as a marker of epidermal basal cells that govern interfollicular epidermal renewal and cornification.


New applications of genetically modified Pseudomonas aeruginosa for toxicity detection in water.
A novel mediator-free method based on genetically modified bacteria was developed for detecting water toxicity, where genetically modified Pseudomonas aeruginosa (GM P. aeruginosa) was selected as the biosensor strain and pyocyanin (PYO) produced by this strain was used as the indicator. The toxicity response of GM P. aeruginosa to 3, 5-dichlorophenol (3, 5-DCP) was measured electrochemically and spectroscopically, and the half maximal inhibitory concentration (IC50) of 3, 5-DCP was determined to be 15.1 mg/L. Strikingly, the toxicity of sample solution with 3, 5-DCP could also be estimated visually by naked eyes at a concentration as low as 10 mg/L. The present study provided a convenient, sensitive and cost-effective method for water toxicity detection, and extended biosensing application of the genetically modified bacterium.


Relationship between clinical outcomes measures and personal and social performance functioning in a prospective, interventional study in schizophrenia.
To explore clinical and demographic characteristics impacting patient functioning by determining extent of overlap in factors driving change in Personal and Social Performance (PSP) and other clinical outcomes. Post-hoc analysis from a single-arm trial of paliperidone extended release in adult patients with nonacute symptomatic schizophrenia. Psychosocial functioning measures: PSP, Clinical Global Impression-Severity (CGI-S), Positive and Negative Syndrome Scale (PANSS), Short-Form 36 (SF-36), treatment satisfaction, sleep quality/daytime drowsiness, and Extrapyramidal Symptoms Rating Scale. Highest correlations with PSP total score change included PANSS total score change (Spearman's r = 0.607), PANSS general psychopathology change (r = 0.579), and CGI-S change (r = 0.569). A PSP score change of -32 predicted 90% probability of deterioration in CGI-S (score change of ≥1). The power of PSP change to predict PANSS total score change was lower. Linear stepwise regression demonstrated independent relationships for PSP change and: PANSS total change; CGI-S change; SF-36 Mental Component change; treatment satisfaction at endpoint; PSP at baseline; previous psychiatric hospitalizations. R 2 = 0.55 meant that 45% of PSP variation could not be explained by other clinical outcome measures. Psychosocial functioning improvement is important in schizophrenia. PSP may be valuable for assessing functioning; it encompasses psychosocial and clinical factors not measured by other established assessments.


Distributions and sources of polycyclic aromatic hydrocarbons in surface sediments from the Cross River estuary, S.E. Niger Delta, Nigeria.
Polycyclic aromatic hydrocarbon (PAH) analyses of surface sediments from the Cross River estuary by gas chromatography-mass spectrometry indicated natural diagenetically derived PAHs in the upper estuary, with minor and variable amounts of petrogenic and combustion-derived PAHs from human activities (lower estuary). The occurrence of significant amounts of perylene (average 23% of all PAHs) with the diagenetic natural PAHs in the middle estuary bordered by mangrove forests supports its origin from terrestrial organic matter. The natural PAHs represent the highest percentage (average 76%) of the total PAHs in this tropical environment. The traditional geochemical parameters, including the petrogenic PAHs, confirmed trace petroleum contamination in the estuary. Specific PAH ratios such as Fl/Py and Fl/(Fl+Py) also support this source contribution.


Achiral and chiral high-performance liquid chromatographic determination of tramadol and its major metabolites in urine after oral administration of racemic tramadol.
A reversed-phase high-performance liquid chromatographic method for the simultaneous determination of tramadol and its major metabolites O-demethyltramadol and N-demethyltramadol in urine has been developed. The determination of the enantiomeric ratios of the three compounds was achieved using a Chiralpak AD column and a Chiralcel OD column, respectively. After oral administration of racemic tramadol to five healthy volunteers, inter-individual differences of the excreted amounts and the enantiomeric ratios of the compounds were observed.


Cerebrovascular atherosclerosis in type III hyperlipidemia is modulated by variation in the apolipoprotein A5 gene.
Type III Hyperlipoproteinemia is a rare lipid disorder with a frequency of 1-5 in 5000. It is characterized by the accumulation of triglyceride rich lipoproteins and patients are at increased risk of developping atherosclerosis. Type III HLP is strongly associated with the homozygous presence of the ε2 allele of the APOE gene. However only about 10% of subjects with APOE2/2 genotype develop hyperlipidemia and it is therefore assumed that further genetic and environmental factors are necessary for the expression of disease. It has recently been shown that variation in the APOA5 gene is one of these co-factors. The aim of this study is to investigate the development of cerebrovascular athero?sclerosis in patients with Type III hyperlipopro?teinemia (Type III HLP) and the role of variation in the APOA5 gene as a risk factor. 60 patients with type III hyperlipidemia and ApoE2/2 genotype were included in the study after informed consent. The presence of cerebrovascular atherosclerosis was investigated using B-mode ultrasonography of the carotid artery. Serum lipid levels were measured by standard procedures.The APOE genotype and the 1131T>C and S19W SNPs in the APOA5 gene and the APOC3 sstI SNP were determined by restriction isotyping. Allele frequencies were determined by gene counting and compared using Fisher's exact test. Continuous variables were compared using the Mann Whitney test. A p value of 0.05 or below was considered statistically significant. Analysis was performed using Statistica 7 software. The incidence of the APOA5 SNPs, -1131T>C and S19W and the APOC3 sstI SNP were determined as a potential risk modifier. After correction for conventional risk factors, the C allele of the -1131T>C SNP in the APOA5 gene was associated with an increased risk for the development of carotid plaque in patients with Type III HLP with an odds ratio of 3.69. Evaluation of the genotype distribution was compatible with an independent effect of APOA5. The development of atherosclerosis in patients with Type III HLP is modulated by variation in the APOA5 gene.


Frontier of epilepsy research - mTOR signaling pathway.
Studies of epilepsy have mainly focused on the membrane proteins that control neuronal excitability. Recently, attention has been shifting to intracellular proteins and their interactions, signaling cascades and feedback regulation as they relate to epilepsy. The mTOR (mammalian target of rapamycin) signal transduction pathway, especially, has been suggested to play an important role in this regard. These pathways are involved in major physiological processes as well as in numerous pathological conditions. Here, involvement of the mTOR pathway in epilepsy will be reviewed by presenting; an overview of the pathway, a brief description of key signaling molecules, a summary of independent reports and possible implications of abnormalities of those molecules in epilepsy, a discussion of the lack of experimental data, and questions raised for the understanding its epileptogenic mechanism.


Spatio-temporal variation of the microbiome and resistome repertoire along an anthropogenically dynamic segment of the Ganges River, India.
Aquatic ecosystems are regarded as a hub of antibiotic and metal resistance genes. River Ganges is a unique riverine system in India with socio-cultural and economic significance. However, it remains underexplored for its microbiome and associated resistomes along its anthropogenically impacted course. The present study utilized a nanopore sequencing approach to depict the microbial community structure in the sediments of the river Ganges harboring antibiotic and metal resistance genes (A/MRGs) in lower stretches known for anthropogenic impact. Comprehensive microbiome analyses revealed resistance genes against 23 different types of metals and 28 classes of antibiotics. The most dominant ARG category was multidrug resistance, while the most prevalent MRGs conferred resistance against copper and zinc. Seasonal differences dismally affected the microbiota of the Ganges. However, resistance genes for fosmidomycin and tetracycline varied with season ANOVA, p < 0.05. Interestingly, 333 and 334 ARG subtypes were observed at all the locations in pre-monsoon and post-monsoon, respectively. The taxa associated with the dominant ARGs and MRGs were Pseudomonas and Burkholderia, which are important nosocomial pathogens. A substantial phage diversity for pathogenic and putrefying bacteria at all locations attracts attention for its use to tackle the dissemination of antibiotic and metal-resistant bacteria. This study suggests the accumulation of antibiotics and metals as the driving force for the emergence of resistance genes and the affiliated bacteria trafficking them. The present metagenomic assessment highlights the need for comprehensive, long-term biological and physicochemical monitoring and mitigation strategies toward the contaminants associated with ARGs and MRGs in this nationally important river.


Rapid and sensitive triple-mode detection of causative SARS-CoV-2 virus specific genes through interaction between genes and nanoparticles.
The recent outbreak of coronavirus disease 2019 (COVID-19) is highly infectious, which threatens human health and has received increasing attention. So far, there is no specific drug or vaccine for COVID-19. Therefore, it is urgent to establish a rapid and sensitive early diagnosis platform, which is of great significance for physical separation of infected persons after rapid diagnosis. Here, we propose a colorimetric/SERS/fluorescence triple-mode biosensor based on AuNPs for the fast selective detection of viral RNA in 40 min. AuNPs with average size of 17 nm were synthesized, and colorimetric, surface enhanced Raman scattering (SERS), and fluorescence signals of sensors are simultaneously detected based on their basic aggregation property and affinity energy to different bio-molecules. The sensor achieves a limit detection of femtomole level in all triple modes, which is 160 fM in absorbance mode, 259 fM in fluorescence mode, and 395 fM in SERS mode. The triple-mode signals of the sensor are verified with each other to make the experimental results more accurate, and the capacity to recognize single-base mismatch in each working mode minimizes the false negative/positive reading of SARS-CoV-2. The proposed sensing platform provides a new way for the fast, sensitive, and selective detection of COVID-19 and other diseases.


A year after COVID-19: Its impact on nurses' psychological well-being.
Nurses' burnout and psychological well-being are a significant concern during the pandemic. The aim of this study is to (i) examine the level of burnout, anxiety, depression, perceived stress and self-rated health for nurses at two time-points, 2020 and 2021, and (ii) examine the socio-demographic characteristics, work-related factors and perceived workplace support factors in relation to the level of burnout. This is a cross-sectional study with a longitudinal approach. A convenience sample of registered nurses who worked in an acute care tertiary hospital in Singapore were surveyed during two time-points. Participants' health, socio-demographic characteristics, work-related factors and perceived workplace support factors were collected. Among the 179 nurses, there was a significant increase in burnout level, poorer self-rated health and reduced job dedication. A decrease in the percentage of nurses who felt appreciated at work was reported in 2021 (p = 0.04). Nurses who felt their team was not working well together were 3.30 times more likely to experience burnout (95% CI 1.12 to 9.69; p = 0.03). Nurses who reported that they never felt appreciated by their department/hospital were 8.84 times more likely to experience burnout (95% CI 2.67 to 29.21; p < 0.001). Nurses with poorer self-rated health were more likely to report burnout (95% CI: 1.32-6.03; p = 0.008). Nurses had an increased experience of burnout, reduced job dedication and poorer self-rated health after the outbreak. Interventions at the departmental and organizational levels are needed to improve the workplace support. Strategies to support nurses' psychological well-being during the aftermath of COVID-19 are vital to managing nurses' burnout and improving job dedication and self-rated health.


Using Artificial Orthographies for Studying Cross-Linguistic Differences in the Cognitive and Neural Profiles of Reading.
Reading and writing are cultural inventions that have become vital skills to master in modern society. Unfortunately, writing systems are not equally learnable and many individuals struggle to become proficient readers. Languages and their writing systems often have co-varying characteristics, due to both psycholinguistic and socio-cultural forces. This makes it difficult to determine the source of cross-linguistic differences in reading and writing. Nonetheless, it is important to make progress on this issue: a more precise understanding of the factors that affect reading disparities should improve reading instruction theory and practice, and the diagnosis and treatment of reading disorders. In this review, we consider the value of artificial orthographies as a tool for unpacking the factors that create cognitive and neural differences in reading acquisition and skill. We do so by focusing on one dimension that differs among writing systems: grain size. Grain size, or the unit of spoken language that is mapped onto a visual graph, is thought to affect learning, but its impact is still not well understood. We review relevant literature about cross-linguistic writing system differences, the benefits of using artificial orthographies as a research tool, and our recent work with an artificial alphasyllabic writing system for English. We conclude that artificial orthographies can be used to elucidate cross-linguistic principles that affect reading and writing.


Anatomic study of femoral vein occlusion during simulated hip arthroplasty.
An anatomic study was undertaken to establish whether positioning of the leg and surgical approaches for total hip replacement (THR) cause changes in the femoral v. which may contribute to the development of deep vein thrombosis (DVT). The patency of 32 femoral vv. of 18 cadavers was inspected at different levels during simulated THR. Before and after removal of the femoral head through a transgluteal or posterior approach, a wide-angle endoscope was inserted into the femoral v. via the external iliac v. Blood flow was simulated by proximal irrigation with saline through the popliteal v. After removal of the femoral head distinct changes were observed in both approaches. In the transgluteal approach the changes were dependent on the degree of adduction and the body build of the cadaver. Initially, an oval form was seen in a constricted lumen with an increasingly oblique oval deformation and a final facet-like closure, usually at about 5 to 7.5 cm below the inguinal ligament. In total adduction this stenosis occurred regardless of build. Using a posterior approach, the necessary internal rotation caused a closure of the vein in 50% of cases. In combination with flexion and adduction there was stenosis in all cadavers regardless of body build. Our results indicate that the duration of the adducted position of the thigh during THR via a transgluteal approach should be minimised, as there is a reduction in blood flow with even minor degrees of adduction. In the posterior approach the stenosis occurs earlier, and is independent of the build of the cadaver.


Perfluorooctane sulfonate-induced apoptosis in kidney cells by triggering the NOX4/ROS/JNK axis and antagonism of cannabidiol.
Perfluorooctane sulfonate (PFOS) is one of the persistent organic pollutants (POPs), which can cause severe nephrotoxicity in mammals. Cannabinol (CBD), a nonpsychoactive cannabinoid obtained from the cannabis plant, has attracted attention in recent years for its excellent antioxidant properties. NADPH oxidase 4 (NOX4) has an important effect in supporting normal renal physiological function. The potential mechanisms of PFOS nephrotoxicity and whether CBD can prevent renal damage caused by PFOS remain unclear. This work aimed to study the mechanisms of PFOS-induced kidney damage and the protective role of CBD against PFOS-induced kidney damage. We demonstrated that PFOS led to renal insufficiency and structural damage in mice, induced overexpression of NOX4 and the onset of oxidative stress, and activated apoptosis of the mitochondrial pathway via the JNK signaling pathway. However, treatment with CBD reversed these changes. For further investigation of the potential mechanism of PFOS-induced renal cell apoptosis, the expression of NOX4 was inhibited in vitro experiments using Apocynin, an effective NOX4 inhibitor. The outcomes showed that PFOS-induced ROS production and JNK signaling pathway activation and apoptosis in human embryonic kidney (HEK293) cells were significantly reduced after inhibition of NOX4. This suggests that PFOS-induced NOX4 overexpression serves as an upstream event for JNK pathway activation. In conclusion, the findings suggest that PFOS induces apoptosis in renal cells via the NOX4/ROS/JNK pathway. Meanwhile, CBD alleviated PFOS-induced renal apoptosis through the inhibition of NOX4/ROS/JNK axis activation.


Growth Differentiation Factor 15 Is Superior to Troponin I in the Evaluation of Kidney Transplant Candidates.
Pretransplant cardiac troponin I (cTNI) has demonstrated its predicting value in survival after kidney transplant. Growth differentiation factor 15 (GDF-15) is a biomarker currently studied as a predictor of mortality and cardiovascular events (CVE) in different scenarios. The aim of this study was to compare the utility of these two biomarkers in the prediction of events after kidney transplant. We included 359 kidney transplants performed in our center between 2005 and 2015. cTNI and GDF-15 were measured on stored serum samples obtained pretransplant. Median GDF-15 was 5,346.4 pg/mL, and cTNI was 5.6 ng/L. After follow-up, 77 (21.5%) patients died, and the incidence of cerebrovascular accident (CVA), acute coronary syndrome (ACS), and major adverse CVEs (MACE) was 6.38%, 12.68%, and 20.56%, respectively. Patients were stratified in tertiles according to GDF-15 and cTNT levels. By multivariate cox regression analysis including both biomarkers and different clinical characteristics, we found a significant relation between GDF-15 and mortality, CVAs, and MACE (highest tertile hazard ratio [HR] 2.2 95% confidence interval [CI] [1.2-4.1], p = 0.01, HR 9.7 CI 95% [2.2-43.1], p = 0.003 and HR 2.7 CI 95% [1.4-5.1], p = 0.002). On the contrary, posttransplant ACS was related to cTNI (highest cTNI tertile HR 3.2 CI 95% [1.5-7.3], p = 0.003). Our study indicates the potential utility of GDF-15 as a mortality and CVE predictor after kidney transplant and its superiority compared to cTNI. By contrast, probably due to its tissue specificity, cardiac troponin showed a stronger correlation with acute coronary events. Although more studies are needed to confirm our findings, these two molecules could be used in conjunction with other tools to predict adverse events after transplant and ideally find strategies to minimize them.


The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition.
Myocardial infarction is a manifestation of necrotic cell death as a result of opening of the mitochondrial permeability transition (MPT). Receptor-mediated cardioprotection is triggered by an intracellular signaling pathway that includes phosphatidylinositol 3-kinase, endothelial nitric-oxide synthase, guanylyl cyclase, protein kinase G (PKG), and the mitochondrial K(ATP) channel (mitoK(ATP)). In this study, we explored the pathway that links mitoK(ATP) with the MPT. We confirmed previous findings that diazoxide and activators of PKG or protein kinase C (PKC) inhibited MPT opening. We extended these results and showed that other K(+) channel openers as well as the K(+) ionophore valinomycin also inhibited MPT opening and that this inhibition required reactive oxygen species. By using isoform-specific peptides, we found that the effects of K(ATP) channel openers, PKG, or valinomycin were mediated by a PKCepsilon. Activation of PKCepsilon by phorbol 12-myristate 13-acetate or H(2)O(2) resulted in mitoK(ATP)-independent inhibition of MPT opening, whereas activation of PKCepsilon by PKG or the specific PKCepsilon agonist psiepsilon receptor for activated C kinase caused mitoK(ATP)-dependent inhibition of MPT opening. Exogenous H(2)O(2) inhibited MPT, because of its activation of PKCepsilon, with an IC(50) of 0.4 (+/-0.1) microm. On the basis of these results, we propose that two different PKCepsilon pools regulate this signaling pathway, one in association with mitoK(ATP) and the other in association with MPT.


Assignment of heme and distal amino acid resonances in the 1H-NMR spectra of the carbon monoxide and oxygen complexes of sperm whale myoglobin.
Assignments of resonances of the heme and distal amino acid protons in spectra of the CO and O2 complexes of sperm whale myoglobin are reported. These resonances provide information on the conformation of the heme pocket. For oxymyoglobin, the assignments of the heme meso protons disagree with those proposed previously on the basis of partial deuteration experiments. Rapid ring flips about the C beta-C gamma bond are detected for Phe-CD1. Recent claims for two conformational substates of valine-E11 in carbonmonoxymyoglobin (Bradbury, J.H. and Carver, J.A. (1984) Biochemistry 23, 4905-4913) are shown to be in error. The pK of His-97 (FG3) in carbonmonoxymyoglobin has been determined (pK = 5.9). This residue appears to influence many spectroscopic properties of myoglobin. The distal His-E7 in carbonmonoxymyoglobin has pK less than 5.0. Differences in the heme pocket conformation in the CO complexes of myoglobin and leghemoglobin are discussed. These differences may be influential in O2 and CO association reactions.


Ataxia telangiectasia mutated is required for efficient proximal airway epithelial cell regeneration following influenza A virus infection.
Children and young adults with mutant forms of ataxia telangiectasia mutated (ATM), a kinase involved in DNA damage signaling and mitochondrial homeostasis, suffer from recurrent respiratory infections, immune deficiencies, and obstructive airways disease associated with disorganized airway epithelium. We previously showed in mice how Atm was required to mount a protective immune memory response to influenza A virus [IAV; Hong Kong/X31 (HKx31), H3N2]. Here, Atm wildtype (WT) and knockout (Atm-null) mice were used to investigate how Atm is required to regenerate the injured airway epithelium following IAV infection. When compared with WT mice, naive Atm-null mice had increased airway resistance and reduced lung compliance that worsened during infection before returning to naïve levels by 56 days postinfection (dpi). Although Atm-null lungs appeared pathologically normal before infection by histology, they developed an abnormal proximal airway epithelium after infection that contained E-cadherin+, Sox2+, and Cyp2f2+ cells lacking secretoglobin family 1 A member 1 (Scgb1a1) protein expression. Patchy and low expression of Scgb1a1 were eventually observed by 56 dpi. Genetic lineage tracing in HKx31-infected mice revealed club cells require Atm to rapidly and efficiently restore Scgb1a1 expression in proximal airways. Since Scgb1a1 is an immunomodulatory protein that protects the lung against a multitude of respiratory challenges, failure to efficiently restore its expression may contribute to the respiratory diseases seen in individuals with ataxia telangiectasia.


Induction of proliferation by high molecular weight B cell growth factor or low molecular weight B cell growth factor is associated with increases in intracellular calcium in different subpopulations of human B lymphocytes.
The activation of resting B cells with anti-surface Ig is associated with transient increases in intracellular calcium. In the present study, we demonstrate that stimulation of B cells which have already been activated by Staphylococcus aureus Cowan I (Sac), with high molecular weight B cell growth factor (HMW-BCGF) or low molecular weight B cell growth factor (LMW-BCGF), but not IL-2, IL-4, or interferon-gamma, is associated with an increase in intracellular calcium, which is modest compared to that seen with anti-Ig (approximately 100 nM vs approximately 400 nM). The increases in intracellular calcium induced by HMW-BCGF or LMW-BCGF occur in distinct but overlapping subpopulations of B cells. Thus, increases in intracellular calcium in human B cells occur not only upon activation but also upon the induction of proliferation by certain (but not all) B cell growth factors. Presumably, the effect of increasing intracellular calcium during the induction of proliferation is to modify a different group of intracellular molecules than those induced during activation.


Quality and Safety in Healthcare, Part LXX: Qualifications and Leadership of the Chief Medical Officer.
The chief medical officer ideally has a degree in business, hospital administration, or related subjects and has also pursued training in leadership. This is very important to be able to read and interpret financial documents, understand the language of hospital executives, and be able to advise the administrators and physicians on many projects. The chief medical officer must be trusted by both the C-suite executives and the medical staff and be able to communicate effectively and diplomatically with both. In order to optimize value, it is important to engage the medical staff and to align the goals of not only the executives and doctors, but also of the patients and their families.


Prevalence of caregiving and high caregiving strain among late-career medical school faculty members: workforce, policy, and faculty development implications.
Nearly one-third of medical school faculty members are age 55 + . As our population ages, the prevalence of family caregiving is increasing, yet we know very little about the caregiving experiences of aging faculty members in academic medicine. Faculty caregiving responsibilities coupled with projected physician shortages will likely impact the future academic medical workforce. We examined the prevalence of caregiving, concomitant caregiving strain, general well-being, and thoughts about retirement for medical school faculty members age 55 and older. We analyzed data from a survey of 2,126 full-time medical school faculty 55 + years of age conducted in 2017. Chi-square tests of independence and independent samples t-tests were used to examine statistical differences between subgroups. Of the 5,204 faculty members invited to complete the parent survey, 40.8% participated (N = 2126). Most were male (1425; 67.2%), White (1841; 88.3%), and married/partnered (1803; 85.5%). The mean age was 62.3 years. Of this sample, 19.0% (n = 396) reported providing care on an on-going basis to a family member, friend, or neighbor with a chronic illness or disability, including 22.4% (n = 154) of the female respondents and 17.3% (n = 242) of the male respondents. Among the caregiving faculty members, 90.2% reported experiencing some or a lot of mental or emotional strain from caregiving. Caregivers gave lower ratings of health, social and emotional support, and quality of life, but greater comfort in religion or spirituality than non-caregivers. Both caregiving and non-caregiving faculty members estimated retiring from full-time employment at age 67.8, on average. These data highlight caregiving responsibilities and significant concomitant mental or emotional strain of a significant proportion of U.S. medical schools' rapidly aging workforce. Human resource and faculty development leaders in academia should strategically invest in policies, programs, and resources to meet these growing workforce needs.


Intracerebral cystic rhabdoid papillary meningioma in an 11-year-old patient.
Rhabdoid papillary meningioma is a rare meningioma variant categorized as WHO grade III. We report an 11-year-old girl with an intracerebral rhabdoid papillary meningioma. An 11-year-old girl presented to our hospital with a short history of severe headache and vomiting. MRI revealed a left frontal intracerebral cystic lesion with rim enhancement. The tumor, including the cyst wall, was totally removed. Since the histological diagnosis was rhabdoid papillary meningioma, she was treated with postoperative radiotherapy. She is currently undergoing routine follow-up without any symptoms of recurrence. We discuss the clinical picture of this patient with reference to the published literature on this uncommon diagnosis.


Survey of neonatal candidiasis in Greece.
In order to estimate the extent of neonatal candidiasis in Greece and to identify trends in clinical management, the present study was conducted using a questionnaire directed to Greek neonatologists and pediatric infectious disease specialists. The respondents represented 15 hospitals in the country's seven largest cities, which are currently the only Greek cities with neonatal intensive care units. Based on the responses, the incidence of neonatal candidiasis was determined to be 1.87 and 1.94 cases per unit-year for the years 2001 and 2002, respectively. Although a shift toward the isolation of non-Candida albicans isolates was noted, C. albicans was still the predominant pathogenic species. Deoxycholate amphotericin B remains the most frequently used antifungal agent in neonatal units nationwide.


Combining New Immune Therapies with Traditional Endometriosis Treatment
Surgical treatment of endometriosis removes endometrial implants, but leaves the systemic disease intact. The diagnosis of the disease includes (needle) microlaparoscopy with conscious pain mapping under local anesthesia. Treatment is operative laparoscopy to remove endometrial implants and immune therapy for the systemic disease. The immune treatment program consists of oral tolerization, immune supplement, and diet changes. According to case studies, this therapy looks promising. Multicenter, controlled, long-term studies are warranted.


Association between Medicare's Hospital Readmission Reduction Program and readmission rates across hospitals by medicare bed share.
Medicare's Hospital Readmissions Reduction Program (HRRP), implemented beginning in 2013, seeks to incentivize Inpatient Prospective Payment System (IPPS) hospitals to reduce 30-day readmissions for selected inpatient cohorts including acute myocardial infarction, heart failure, and pneumonia. Performance-based penalties, which take the form of a percentage reduction in Medicare reimbursement for all inpatient care services, have a risk of unintended financial burden on hospitals that care for a larger proportion of Medicare patients. To examine the role of this unintended risk on 30-day readmissions, we estimated the association between the extent of their Medicare share of total hospital bed days and changes in 30-day readmissions. We used publicly available nationwide hospital level data for 2009-2016 from the Centers for Medicare and Medicaid Services (CMS) Hospital Compare program, CMS Final Impact Rule, and the American Hospital Association Annual Survey. Using a quasi-experimental difference-in-differences approach, we compared pre- vs. post-HRRP changes in 30-day readmission rate in hospitals with high and moderate Medicare share of total hospital bed days ("Medicare bed share") vs. low Medicare bed share hospitals. We grouped the 1904 study hospitals into tertiles (low, moderate and high) by Medicare bed share; the average bed share in the three tertile groups was 31.2, 47.8 and 59.9%, respectively. Compared to low Medicare bed share hospitals, high bed share hospitals were more likely to be non-profit, have smaller bed size and less likely to be a teaching hospital. High bed share hospitals were more likely to be in rural and non-large-urban areas, have fewer lower income patients and have a less complex patient case-mix profile. At baseline, the average readmissions rate in the low Medicare bed share (control) hospitals was 20.0% (AMI), 24.7% (HF) and 18.4% (pneumonia). The observed pre- to post-program change in the control hospitals was - 1.35% (AMI), - 1.02% (HF) and - 0.35% (pneumonia). Difference in differences model estimates indicated no differential change in readmissions among moderate and high Medicare bed share hospitals. HRRP penalties were not associated with any change in readmissions rate. The CMS should consider alternative options - including working collaboratively with hospitals - to reduce readmissions.


Chitosan-coated Selenium nanoparticles enhance the efficiency of stem cells in the neuroprotection of streptozotocin-induced neurotoxicity in male rats.
Alzheimer's disease (AD) is one of the common neurodegenerative diseases characterized by memory impairment. The protective effects of stem cell-based therapy have been reported in AD. In this study, it was assumed that Chitosan-coated Selenium nanoparticles (ChSeNPs) increase the efficiency of stem cells in the attenuation of neurotoxicity in the rat AD model. The AD model was induced using Streptozotocin (STZ) and treated by the adipose-derived mesenchymal stem cells (AMSCs) and SeNPs/ChSeNPs (0.4 mg/kg). Passive avoidance learning and recognition memory were assessed using shuttle box and novel object recognition tasks. The amyloid-beta deposition, the injected cells' homing and survival, antioxidant capacity, and BDNF concentration were evaluated using the histological, biochemical, and ELISA methods. The results showed that the combined administration of ChSeNPs and AMSCs is more effective in increasing the step-through latency and discrimination index than administering SeNPs and stem cells. Combined therapy caused a significant increase in antioxidant capacity that ChSeNPs was more effective than SeNPs, while AMSCs beside SeNPs had a greater effect on BDNF levels compared to conventional treatment of nanoparticles or AMSCs alone. Ultimately, the homing and survival of the transplanted AMSCs were greater in the group that received both stem cells and ChSeNPs. Taken together, it seems that the administration of ChSeNPs enhances the efficiency of transplanted stem cells in decreasing the neurotoxicity induced by STZ through an increase in the antioxidant capacity.


Influence of psychological factors on the prognosis of temporomandibular disorders pain.
The leading symptom of temporomandibular disorders (TMD) is pain, and psychological factors are involved in the persistence of TMD-related pain. Therefore, this study was aimed to analyze the influence of psychological factors on the prognosis of TMD-related pain. The medical records of 486 patients with TMD-related pain were analyzed. Each patient's psychological profile was assessed using the Symptom Checklist-90-Revised (SCL-90-R). Patients were classified into two groups according to a post-treatment numeric rating scale (NRS). Patients with an NRS score of 0 or 1 at the last visit were classified into group G, and those with an NRS score of 2 or greater were classified into group P. Following this, all patients were re-classified into groups N and R according to pain recurrence. Statistical analysis was performed to evaluate differences in the SCL-90-R T scores between the groups. In addition, multiple logistic regression analysis was used to identify psychological factors that affected treatment outcome. The patients in groups P and R had higher scores in all subscales of the SCL-90-R than groups G and N, respectively. In particular, somatization (SOM) and psychoticism (PSY) scores showed significant differences between the groups in the treatment outcome. A correlation is identified between psychological factors and treatment outcome in patients with TMD-related pain. In particular, patients with elevated SOM and PSY scores are more likely to develop refractory pain, and thus require additional interventions to control this risk.


Selenite transiently represses transcription of photosynthesis-related genes in potato leaves.
A striking response of potato leaves to aspersion with selenite was observed at the transcriptional level by means of cDNA microarrays analysis. This response is characterized by a general transient repression of genes coding for components of photosynthetic systems and of other light-regulated genes. In particular, maximal repression was observed 8 h after selenite aspersion, while 24 h after the treatment a complete recovery of normal transcriptional levels was detected. Another general feature of the transcriptional response to selenite is represented by the transcriptional induction of genes related to amino acid metabolism, and to stress defense; interestingly, two genes coding for glutathione S-transferases were found early-induced upon selenite treatment.


Effects of growth hormone and insulin-like growth factor 1 on progesterone production in human luteinized granulosa cells.
To investigate the relationship between growth hormone (GH) and luteal function. In vivo comparative and in vitro culture studies. University hospital. Eighteen women who were interested in becoming pregnant and visited our clinic voluntarily participated in the study for urinary GH measurement. Ten women undergoing in vitro fertilization and embryo transfer (IVF-ET) were enrolled in in vitro culture studies. Ten women received IVF-ET. The GH concentrations in the urine collected for 24 hours, and serum progesterone and estradiol concentrations were measured during the midluteal phase. Effects of GH and insulin-like growth factor 1 (IGF-1) on progesterone and estradiol production were examined in the presence or absence of human chorionic gonadotropin (hCG) in human luteinized granulosa cells. Urinary GH concentrations were statistically significantly correlated with serum progesterone and estradiol concentrations. Progesterone production by luteinized granulosa cells was increased by IGF-1 (1, 10, 100 ng/mL) but not by GH (100 ng/mL) in a dose-dependent manner. Progesterone production stimulated by IGF-1 (100 ng/mL) was further increased in the presence of hCG (1 IU/mL). Estradiol production was increased by IGF-1 and GH. Growth hormone may influence luteal function directly or indirectly via IGF-1.


Synthesis and evaluation of chromenyl barbiturates and thiobarbiturates as potential antitubercular agents.
A novel series of barbiturate and thiobarbiturate analogs of 2-benzoyl-3-methyl-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (3a-g and 4a-d, respectively) and 6-methyl-4,8-dioxo-4,8-dihydropyrano[3,2-g]chromenes (7a-c), were synthesized and evaluated for their antitubercular activities against Mycobacterium tuberculosis H37RV, and cytotoxicity (CC(50)) in the VERO cell MABA assay. The results indicate that the furanochromene series of compounds (3a-g and 4a-d) showed only weak to moderate antitubercular activity. However, the pyranochromene analog 7b showed good antitubercular activity (IC(90): 5.9μg/mL) and cytotoxicity (CC(50): 14.27μg/mL). The antitubercular activity of 7b was superior to the antituberculosis drug, pyrazinamide (PZA; IC(90): >20μg/mL). Analog 7b was considered to be a lead compound for subsequent structural optimization.


Modeling gas phase nitric oxide release in lung epithelial cells.
Nitric oxide (NO) is present in exhaled breath and is generally considered to be a noninvasive marker of airway inflammation, and is thus of particular relevance to monitoring asthma. NO is produced when L-arginine is converted to L-citrulline by NO synthase (NOS); however, L-arginine is also the substrate for arginase and both enzymes are upregulated in asthma. Recent reports have speculated that enhanced expression of one or both enzymes could lead to a limitation in substrate availability, and hence impact downstream targets or markers such as exhaled NO. The non-linear nature and vastly different kinetics of the enzymes make predictions difficult, particularly over the wide range of enzyme activity between baseline and inflammation. In this study, we developed a steady state model of L-arginine transmembrane transport, NO production, diffusion, and gas phase NO release from lung epithelial cells. We validated our model with experimental results of gas phase NO release and intracellular l-arginine concentration in A549 cells, and then performed a sensitivity analysis to determine relative impact of each enzyme on NO production. Our model predicts intracellular L-arginine and gas phase NO release over a wide range of initial extracellular L-arginine concentrations following stimulation with cytomix (10ng/ml TNF-α, IL-1β, and INF-γ). Relative sensitivity analysis demonstrates that enhanced arginase activity has little impact on l-arginine bioavailability for NOS. In addition, NOS activity is the dominant parameter which impacts gas phase NO release.


Hormesis induced by silver iodide, hydrocarbons, microplastics, pesticides, and pharmaceuticals: Implications for agroforestry ecosystems health.
Increasing amounts of silver iodide (AgI) in the environment are expected because of the recent massive expansion of weather modification programs. Concurrently, pharmaceuticals, microplastics, hydrocarbons, and pesticides in terrestrial ecosystems continue contaminating forests and agroforests. Our review supports that AgI induces hormesis, a biphasic dose response characterized by often beneficial low-dose responses and toxic high-dose effects, which adds to the evidence for pharmaceuticals, microplastics, hydrocarbons, and pesticides induced hormesis in numerous species. Doses smaller than the no-observed-adverse-effect-level (NOAEL) positively affect defense physiology, growth, biomass, yields, survival, lifespan, and reproduction. They also lead to negative or undesirable outcomes, including stimulation of pathogenic microbes, pest insects, and weeds with enhanced resistance to drugs and potential negative multi- or trans-generational effects. Such sub-NOAEL effects perplex terrestrial ecosystems managements and may compromise combating outbreaks of disease vectors that can threaten not only forest and agroforestry health but also sensitive human subpopulations living in remote forested areas.


Dipeptide inhibitors of the prostate specific membrane antigen (PSMA): A comparison of urea and thiourea derivatives.
Glutamate carboxypeptidase II (GCP(II)), also known as the prostate-specific membrane antigen (PSMA), is a transmembrane zinc(II) metalloenzyme overexpressed in prostate cancer. Inhibitors of this receptor are used to target molecular imaging agents and molecular radiotherapy agents to prostate cancer and if the affinity of inhibitors for GCP(II)/PSMA could be improved, targeting might also improve. Compounds containing the dipeptide OH-Lys-C(O)-Glu-OH (compound 3), incorporating a urea motif, have high affinity for GCP(II)/PSMA. We hypothesized that substituting the zinc-coordinating urea group for a thiourea group, thus incorporating a sulfur atom, could facilitate stronger binding to zinc(II) within the active site, and thus improve affinity for GCP(II)/PSMA. A structurally analogous urea and thiourea pair (HO-Glu-C(O)-Glu-OH - compound 5 and HO-Glu-C(S)-Glu-OH - compound 6) were synthesized and the inhibitory concentration (IC50) of each compound measured with a cell-based assay, allowing us to refute the hypothesis: the thiourea analogue showed 100-fold weaker binding to PSMA than the urea analogue.


α-Synuclein decoy peptide protects mice against α-synuclein-induced memory loss.
We previously found that a decoy peptide derived from the C-terminal sequence of α-Synuclein (αSyn) prevents cytotoxic αSyn aggregation caused by fatty acid-binding protein 3 (FABP3) in vitro. In this study, we continued to utilize αSyn-derived peptides to further validate their effects on αSyn neurotoxicity and behavioral impairments in αSyn preformed fibrils (PFFs)-injected mouse model of Parkinson's disease (PD). Mice were injected with αSyn PFFs in the bilateral olfactory bulb (OB) and then were subjected to behavioral analysis at 2-week intervals post-injection. Peptides nasal administration was initiated one week after injection. Changes in phosphorylation of αSyn and neuronal damage in the OB were measured using immunostaining at week 4. The effect of peptides on the interaction between αSyn and FABP3 was examined using co-immunoprecipitation. αSyn PFF-injected mice showed significant memory loss but no motor function impairment. Long-term nasal treatment with peptides effectively prevented memory impairment. In peptide-treated αSyn PFF-injected mice, the peptides entered the OB smoothly through the nasal cavity and were mainly concentrated in neurons in the mitral cell layer, significantly suppressing the excessive phosphorylation of αSyn and reducing the formation of αSyn-FABP3 oligomers, thereby preventing neuronal death. The addition of peptides also blocked the interaction of αSyn and FABP3 at the recombinant protein level, and its effect was strongest at molar concentrations comparable to those of αSyn and FABP3. Our findings suggest that the αSyn decoy peptide represents a novel therapeutic approach for reducing the accumulation of toxic αSyn-FABP3 oligomers in the brain, thereby preventing the progression of synucleinopathies.


Combination of straight and tilted implants for supporting screw-retained dental prostheses in atrophic posterior maxillae: A 2-year prospective study.
To evaluate the two-year survival rate (SR) and marginal bone loss (MBL) of fixed dental prostheses (FDPs) supported by straight (S) and tilted (T) implants under the influence of diverse study variables. A prospective investigation comprising 21 patients provided with a total of 27 maxillary screw-retained restorations fixed to 70 dental implants was developed. Two groups of implants were considered depending on their inclination with respect to the occlusal plane: Group 1 (S, n=37): straight/axial implants and Group 2 (T, n=33): tilted/angled fixations. Each FDP was supported by a combination of S and T implants. SR and MBL were assessed at the time of loading and two years after surgery. Patient-, surgical- and/or rehabilitation-related information was gathered. Data were statistically analysed at the α=0.05 significance level. After 24 months, a 100% SR was achieved and the MBL of S and T implants were statistically similar. T implants located in the molar region showed lower MBL than did those replacing premolars (p=0.031). Upright and angled fixations inserted at posterior maxillary areas resulted in comparable survival rates and peri-implant MBL after two years. The marginal bone resorption around tilted implants depended on their location. Screw-retained restorations fixed to straight and tilted implants seem to be a safe treatment option in posterior atrophic maxillae.


Changes in Tissue Composition and Load Response After Transtibial Amputation Indicate Biomechanical Adaptation.
Despite the potential for biomechanical conditioning with prosthetic use, the soft tissues of residual limbs following lower-limb amputation are vulnerable to damage. Imaging studies revealing morphological changes in these soft tissues have not distinguished between superficial and intramuscular adipose distribution, despite the recognition that intramuscular fat levels indicate reduced tolerance to mechanical loading. Furthermore, it is unclear how these changes may alter tissue tone and stiffness, which are key features in prosthetic socket design. This study was designed to compare the morphology and biomechanical response of limb tissues to mechanical loading in individuals with and without transtibial amputation, using magnetic resonance imaging in combination with tissue structural stiffness. The results revealed higher adipose infiltrating muscle in residual limbs than in intact limbs (residual: median 2.5% (range 0.2-8.9%); contralateral: 1.7% (0.1-5.1%); control: 0.9% (0.4-1.3%)), indicating muscle atrophy and adaptation post-amputation. The intramuscular adipose content correlated negatively with daily socket use, although there was no association with time post-amputation. Residual limbs were significantly stiffer than intact limbs at the patellar tendon site, which plays a key role in load transfer across the limb-prosthesis interface. The tissue changes following amputation have relevance in the clinical understanding of prosthetic socket design variables and soft tissue damage risk in this vulnerable group.


Identifying longitudinal sustainable hierarchies in activities of daily living.
Activities of daily living serve as an indicator of progression in disability and rehabilitation. It is know that some of the measurement scales used show hierarchical properties indicating that activities of daily living are lost and gained in a consistent pattern. Few studies have investigated the extent to which these patterns are sustained across time and across a range of disability. The study aimed to investigate the hierarchical properties of the activity of daily living items in the ValGraf functional ability scale, to establish if there is a hierarchy of items in the scale and to study the sustainability of the hierarchy over time. Secondary analysis of a retrospective database from 13,113 people over 65 years in 105 nursing homes in northern Italy, between 2008 and 2013 was conducted. Data were gathered 6-monthly and analysed using Mokken scaling to identify a hierarchy of items in the scale and if this was sustainable over time. A sustainable hierarchy of items was observed running in difficulty from urinary incontinence to feeding. The hierarchical structure of the activities of daily living observed in the present study is stable over time meaning that changes in total score for these items can be compared meaningfully across time.


Examining variable nurse practitioner independence across jurisdictions: A case study of the United States.
Nurse Practitioners have the potential to reduce primary care shortages for underserved populations. Yet, scopes of practice in some political jurisdictions (e.g. states, provinces) are more restrictive than others, and prevent Nurse Practitioners from working to the full extent of their training. The research is limited as to which intrastate or interstate characteristics contribute to understanding why scope of practice differences exist. To estimate associations between intrastate/interstate characteristics and US state-level Nurse Practitioner Scope of Practice policy. Retrospective study of state-level factors influencing Nurse Practitioner Scopes of Practice. U.S. states from 2001 to 2015. Our dependent variable is state-level Scope of Practice policy, indicating the extent to which Nurse Practitioners are autonomous in a state (Independent, Collaboration or Supervision). The intrastate characteristics that we include are numbers of Nurse Practitioners, Primary Care Physicians and rural hospitals per capita, state Board of Medicine governance and Nursing License Compact membership. We also measure the number of border-states that adopt specific policies in order to indicate the extent to which interstate characteristics influence focal states to adopt similar policies. Among intrastate characteristics, we found that rural hospital concentrations (Odds Ratio=0.78; 95% Confidence Interval: 0.71-0.85) and Nursing License Compact membership (Odds Ratio=0.23; 95% Confidence Interval: 0.0-0.60) were associated with lower levels of restrictions, while Board of Medicine governance (Odds Ratio=27.36; 95% Confidence Interval: 5.75-130.20) was associated with increased levels of restrictions. Among interstate characteristics, higher numbers of border-states adopting Nursing License Compact membership (Odds Ratio=0.51; 95% Confidence Interval: 0.32-0.80) was associated with lower levels of restrictions. Barriers to Nurse Practitioner independence are largely attributable to unfavorable governance arrangements and non-participation in reciprocal licensing networks. Achieving Nurse Practitioner independence will require cooperation between nursing, medicine and policy makers. We offer some suggestions as to where parties interested in seeing increased Nurse Practitioner independence should focus their efforts when attempting to remove restrictions on Nurse Practitioner practice.


On ochratoxin A and fungal flora in Polish cereals from conventional and ecological farms - Part 1: occurrence of ochratoxin A and fungi in cereals in 1997.
Over 200 samples of Polish cereal grain from the 1997 harvest obtained from conventional and ecological farms were tested for the presence of ochratoxin A as well as for contamination by microscopic fungi. Ochratoxin A contamination of rye from ecological farms was over six times more frequent than that from conventional cultivation. The ochratoxin A content in wheat and barley samples from ecological farms was also higher. No wheat sample from conventional farms contained the mycotoxin. In the group of ecological farms, there were differences in the percentage of cereal samples containing ochratoxin A. The ochratoxin A levels ranged from 0.2 to 57 microg kg(-1). The mean concentration of ochratoxin A in investigated cereal grain was 5.7 microg kg(-1). From samples containing detectable amounts of ochratoxin A, fungi producing ochratoxin A under laboratory conditions were isolated. They were classified as belonging to the species Penicillium cyclopium, P. viridicatum, P. chrysogenum and also Aspergillus alliaceus, A. versicolor, A. glaucus and A. flavus. Penicillium strains - producers of ochratoxin A - were isolated from 93% of the samples; in 7% of samples, only Aspergillus strains producing this mycotoxin were noted. Rye samples mainly from one farm with an ecological type of cultivation and from one conventional farm were contaminated with both Aspergillus and Penicillium mycotoxigenic strains.