Midlife Metabolic Profile and the Risk of Late-Life Cognitive Decline.
Among metabolic syndrome components, the effects of higher plasma glucose levels on cognitive decline (CD) have been considered in few studies. We evaluated the associations among midlife glycemia, total cholesterol, high-density lipoprotein cholesterol, triglycerides, midlife insulin resistance [homeostasis model assessment for insulin resistance (HOMA-index)], and CD in the older subjects of the population-based MICOL Study (Castellana Grotte, Italy) at baseline (M1) and at follow-ups seven (M2) and twenty years later (M3). At M1, a dementia risk score and a composite cardiovascular risk score for dementia were calculated. For 797 subjects out of 833, we obtained a Mini-Mental State Examination (MMSE) score at M3, subdividing these subjects in three cognitive functioning subgroups: normal cognition, mild CD, and moderate-severe CD. Mean fasting glycemia at baseline was significantly higher in moderate-severe CD subgroup (114.6±71.4 mg/dl) than in the normal cognition subgroup (101.2±20.6). Adjusting for gender, age, and other metabolic components, higher fasting glycemia values both at M1 [odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.08-1.59] and M2 (OR = 1.26; 95% CI: 1.01-1.57) were associated with an increased risk of moderate-severe CD. Mean HOMA index value was significantly higher in the moderate-severe CD subgroup (5.7±9.4) compared to the normal cognition subgroup (2.9±1.4) at M1. The dementia risk probability (MMSE < 24) increased moving through higher categories of the dementia risk score and decreased as long as the cardiovascular score increased. The present findings highlighted the indication to control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia.


The mechanics of elastic loading and recoil in anuran jumping.
Many animals use catapult mechanisms to produce extremely rapid movements for escape or prey capture, resulting in power outputs far beyond the limits of muscle. In these catapults, muscle contraction loads elastic structures, which then recoil to release the stored energy extremely rapidly. Many arthropods employ anatomical 'catch mechanisms' to lock the joint in place during the loading period, which can then be released to allow joint motion via elastic recoil. Jumping vertebrates lack a clear anatomical catch, yet face the same requirement to load the elastic structure prior to movement. There are several potential mechanisms to allow loading of vertebrate elastic structures, including the gravitational load of the body, a variable mechanical advantage, and moments generated by the musculature of proximal joints. To test these hypothesized mechanisms, we collected simultaneous 3D kinematics via X-ray Reconstruction of Moving Morphology (XROMM) and single-foot forces during the jumps of three Rana pipiens. We calculated joint mechanical advantage, moment and power using inverse dynamics at the ankle, knee, hip and ilio-sacral joints. We found that the increasing proximal joint moments early in the jump allowed for high ankle muscle forces and elastic pre-loading, and the subsequent reduction in these moments allowed the ankle to extend using elastic recoil. Mechanical advantage also changed throughout the jump, with the muscle contracting against a poor mechanical advantage early in the jump during loading and a higher mechanical advantage late in the jump during recoil. These 'dynamic catch mechanisms' serve to resist joint motion during elastic loading, then allow it during elastic recoil, functioning as a catch mechanism based on the balance and orientation of forces throughout the limb rather than an anatomical catch.


Treatment with Circular External Fixation of Bicondylar Tibial Fractures: Potential in Accurate Reduction and Efficacy on Functional Results.
Surgical reconstruction of bicondylar tibial fractures with external fixation relies on indirect fracture reduction that could affect anatomical restoration. The aim of the present study is to evaluate the radiographic and clinical outcomes of tibial bicondylar fractures treated with circular external fixation. A total of 20 bicondylar fractures of the proximal tibia in 20 patients treated with circular external fixation were included in the study. Two fractures were open. Mean clinical and radiographic follow-up was 37.3 months after frame removal. Angular, translation, and length deformities were assessed on nonweight-bearing anteroposterior, lateral, and two 45 degrees oblique views. The medial proximal tibia (MPTA) and posterior proximal tibia angles (PPTA) were calculated in all cases. The condylar widening was calculated in relation to the width of the femoral condyles. Joint depressions or gaps of the articular surface were identified on the four views of the knee. The modified Hospital for Special Surgery (HSS) knee scoring system was used for clinical evaluation. The MPTA was good in 18 (90%) and fair in 2 patients (10%). The PPTA was good in 13 (65%), fair in 6 (30%), and poor in 1 patient (5%). The articular reduction was good in 12 (60%) and fair in 8 patients (40%). The condylar widening was good in 15 (75%) and fair in 5 patients (25%). Mechanical axis deviation was within the normal range in 11/12 patients (91.7%). All fractures consolidated. One deep infection was successfully treated with local debridement, the mean modified HSS knee score at the latest follow-up was 90.5 (range: 67-100). Articular reconstruction and tibia alignment based on radiographic evaluation in the present study, along with functional results compare favorably with those of external and internal fixation presented in the literature.


Intramolecular Crossed [2+2] Photocycloaddition through Visible Light-Induced Energy Transfer.
Herein, we present the intramolecular [2+2] cycloadditions of dienones promoted through sensitization, using a polypyridyl iridium(III) catalyst, to form bridged cyclobutanes. In contrast to previous examples of straight [2+2] cycloadditions, these efficient crossed additions were achieved under irradiation with visible light. The reactions delivered desired bridged benzobicycloheptanone products with excellent regioselectivity in high yields (up to 96%). This process is superior to previous syntheses of benzobicyclo[3.1.1]heptanones, which are readily converted to B-norbenzomorphan analogues of biological significance. Electrochemical, computational, and spectroscopic studies substantiated the mechanism of triplet energy transfer and explained the unusual regiocontrol.


Long term benzodiazepine use for insomnia in patients over the age of 60: discordance of patient and physician perceptions.
The aim of this study was to determine and compare patients' and physicians' perceptions of benefits and risks of long term benzodiazepine use for insomnia in the elderly. A cross-sectional study (written survey) was conducted in an academic primary care group practice in Toronto, Canada. The participants were 93 patients over 60 years of age using a benzodiazepine for insomnia and 25 physicians comprising sleep specialists, family physicians, and family medicine residents. The main outcome measure was perception of benefit and risk scores calculated from the mean of responses (on a Likert scale of 1 to 5) to various items on the survey. The mean perception of benefit score was significantly higher in patients than physicians (3.85 vs. 2.84, p < 0.001, 95% CI 0.69, 1.32). The mean perception of risk score was significantly lower in patients than physicians (2.21 vs. 3.63, p < 0.001, 95% CI 1.07, 1.77). There is a significant discordance between older patients and their physicians regarding the perceptions of benefits and risks of using benzodiazepines for insomnia on a long term basis. The challenge is to openly discuss these perceptions in the context of the available evidence to make collaborative and informed decisions.


[Prostaglandin interaction in the human liver].
The binding of prostaglandin (PG) E1 and Iloprost, a chemically stable PGI2-analogue, to purified plasma cell membranes (LPZM) from liver tissue samples obtained at surgery revealed heterogeneity of the binding sites identifying high and low affinity subpopulations. In contrast to these findings only high affinity binding sites were characterized for PGE2. Displacement studies exhibited the highest competition for the PGE1-sites by PGE1 and subsequently by PGE2, Iloprost, PGD2 and PGF2 alpha. The binding of PGE2 to the hepatic receptor could be best displaced by PGE2 and subsequently by PGE1 and Iloprost, PGD2 and PGF2 alpha. In addition, PGE1, PGE2 and Iloprost enhanced cAMP-production dose-dependently over baseline. Clinical studies revealed a remarkably lower binding capacity for PGE1 in hepatocellular cancer tissue than in normal liver parenchyma. The different binding behaviour of PGE1 (Iloprost) and PGE2 for the first time provides evidence that PGE1 and PGI2 like at platelet membranes occupate the same receptor also at human LPZM. Since a reasonable number of binding sites for these substances and an enhanced cAMP-production were shown in the liver, the study indicates a regulatory role of PGs in hepatic function.


The stochastic nature of larval connectivity among nearshore marine populations.
Many nearshore fish and invertebrate populations are overexploited even when apparently coherent management structures are in place. One potential cause of mismanagement may be a poor understanding and accounting of stochasticity, particularly for stock recruitment. Many of the fishes and invertebrates that comprise nearshore fisheries are relatively sedentary as adults but have an obligate larval pelagic stage that is dispersed by ocean currents. Here, we demonstrate that larval connectivity is inherently an intermittent and heterogeneous process on annual time scales. This stochasticity arises from the advection of pelagic larvae by chaotic coastal circulations. This result departs from typical assumptions where larvae simply diffuse from one site to another or where complex connectivity patterns are created by transport within spatially complicated environments. We derive a statistical model for the expected variability in larval settlement patterns and demonstrate how larval connectivity varies as a function of different biological and physical processes. The stochastic nature of larval connectivity creates an unavoidable uncertainty in the assessment of fish recruitment and the resulting forecasts of sustainable yields.


Prognostic significance of X-ray cross-complementing gene 1 expression in gastric cancer.
The aim of this study is to identify the prognostic significance of X-ray cross-complementing gene 1 (XRCC1) in patients with gastric cancer undergoing surgery and platinum-based adjuvant chemotherapy. Immunohistochemistry (IHC) was used to evaluate XRCC1 protein expression profiles on surgical specimens of 612 gastric cancer patients. The relationship between XRCC1 expression and existing prognostic factors, platinum-based adjuvant chemotherapy, disease-free survival (DFS) and overall survival (OS) were analyzed. Among 612 patients staged Ⅱ/Ⅲ in our study, 182 (29.74%) were evaluated as XRCC1 IHC positive. XRCC1 expression was not significantly related to OS (P = 0.347) or DFS (P = 0.297). Compared with surgery only, platinum-based adjuvant chemotherapy significantly improved the OS (P = 0.031). And the patients with negative XRCC1 expression benefited more from platinum-based adjuvant chemotherapy (P = 0.049). Multivariate analysis demonstrated that tumor size, T category, N category, vascular or nerve invasion and platinum-based chemotherapy were good prognostic factors for OS (P < 0.05). Though XRCC1 plays an important role in DNA repair pathways, no significant relationship is found in XRCC1 expression and OS among gastric cancer in our study. XRCC1 might be an alternative prognostic marker for the patients of gastric cancer after radical resection. The patients with negative XRCC1 expression can benefit more from platinum-based adjuvant chemotherapy.


Does resiliency mediate the association of psychological adaptability with disability and pain in patients with an upper extremity injury or illness?
Symptom intensity and magnitude of limitations are highly variable for a given nociception and pathophysiology. As psychological determinants are of great influence to physical wellbeing, we assessed the influence of the protective factor measured and labelled as resilience in upper extremity illness. One hundred and six patients completed a survey of demographics, the Brief Resilience Scale (BRS), the Psychological Adaptation Scale (PAS), an 11-point ordinal measure of pain intensity, and the PROMIS Physical Function (PROMIS PF) Computer Adaptive Test (CAT). Measures of pain intensity and PROMIS PF were repeated 3 months later. We created mediation models using structural equation modeling (SEM) to assess the mediation effect of BRS on the association of PAS and other confounding variables with disability and pain at initial assessment and 3 months later. Resiliency does not mediate the association of psychological adaptability with physical limitations and pain intensity at baseline (P = .89 and .82 respectively) or 3 months after enrollment (P = .65 and .72 respectively). Positive and protective factors promote beneficial resilience mechanisms that strengthen coping responses to pain and disability. In future studies we should either include more patients to improve power and provide more information about the health benefits of resilience or focus more on mood and self-efficacy on symptoms and limitations in patients with musculoskeletal illness. Prospective, longitudinal cohort study; Level II.


Sex difference in mortality rates of Leghorn-Red reciprocal crosses.
Mortality rates among White Leghorn-Rhode Island Red pure-line and reciprocal cross adult female progeny were recorded for 8 years. The mortality rate among progeny of White Leghorn males exceeded that of the progeny of Rhode Island Red males in both pure-line and crossbreds. White Leghorn X Rhode Island Red crossbred progeny had the highest mortality rate. In a second phase of the study, a comparison was made between mortality rates of male and female progeny of White Leghorn-Rhode Island Red reciprocal crosses. Rate of loss was significantly lower in males than in females but did not differ between crosses. These results support a conclusion that sex linkage is a major factor in differential mortality rates between progeny of White Longhorn-heavy breed reciprocal crosses.


An inulin-type fructan isolated from Serratula chinensis alleviated the dextran sulfate sodium-induced colitis in mice through regulation of intestinal barrier and gut microbiota.
Herein, we aimed to explore the polysaccharide material basis of Serratula chinensis and establish its beneficial effects against colitis. A neutral polysaccharide (SCP) was extracted from S. chinensis in high yield using hot water. The molecular weights were calculated by HPSEC as Mw = 2928 Da, Mn = 2634 Da, and Mw/Mn = 1.11. FT-IR and 1D/2D-NMR spectroscopic analyses confirmed that SCP was an inulin-type fructan with α-D-Glcp-(1 → [1)-β-D-Fruf-(2]17) linkages. Treatment with SCP (200 or 400 mg/kg) alleviated dextran sulfate sodium (DSS)-induced mouse colitis symptoms, including the loss of body weight, increase of disease activity index score, and shortening of colon length. Histopathological and immunofluorescence assessments revealed that SCP could reduce pathological damage to the colon, restore the number of goblet cells, increase the content of glycoproteins in goblet cells and mucins in crypts, and enhance the expression of tight junction proteins ZO-1 and occludin. In addition, metagenomic sequencing revealed that SCP could improve the dysbiosis of gut microbiomes and act on multiple microbial functions. Moreover, SCP treatment increased the content of colonic acetic acid and butanoic acid. Collectively, these results indicated that SCP could alleviate the DSS-induced colitis in mice through regulation of intestinal barrier and gut microbiota.


Differential diagnosis of the hip vs. lumbar spine: five case reports.
With recent health care policy changes and the implementation of direct access in many states, physical therapists must be able to identify pathology that is beyond their scope of practice. The five case reports presented in this series required the differential diagnosis of hip vs. lumbar spine pathology. All of the cases required a referral from the physical therapist to either the patient's physician or a specialist because of abnormal screening test results. Each referral resulted in a new diagnosis of pathology that was beyond the scope of physical therapy. Cyriax's concepts of capsular and noncapsular patterns of joint restriction and the "Sign of the Buttock" proved useful in differentiating between hip and lumbar spine pathology in each patient. Our clinical experience indicates that utilizing the presence/absence of a capsular pattern and a "Sign of the Buttock" to screen out hip pathology in patients may be effective; however, further research is needed to support these claims.


[Interferons and their importance for prevention and therapy in man and animals].
In form of a survey of the actual international literature, taking into consideration own investigations, the present stage of knowledge concerning properties of interferones, inductors, course of synthesis and therapeutic mechanism is described. The effect of the interferones is in a manifold way connected with the effect of other factors of the infection defence, with complement, properdin, activity of phagocytosis and formation of antibodies. Though the application of interferone is still connected with great difficulties, encouraging results were yielded already in respiratory diseases and in tumour diseases, too. These results justify the performance of further experiments.


Delineating biological and technical variance in single cell expression data.
Single cell transcriptomics is becoming a common technique to unravel new biological phenomena whose functional significance can only be understood in the light of differences in gene expression between single cells. The technology is still in its early days and therefore suffers from many technical challenges. This review discusses the continuous effort to identify and systematically characterise various sources of technical variability in single cell expression data and the need to further develop experimental and computational tools and resources to help deal with it.


How Kaiser Permanente uses video ethnography of patients for quality improvement, such as in shaping better care transitions.
Keeping patients and caregivers at the center of quality improvement is critical. Kaiser Permanente's Care Management Institute adapted video ethnography to achieve this aim, using video to capture interviews with-and observations of-patients and caregivers, identify patient-centered improvement opportunities, and communicate them effectively to clinical and administrative leaders and front-line staff. This method is particularly effective for helping understand the needs of frail elders, patients nearing the end of life, those with multiple chronic conditions, and other vulnerable people who are not well represented in focus groups and patient advisory councils. As part of an initiative to improve care transitions for elders with heart failure, video ethnography contributed to greatly reduced thirty-day hospital readmission rates, helping reduce readmissions at one medical center from 13.6 percent to 9 percent in six months. It also helped improve the reliability of the readmissions reduction program. When embedded within an established quality improvement framework, video ethnography can be an effective tool for innovating new solutions, improving existing processes, and spreading knowledge about how best to meet patient needs.


A retrospective 5-year study of dental treatment in a group of elderly persons.
In a retrospective study, 50 patients over 70 years of age, selected from a private specialist clinic for fixed and removable prosthodontics, were studied. They all had remaining natural teeth and had undergone complete dental treatment at least 5 years before. The age-range was 70-96 and they had been treated 6-25 years before the study. The patients had on average 13.9 teeth. During the five-year observation period, 32 patients developed caries, with a mean number of 5.0 lesions (range 1-22). 79 fillings were made due to other defects than caries. 25 root canal fillings were made, due to caries lesions after loosened fillings or crowns in 5 cases and for other reasons than caries in 20 cases. 4.4% of the natural teeth had to be extracted. 19 crowns, 11 bridges and 1 splint were made. The prophylactic periodontal and cariological care delivered during the 5 years varied from 0 to 350 minutes (mean 89). The time for prophylactic treatment was not significantly correlated to the total number of natural teeth per patient but instead to the number of periodontally severely involved teeth (i.e. with 50% or less marginal bone support). The overall conclusion is that 3.5 times as much chairside treatment time was used for therapeutic measures as for prophylaxis.


The implant-supported single-tooth restoration. Preoperative evaluation and clinical procedure.
The implant-supported restoration is a relatively new and promising treatment modality. The CeraOne system offers a complete set of easy-to-use prosthetic components plus the all-ceramic and ceramometal restorative alternatives. No clinical signs of loosening have been reported since the adjunct of a torque controller that provides a tightening force of 32 Ncm to the abutment gold fixation screw. Even with these developments, however, a meticulous presurgical evaluation of the periodontium and careful fixture placement are still imperative for a successful esthetic and functional result.


Establishing and prioritizing research questions for the prevention, diagnosis and treatment of hair loss (excluding alopecia areata): the Hair Loss Priority Setting Partnership.
Hair and scalp problems are common. Unfortunately, many uncertainties exist around the most effective management and treatment strategies for these disorders. To identify uncertainties in hair-loss management, prevention, diagnosis and treatment that are important to both people with hair loss and healthcare professionals. A Hair Loss Priority Setting Partnership was established between patients, their carers and relatives, and healthcare professionals to identify the most important uncertainties in hair loss. The methodology of the James Lind Alliance was followed to ensure a balanced, inclusive and transparent process. In total, 2747 treatment uncertainties were submitted by 912 participants; following exclusions 884 uncertainties relating to hair loss (excluding alopecia areata) were analysed. Questions were combined into 'indicative uncertainties' following a structured format. A series of ranking exercises further reduced this list to a top 25 that was taken to a final prioritization workshop where the top 10 priorities were agreed. We present the top 10 research priorities for hair loss (excluding alopecia areata) to guide researchers and funding bodies to support studies important to both patients and clinicians.


Analysis of the PTEN gene in human meningiomas.
Previous observations demonstrated that the neurofibromatosis type 2 gene (NF2) plays an important role in the pathogenesis of the transitional, fibroblastic and malignant variants of human meningiomas. No specific genes have been associated with the pathogenesis of meningothelial meningiomas and with the progression to anaplastic meningiomas. However, allelic losses on chromosomal arms 1p, 10q and 14q have been implicated in the process of malignant progression. Recently, PTEN (phosphatase and tensin homolog deleted on chromosome ten) also termed MMAC1 (mutated in multiple advanced cancers 1) or TEP1 (TGF--regulated and epithelial cell-enriched phosphatase), emerged as a candidate gene on chromosome 10q23.3. Initial studies revealed mutations of PTEN in limited series of glioblastomas, breast, kidney and prostate carcinomas mainly as cell lines. In order to evaluate the involvement of PTEN in the development of meningiomas, we have analysed the entire coding sequence of the gene in a series of 55 meningiomas (WHO grade I). 10 atypical meningiomas (WHO grade II) and 10 anaplastic meningiomas (WHO grade III). No PTEN mutations were seen in the WHO grade I meningiomas. However, one of the anaplastic meningiomas carried a somatic mutation. In addition, all tumours were examined for the presence of homozygous deletions of PTEN but these were not detected in any of the meningiomas. Our data suggest that mutations in PTEN are not involved in the formation of low grade meningiomas, but may contribute to malignant progression in a fraction of anaplastic meningiomas.


Chenodeoxycholic acid and deoxycholic acid inhibit 11 beta-hydroxysteroid dehydrogenase type 2 and cause cortisol-induced transcriptional activation of the mineralocorticoid receptor.
Inappropriate activation of the mineralocorticoid receptor (MR) results in renal sodium retention and potassium loss in patients with liver cirrhosis. Recent evidence suggested that this MR activation is, at least in part, a result of bile acid-dependent reduction in 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) activity, an enzyme preventing cortisol-dependent activation of MR by converting cortisol to cortisone. Here, we investigated the molecular mechanisms underlying bile acid-mediated MR activation. Analysis of urinary bile acids from 12 patients with biliary obstruction revealed highly elevated concentrations of chenodeoxycholic acid (CDCA), cholic acid (CA), and deoxycholic acid (DCA), with average concentrations of 50-80 microm. Although CDCA and DCA both mediated nuclear translocation of MR in the absence of 11 beta HSD2 and steroids in transiently expressing HEK-293 cells, the transcriptional activity of MR was not stimulated. In contrast, CDCA and DCA both inhibited 11 beta HSD2 with IC(50) values of 22 and 38 microm, respectively and caused cortisol-dependent nuclear translocation and increased transcriptional activity of MR. LCA, the bile acid that most efficiently inhibited 11 beta HSD2, was present at very low concentrations in cholestatic patients, whereas the weak inhibitor CA did not cause MR activation. In conclusion, these findings indicate that CDCA, and to a lesser extent DCA, by inhibiting 11 beta HSD2, mediate cortisol-dependent nuclear translocation and transcriptional activation of MR and are responsible at least for a part of the sodium retention and potassium excretion observed in patients with biliary obstruction.


Increased Synthetic Control-Gaining Access to Predicted Mg2 Si5 N8 and β-Ca2 Si5 N8.
Nitridosilicates represent an intriguing class of materials and are typically made up of highly condensed tetrahedral network structures. Alkaline-earth nitridosilicates emerged as unique host materials for Eu2+ doped luminophores which found broad application in phosphor-converted (pc)-LEDs. In contrast to common strategies of preparing nitridosilicates by bottom-up syntheses, we have now succeeded to post-synthetically design nitridosilicates by ion exchange in metal halide melts. We describe the syntheses of hitherto unknown but predicted alkaline-earth nitridosilicates, Mg2 Si5 N8 and β-Ca2 Si5 N8 . Both compounds were obtained by ion exchange starting from pre-synthesized nitridosilicates. In situ investigations of the ion-exchange process show that the Si-N network topology remains preserved. Therefore the reaction offers a significant increase of synthetic control with respect to classical bottom-up syntheses.


High-fidelity indoor MIMO radio access for 5G and beyond based on legacy multimode fiber and real-time analog-to-digital-compression.
Dedicated indoor radio access network (RAN, such as C-RAN with fronthaul) will be in urgent demand for 5G and beyond ((B)5G), as it becomes more difficult for outdoor base stations to serve indoor mobile/IoT terminals due to the loss issue induced by higher carrier frequency. One cost-effective and time-saving strategy for indoor (B)5G RAN is to reuse the legacy multimode fibers (MMF) deployed in buildings and premises worldwide. In this work, we introduce the concept of indoor (B)5G fronthaul over legacy MMF based on analog-to-digital-compression (ADX), termed as ADX-RoMMF. Enabled by ADX for MIMO data compression, both high radio signal fidelity and fronthaul bandwidth efficiency can be achieved, which alleviates the limitation of low MMF bandwidth-distance product and supports decent indoor coverage. Meanwhile, its digital nature is highly compatible with low-cost optical transceivers (with nonlinearity and/or imperfection) and packet-based fronthaul networking such as time-sensitive networking. Furthermore, the ultralow latency of ADX processing meets the requirement of low-delay (B)5G fronthauling. We experimentally demonstrate an ADX-RoMMF link serving 16-channel MIMO signals with NR-class bandwidth and 1024QAM, leveraging a real-time ADX prototyped on a single-chip field-programmable radio platform. Results show that this 32Gb/s CPRI-equivalent rate can be transported over MMF distance of 850m within 1024QAM EVM requirement, which is 4-fold larger than that of conventional fronthaul compression scheme. Moreover, 500ns ADX latency overhead is also verified.


Engineering a 3D vascular network in hydrogel for mimicking a nephron.
Engineering functional vascular networks in vitro is critical for tissue engineering and a variety of applications. There is still a general lack of straightforward approaches for recapitulating specific structures and functions of vasculature. This report describes a microfluidic method that utilizes fibrillogenesis of collagen and a liquid mold to engineer three-dimensional vascular networks in hydrogel. The well-controlled vascular network demonstrates both mechanical stability for perfusing solutions and biocompatibility for cell adhesion and coverage. This technique enables the mimicry of passive diffusion in a nephron one of the main routes transferring soluble organic molecules. This approach could be used for in vitro modelling of mass transfer-involved physiology in vasculature-rich tissues and organs for regeneration and drug screening.


cDNA cloning, sequencing and chromosome mapping of a non-erythroid spectrin, human alpha-fodrin.
Several overlapping cDNA clones encompassing 2760 nucleotides of the alpha-subunit of a human non-erythroid spectrin (termed fodrin) were isolated from a human lung fibroblast cDNA library. DNA and RNA blot analyses indicated that a single copy alpha-fodrin gene encodes a 9-kb transcript. The cDNA clones were sequenced, and all were found to contain long open reading frames. The overlapping regions were identical except for a 60-nucleotide inframe insertion at position 1133 in the composite sequence. This result suggests that at least two distinct transcripts exist in fibroblast cells. The chromosomal location of human alpha-fodrin was assigned to 1p34-1p36.1 by hybridization to somatic cell hybrids, and it is thus distinct from that of human alpha-spectrin which has been mapped to 1q22-1q25. Alignment of the composite 919 amino acids of the predicted protein sequence of human alpha-fodrin with that of human alpha-spectrin indicated that alpha-fodrin has a similar 106-amino-acid repeating structure, which is homologous with alpha-spectrin repeats 7-15. Repeats 10 and 11 are anomalous in sequence and structure from other repeats. A comparison of nucleic acid and amino acid homologies between alpha-spectrin and the alpha-fodrin of several vertebrates indicated that human non-erythroid alpha-fodrin and the common alpha-subunit of erythroid and non-erythroid cells of non-mammalian vertebrates are closely related (90%-96% amino acid homology), whereas alpha-fodrin is only distantly related to the erythroid-specific alpha-spectrin subunit of mammals (55%-59% amino acid homology). These data suggest that mammalian erythroid alpha-spectrin evolved by duplication and rapid divergence from an ancestral alpha-fodrin-like gene.


Orthodontic assisted tooth eruption in a dentigerous cyst: a case report.
In an orthodontic practice, it is common to deal with impacted teeth, which are one of the most difficult situations dealt with by dentists. This case report describes the surgical and orthodontic management of the impacted teeth in a large dentigerous cyst. In the initial stage of treatment, the cyst was marsupialized over 7 months. After decompression of the cyst, spontaneous eruptions of the impacted tooth were noticed. Then, they were orthodontically brought into the proper occlusion.


Identification of differentially expressed genes regulated by transcription factors in glioblastomas by bioinformatics analysis.
The present study aimed to identify differentially expressed genes (DEGs) regulated by transcription factors (TFs) in glioblastoma, by conducting a bioinformatics analysis. The results of the present study may provide potential therapeutic targets that are involved in the development of glioblastoma. The GSE4290 raw data set was downloaded from the Gene Expression Omnibus database, and consisted of 23 non‑tumor samples and 77 glioblastoma (grade 4) tumor samples. Robust Multichip Averaging was used to identify DEGs between the glioblastoma and non‑tumor samples. Functional enrichment analysis of the DEGs was also performed. Based on the TRANSFAC® database, TFs associated with the glioblastoma gene expression profile were used to construct a regulatory network. Furthermore, trimmed subnets were identified according to calculated Z‑scores. A total of 676 DEGs were identified, of which 190 were upregulated and 496 were downregulated. Gene Ontology analysis demonstrated that the majority of these DEGs were functionally enriched in synaptic transmission, regulation of vesicle‑mediated transport and ion‑gated channel activity. In addition, the enriched Kyoto Encyclopedia of Genes and Genomes pathway included neuroactive ligand‑receptor interaction, calcium signaling pathway, p53 signaling pathway and cell cycle. Based on the TRANSFAC® database, transcriptional regulatory networks with 2,246 nodes and 4,515 regulatory pairs were constructed. According to the Z‑scores, the following candidate TFs were identified: TP53, SP1, JUN, STAT3 and SPI1; alongside their downstream DEGs. TP53 was the only differentially expressed TF. These candidate TFs and their downstream DEGs may have important roles in the progression of glioblastoma, and could be potential biomarkers for clinical treatment.


Pembrolizumab-Induced Hypothyroidism: A Case Report.
Pembrolizumab is a monoclonal antibody frequently used as immunotherapy for lung cell carcinoma that has been reported to cause hypothyroidism and myasthenia gravis among other, unwanted side effects. Here, we present an interesting case of a 77-year-old male previously diagnosed with lung adenocarcinoma managed with pembrolizumab. Initially, he was admitted after a mechanical fall sustaining a facial laceration and subacute fracture in the nasal bone. However, during the workup, thyroid-stimulating hormone (TSH) was found to be elevated, which was attributed to the history of pembrolizumab usage.


Maize Transposable Elements Ac/Ds as Insertion Mutagenesis Tools in Candida albicans.
In nonmodel systems, genetic research is often limited by the lack of techniques for the generation and identification of gene mutations. One approach to overcome this bottleneck is the application of transposons for gene tagging. We have established a two-element transposon tagging system, based on the transposable elements Activator (Ac)/Dissociation (Ds) from maize, for in vivo insertion mutagenesis in the fungal human pathogen Candida albicans A nonautonomous Ds transposon carrying a selectable marker was constructed into the ADE2 promoter on chromosome 3 and a codon usage-adapted Ac transposase gene was inserted into the neutral NEUT5L locus on chromosome 5. In C. albicans cells expressing the transposase, the Ds element efficiently excised and reintegrated elsewhere in the genome, which makes the Ac/Ds transposons promising tools for saturating insertion mutagenesis in clinical strains of C. albicans.


Cardioprotection by postconditioning is lost in WOKW rats with metabolic syndrome: role of glycogen synthase kinase 3beta.
Postconditioning by repetitive I/R cycles immediately after onset of reperfusion protects the heart. Metabolic disorders undermine the protection of preconditioning. The present study tested whether postconditioning protects hearts from rats with established metabolic syndrome [Wistar-Ottawa-Karlsburg W rats (WOKW)]. After 28 weeks of age, WOKW rats were much heavier than DA (Dark Agouti) and Wistar control rats and showed the pattern of the metabolic syndrome. Postconditioning was performed by 3 30-second cycles of reperfusion/ischemia immediately after the regional ischemia (30 minutes). Infarct size was comparable in all control hearts from DA, Wistar, and WOKW rats (58 +/- 2%, 49 +/- 3%; 49 +/- 2%, respectively). Postconditioning significantly reduced the infarct size in DA rats (39 +/- 5%) and Wistar rats (29 +/- 3%). In WOKW rats, the infarct sparing effect of postconditioning was lost (43 +/- 4%).GSK-3beta and Erk are involved in the signaling of postconditioning. Therefore, the phosphorylation of these proteins was determined by Western blot analysis. Postconditioning significantly increased the phosphorylation of GSK-3beta in DA and Wistar rats (1.6-fold in DA rats, 2.3-fold in Wistar rats, P < 0.05) but failed to do so in WOKW rats. Similarly, a trend for an increased phosphorylation of Erk was found in DA rats but not in WOKW rats. Thus the inefficacy of postconditioning in reducing infarct size in rats with metabolic syndrome is paralleled by a lack of phosphorylation of GSK-3beta and Erk. The metabolic syndrome, as shown in this animal model, completely abrogates the postconditioning. This blockade involves the phosphorylation of GSK-3beta. Further studies have to evaluate whether this block of postconditioning makes patients with a metabolic syndrome more susceptible to myocardial damage after infarction.


Super-resolution imaging based on cascaded microsphere compound lenses.
In this paper, a cascaded microsphere compound lens (CMCL) is introduced, in which a 20-µm-diameter barium titanate glass (BTG) primary microsphere and a 250-nm-diameter or 200-nm-diameter polystyrene (PS) secondary microsphere array constitute CMCL1 and CMCL2, respectively. The field of view (FOV) depends on the size of the BTG microsphere, while the waist of the photon nanojet (PNJ) can be adjusted by the size of the PS microsphere. The narrower the waist of the PNJ, the higher the imaging resolution. In the experiment, a 200-nm-diameter hexagonally close-packed PS nanoparticle array is successfully observed by the CMCL with a high magnification of ∼11.6× and a FOV of ∼14µm, while the single BTG microsphere is incapable of observing the array. The point spread function is used to quantify the resolution of the CMCL. A well-designed CMCL can improve the imaging performances of a microsphere-assisted microscope.


Resolvin D1 protects against cadmium chloride-induced memory loss and hippocampal damage in rats: A comparison with docosahexaenoic acid.
Intoxication with cadmium (Cd) ions leads to hippocampal damage and cognitive impairment. However, omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert neuroprotective effects in different animal models of neurodegeneration. This study compared the neuroprotective effect of the n-3 PUFA, docosahexaenoic acid (DHA), and its downstream metabolite, resolvin D1 (RVD1), on hippocampal damage and memory deficits in cadmium chloride (CdCl2)-treated rats. Control or CdCl2 (0.5 mg/kg)-treated rats were subdivided into three groups (n = 18/each) and treated for 6 weeks as follows: (1) fed control diet, (2) fed DHA-rich diets (0.7 g/100 g), or (3) treated with RVD1 (0.2 μg/kg, i.p). Treatment with a DHA-rich diet or RVD1 significantly increased the levels of docosahexaenoic acid and RVD1, respectively, in the hippocampal of CdCl2-treated rats without affecting the reduction in the expression of the 15-lipooxygenase-1 (ALOX15). These effects were associated with improvements in rats' memory function and hippocampal structure, as well as a redction in the hippocampal levels of reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nuclear localization of the nuclear factor-kappa beta p65 (NF-κB p65), and expression of cleaved caspase-3. Concomitantly, hippocampi of both groups of rats showed significantly higher levels of Bcl-2, superoxide dismutase (SOD), and glutathione (GSH), as well as enhanced nuclear levels of the nuclear factor erythroid 2-related factor 2 (Nrf-2). The effects of RVD1 on all these markers in the CdCl2-induced rats were more profound than those of DHA. Also, the increase in the nuclear protein levels of Nrf-2 and the decrease in the levels of Bax and nuclear protein levels of NF-κB p65 were only seen in the hippocampal of CdCl2 + RVD1-treated rats. RVD1 is more powerful than DHA in preventing CdCl2-induced memory loss and hippocampal damage in rats.


Reconstruction of a large leg defect with a combined hatchet flap technique.
The repair of lower leg defects, not amenable to primary closure, may be challenging, since the skin at this level is scarcely elastic and difficult to mobilize. Local skin flaps are generally utilized only to restore moderately sized losses, whereas grafting becomes a realistic choice in presence of larger wounds. We present the case of a 70-year-old man with a wide defect on his right leg following the surgical excision of a squamous cell carcinoma. The wound was successfully closed with a combination of three hatchet flaps. The various steps of the procedure and the subsequent outcome are illustrated. Our choice proved to be an easy, time-sparing, but effective reconstructive solution for a large skin defect involving the leg.


Total parathyroidectomy with autotransplantation in patients with renal hyperparathyroidism: indications and surgical approach.
renal hyperparathyroidism (rH) is one of the most serious complications in long-term hemodialysis patients. the purpose of this retrospective study was the evaluation of the surgical indications, parathyroid histology, and the results of total parathyroidectomy with autotransplantation (Ptx+At) in patients with rH. the study included 36 patients with rH in whom Ptx+At was carried out at the First surgical Department of the Evangelismos Hospital over a 5-year period. Indications for Ptx+At were high levels of parathyroid hormone (PtH >800 ng/L) associated with hypercalcemia and/or hyperphosphatemia, that were refractory to medical treatment, as well as clinical effects of rH, including pruritus, bone and joints pain, muscle weakness, progression of soft tissue calcification, and spontaneous fractures. Ultrasonography, (99m)Tc sestamibi scan and computed tomography were used to evaluate the thyroid and parathyroids. there was no mortality related to surgery. Preoperative symptoms, serum PtH, serum alkaline phosphatace, hyperphosphatemia, and hypercalcemia were improved or normalised in most patients. recurrence was observed in one case; this autotransplanted patient required resection of transplanted tissue from his forearm. Hypoparathyroidism was not recorded. Ptx+At is a safe option for the treatment of rH that is accompanied by low morbidity, mortality, and recurrence rate. It is important to identify all parathyroid glands at surgery and to choose adequate parathyroid tissue for autograft.


Quantum transport across van der Waals domain walls in bilayer graphene.
Bilayer graphene can exhibit deformations such that the two graphene sheets are locally detached from each other resulting in a structure consisting of domains with different van der Waals inter-layer coupling. Here we investigate how the presence of these domains affects the transport properties of bilayer graphene. We derive analytical expressions for the transmission probability, and the corresponding conductance, across walls separating different inter-layer coupling domains. We find that the transmission can exhibit a valley-dependent layer asymmetry and that the domain walls have a considerable effect on the chiral tunnelling properties of the charge carriers. We show that transport measurements allow one to obtain the strength with which the two layers are coupled. We perform numerical calculations for systems with two domain walls and find that the availability of multiple transport channels in bilayer graphene significantly modifies the conductance dependence on inter-layer potential asymmetry.


Local structure around chloride ion in anion exchange resin.
Neutron diffraction measurements on 35Cl/37Cl isotopically substituted anion exchange resins were carried out in order to obtain direct information on the local structure around the chloride ion absorbed in the resin. Structural parameters concerning the first nearest-neighbor interaction of chloride ions were determined through a least-squares fitting procedure of the observed first-order difference function, DeltaCl(Q). It has been revealed that the chloride ion is neighboring an ion exchange group (-CH2(CH3)3N+) with a Cl-...N distance of 3.10(3) A, and simultaneously bonded with 2.4(1) D2O molecules with a Cl-...D distance of 2.25(2) A. The second and third nearest water molecules around Cl- have also been observed. These results indicate that the direct ionic interaction between Cl- and -CH2(CH3)3N+ drastically reduces the number of first-neighbor water molecules around Cl- but enhances the long-distance structuring of the remaining water molecules in the environment surrounded by a hydrophobic polymer matrix.


Solid State Multicolor Emission in Substitutional Solid Solutions of Metal-Organic Frameworks.
Preparing crystalline materials that produce tunable organic-based multicolor emission is a challenge due to the inherent inability to control the packing of organic molecules in the solid state. Utilizing multivariate, high-symmetry metal-organic frameworks, MOFs, as matrices for organic-based substitutional solid solutions allows for the incorporation of multiple fluorophores with different emission profiles into a single material. By combining nonfluorescent links with dilute mixtures of red, green, and blue fluorescent links, we prepared zirconia-type MOFs and found that the bulk materials exhibit features of solution-like fluorescence. Our study found that MOFs with a fluorophore link concentration of around 1 mol % exhibit fluorescence with decreased inner filtering, demonstrated by changes in spectral profiles, increased quantum yields, and lifetime dynamics expected for excited-state proton-transfer emitters. Our findings enabled us to prepare organic-based substitutional solid solutions with tunable chromaticity regulated only by the initial amounts of fluorophores. These materials emit multicolor and white light with high quantum yields (∼2-14%), high color-rendering indices (>93), long shelf life, and superb hydrolytic stability at ambient conditions.


[A Case of Advanced Gastric Cancer in Which Tumor Relapse Was Observed after Discontinuation of Nivolumab Due to Complete Response, and for Which Re-Administration Was Initiated].
A 61-year-old male was diagnosed with unresectable advanced gastric cancer(cT4b[SI; panc], N+, M0, cStage ⅣA). However he was administered S-1 plus oxaliplatin as a primary treatment and ramucirumab plus paclitaxel as a secondary treatment, the primary tumor and lymph nodes were enlarged. We judged PD and switched to the third-line treatment with nivolumab. After starting nivolumab, both the primary tumor and the lymph nodes shrank, and the PET-CT scan after 24 courses showed no FDG accumulation in the primary tumor or lymph nodes, so we judged the response as CR. The patient requested discontinuation of nivolumab, and nivolumab administration was stopped. Twenty months later after nivolumab administration was discontinued, CT scan showed re-growth of the primary tumor, and nivolumab administration was resumed. After resumption, he received 22 courses of nivolumab for 10 months with maintenance of SD.


Application of Quality by Design: Development to Manufacturing of Diclofenac Sodium Topical Gel.
The objective of the present study was to develop and optimize generic topical gel formulation of diclofenac sodium through quality by design approaches. The quality target product profile was set for the critical quality attributes of the gel. The key material variables like hydrophilic gelling agent carbopol and penetration enhancer kolliphor were optimized using design of experiments. A central composite design was used considering viscosity and cumulative percent diffusion of the drug after 0.5, 1, 2, 4 and 6 h as responses. The p values for all models generated for different responses were statistically significant (<0.5). Design space was established and verified at the laboratory scale. The predicted and observed values were in close agreement. The robustness of the formula was tested at a higher scale (10X and 200X). The capability index was calculated followed by Monte Carlo simulation and the Cpk values for all the responses were more than 1.33.


The epidemiology of quantitative ultrasound: a review of the relationships with bone mass, osteoporosis and fracture risk.
Quantitative ultrasound (QUS) is a simple, inexpensive and non-invasive measure of bone which has been used in research settings for the prediction of osteoporosis. This review summarizes the current status of the epidemiology of QUS analysis, including its relationship with bone mineral density (BMD), risk of osteoporotic fracture and risk factors for osteoporosis. Although only moderately correlated with BMD, QUS appears to be as strong a predictor of osteoporotic fracture as BMD and may predict fracture independent of BMD. Risk factors for low QUS, including age, menopause, body composition and physical inactivity, seem to parallel those of low BMD. More longitudinal research is needed to confirm the clinical utility of QUS and more experimental and population-based studies are needed to determine whether the etiology of low QUS values is different from that of low bone mass.


HLA-G and vertical mother-to-child transmission of human papillomavirus infection.
Role of host factors in transmission of human papillomavirus (HPV)-infection from mother to her offspring is not known. Our aim was to study whether human leukocyte antigen (HLA)-G allele concordance among the mother-child pairs could facilitate vertical transmission of HPV, because HLA-G may contribute to immune tolerance in pregnancy. Altogether, 310 mother-child pairs were included from the Finnish Family HPV study. Overall, nine different HLA-G alleles were identified. The HLA-G genotype concordance of G∗01:01:01/01:04:01 increased the risk of high risk (HR)-HPV genotype positivity in cord blood and infant's oral mucosa. The mother-child concordance of G∗01:01:02/01:01:02 increased the risk of oral HPV positivity with HR-HPV genotypes both in the mother and offspring; OR 2.45 (95%CI 1.24-4.85). Discordant HLA-G allele for G∗01:04:01 and for G∗01:06 was significantly associated with infant's oral low risk (LR)-HPV at birth, OR 3.07 (95%CI 1.01-9.36) and OR 5.19 (95%CI 1.22-22.03), respectively. HLA-G had no association with HPV genotype-specific concordance between the mother and child at birth nor influence on perinatal HPV status of the child. Taken together, our results show that HLA-G molecules have a role in predicting the newborn's likelihood for oral HPV infection at birth.


FGF-23, Klotho and Vitamin D Levels in Scleroderma.
Scleroderma is a chronic connective tissue disease of unknown etiology. Vitamin D and parathyroid hormone (PTH) that play particular functions in calcium and phosphate homeostasis may be involved in the etiology of this disorder. Klotho, the co-receptor of the fibroblast growth factor 23 (FGF-23), can interfere with calcium and phosphate metabolism. The purpose of this study was to evaluate serum Klotho, FGF-23, intact PTH (iPTH) and vitamin D levels in scleroderma patients compared with the healthy controls. The study was performed in Biotechnology Research Center, Tabriz University of Medical Sciences (TUMS) from 2014-2015. Sixty scleroderma patients based on the classification criteria of systemic sclerosis and 30 age- and sex-matched healthy controls were included in this study. Serum Klotho, FGF-23, 25-hydroxy vitamin D (25-OH Vit D), and iPTH levels were analyzed using ELISA. Serum levels of Klotho and 25-OH Vit D in the scleroderma patients were lower than those in the healthy controls (P<0.001). In addition, scleroderma patients had higher serum iPTH levels than the controls (P<0.001). There was no significant difference in serum FGF-23 levels between the patients and controls (P=0.202). The decreased serum Klotho, 25-OH Vit D, and increased iPTH levels in the scleroderma patients may be associated with the pathogenesis of this disease and could be considered a future therapeutic target.


Emergency psychopharmacology.
A review of the literature pertinent to the emergency use of psychotropic agents is presented. Four general principles (underlying organicity, target symptoms, route of administration, and side effect profiles) governing the choice of psychotropic agent are discussed. Pharmacologic management approaches to commonly encountered behavioral emergencies, including drug-related disorders, assaultive patients, suicidal patients, agitated patients, and stuporous/withdrawn patients, are outlined.


Activation of the MAPKs ERK1/2 by cell swelling in turbot hepatocytes.
Activation of MAPKs (mitogen-activated protein kinases), in particular ERK1/2 (extracellular-signal-regulated kinase 1/2), has been reported to take place in a large variety of cell types after hypo-osmotic cell swelling. Depending on cell type, ERK1/2 phosphorylation can then serve or not the RVD (regulatory volume decrease) process. The present study investigates ERK1/2 activation after aniso-osmotic stimulations in turbot hepatocytes and the potential link between phosphorylation of these proteins and RVD. In turbot hepatocytes, Western-blot analysis shows that a hypo-osmotic shock from 320 to 240 mOsm kg(-1) induced a rapid increase in ERK1/2 phosphorylation, whereas a hyper-osmotic shock from 320 to 400 mOsm kg(-1) induced no significant change in the phosphorylation of these proteins. The hypo-osmotic-induced ERK1/2 phosphorylation was significantly prevented when hypo-osmotic shock was performed in the presence of the specific MEK (MAPK/ERK kinase) inhibitor PD98059 (100 microM). In these conditions, the RVD process was not altered, suggesting that ERK1/2 did not participate in this process in turbot hepatocytes. Moreover, the hypo-osmotic-induced activation of ERK1/2 was significantly prevented by breakdown of extracellular ATP by apyrase (10 units ml(-1)), by inhibition of purinergic P2 receptors by suramin (100 microM) or by calcium depletion using EGTA (1 mM) and thapsigargin (1 microM). In turbot hepatocytes, hypo-osmotic swelling but not hyper-osmotic shrinkage induced the activation of ERK1/2. However, these proteins do not seem to be involved in the RVD process. Their hypo-osmotic-induced activation is partially due to cascades of signalling events triggered by the binding of released ATP on purinergic P2 receptors and requires the presence of calcium.


Breath-held MR cholangiopancreatography (MRCP) using a 3D Dixon fat-water separated balanced steady state free precession sequence.
A novel 3D breath-held Dixon fat-water separated balanced steady state free precession (b-SSFP) sequence for MR cholangiopancreatography (MRCP) is described and its potential clinical utility assessed in a series of patients. The main motivation is to develop a robust breath-held alternative to the respiratory gated 3D Fast Spin Echo (FSE) sequence, the current clinical sequence of choice for MRCP. Respiratory gated acquisitions are susceptible to motion artifacts and blurring in patients with significant diaphragmatic drift, erratic respiratory rhythms or sleep apnea. A two point Dixon fat-water separation scheme was developed which eliminates signal loss arising from B0 inhomogeneity effects and minimizes artifacts from perturbation of the b-SSFP steady state. Preliminary results from qualitative analysis of 49 patients demonstrate robust performance of the 3D Dixon b-SSFP sequence with diagnostic image quality acquired in a 20-24s breath-hold.


[Study of left ventricular function using systolic time intervals in a group of patients with polycythemia vera (Vaquez-Osler disease)].
Left ventricular performance has been studied in 50 patients affected by primary polycythemia (P.V.) by determining systolic time intervals. 50 normal subjects were used as control group. All cases underwent a pharmacodynamic test with Amyl Nitrite. The results indicate that patients with P.V. present an abnormal behaviour of left ventricular performance after Amyl Nitrite; this alteration is more evident in patients with arterial hypertension. Amyl Nitrite, through its pharmacological action, causes changes in systolic time intervals and reveals a state of latent cardiac failure.


Seasonality in affective disorders.
Humans retain neurobiological responses to circadian day-night cycles and seasonal changes in daylength in spite of a life-style usually independent of dawn-dusk signals. Seasonality has been documented in many functions, from mood to hormones to gene expression. Research on seasonal affective disorder initiated the first use of timed bright light as therapy, a treatment since extended to non-seasonal major depression and sleep-wake cycle disturbances in many psychiatric and medical illnesses. The growing recognition that sufficient light is important for psychological and somatic well-being is leading to the development of novel lighting solutions in architecture as well as focus on a more conscious exposure to natural daylight.


Effect of dibromochloropropane (DBCP) on the hormone receptors of the male rat reproductive system.
The effects of dibromochloropropane (DBCP), a pesticide, on the male rat reproductive system were examined at morphological and hormonal expression levels. Changes of Leydig cells and seminiferous tubules were examined in rats treated with one subcutaneous (s.c.) injection of DBCP at doses of 10, 50, 75 and 100 mg/kg of body weight. The Leydig cells degenerated and decreased in number in those rats with an s.c. injection of DBCP at a dose of 50 mg/kg of body weight. However, these morphological changes were not significant in those rats that were treated with four separate s.c. injections of DBCP at 10 mg/kg of body weight. The expression of luteinizing hormone receptor mRNA, which is specifically expressed in Leydig cells, was decreased significantly in the DBCP-treated rats as compared with the normal-control rats. The expression of follicle-stimulating hormone receptor mRNA was decreased to a mild degree in DBCP-treated rats. At a dose of 75 mg/kg of body weight, seminiferous tubules as well as Leydig cells were severely damaged morphologically and at hormonal receptor expression levels. Multinucleated giant cells appeared at a dose of 75 mg/kg of body weight. All the rats died at a dose of 100 mg/kg of body weight. Our data indicate that DBCP had a cytotoxic effect on the male rat reproductive system in a dose-dependent manner.


A multidisciplinary team approach to managing Alzheimer's disease.
Patients with Alzheimer's disease experience a range of symptoms that may overwhelm the patients, their families, and the people responsible for their care. With today's drive to reduce health care costs, any plan for managing these patients must produce maximum effectiveness at the lowest possible cost. A multidisciplinary team potentially offers both effective and efficient dementia care by eliminating duplicative or ineffective services and maintaining the optimum health of the patient and family.


Double CH Activation of a Masked Cationic Bismuth Amide.
The transformation of C-H bonds into more reactive C-M bonds amenable to further functionalization is of fundamental importance in synthetic chemistry. We demonstrate here that the transformation of neutral bismuth compounds into their cationic analogues can be used as a strategy to facilitate CH activation reactions. In particular, the double CH activation of bismuth-bound diphenyl amide, (NPh2 )- , is reported along with simple one-pot procedures for the functionalization of the activated positions. The organometallic products of the first and second CH activation steps were isolated in high yields. Analysis by NMR spectroscopy, single-crystal X-ray diffraction, and DFT calculations revealed unusual ground-state properties (e.g., ring strain, moderate heteroaromaticity), and provided mechanistic insight into the formation of these compounds.


Thermodynamic descriptors derived from density functional theory calculations in prediction of aquatic toxicity.
Ab initio Density Functional Theory methods at the B3LYP/6-311+G(2d,p)//HF/3-21G(d) level in the gas and solvent phases (Conductor-like Polarizable Continuum Model) were used to calculate the thermodynamic and charge related descriptors including the first-order dissociation constant for a set of 53 substituted phenols. The absolute values of the pKa DFT descriptor showed significant deviations from the experimental values of dissociation constants, but the relative trends were well-described (R2=0.929, n=40). The descriptors were used for the design of predictive models for two aquatic species Pimephales promelas and Tetrahymena pyriformis. In both cases the best performing 2-descriptor models were based on the descriptors DeltaH298gas) and ClogP and showed good predictivity with R2=0.853, R2CV=0.834 for Pimephales and R2=0.864, R2CV=0.833 for Tetrahymena. The descriptors, models and the mode of action of the compounds are discussed.


Procedural sedation and analgesia in a Canadian adult tertiary care emergency department: a case series.
To examine the safety of emergency department (ED) procedural sedation and analgesia (PSA) and the patterns of use of pharmacologic agents at a Canadian adult teaching hospital. Retrospective analysis of the PSA records of 979 patients, treated between Aug. 1, 2004, and July 31, 2005, with descriptive statistical analysis. This represents an inclusive consecutive case series of all PSAs performed during the study period. Hypotension (systolic blood pressure < or = 85 mm Hg) was documented during PSA in 13 of 979 patients (1.3%; 95% confidence interval [CI] 0.3%-2.3%), and desaturation (SaO2 < or = 90) in 14 of 979 (1.4%; Cl 0.1%-2.7%). No cases of aspiration, endotracheal intubation or death were recorded. The most common medication used was fentanyl (94.0% of cases), followed by propofol (61.2%), midazolam (42.5%) and then ketamine (2.7%). The most frequently used 2-medication combinations were propofol and fentanyl (P/F) followed by midazolam and fentanyl (M/F), used with similar frequencies 58.1% (569/979) and 41.0% (401/979) respectively. There was no significant difference in the incidence of hypotension or desaturation between the P/F and M/F treated groups. In these patients, 9.1% (90/979) of patients received more than 2 different drugs. Adverse events during ED PSA are rare and of doubtful clinical significance. Propofol/fentanyl and midazolam/fentanyl are used safely, and at similar frequencies for ED PSA in this tertiary hospital case series. The use of ketamine for adult PSA is unusual in our facility.


Reactivity Patterns of (Protonated) Compound II and Compound I of Cytochrome P450: Which is the Better Oxidant?
The cytochromes P450 are versatile enzymes in human physiology that perform substrate hydroxylation reactions extremely efficiently. In this work, we present results of a computational study on the reactivity patterns of Compound I, Compound II, and protonated Compound II with model substrates, and we address the question of which of these compounds is the most effective oxidant? All calculations, regardless of the substrate, implicated that Compound I is the superior oxidant of the three. However, Compound II and protonated Compound II were found to react with free energies of activation that are only a few kcal mol-1 higher in energy than those obtained with Compound I. Therefore, Compound II and protonated Compound II should be able to react with aliphatic groups with moderate C-H bond strengths. We have analysed all results in detail and have given electronic, thermochemical, valence bond, and molecular orbital rationalizations on the reactivity differences and explained experimental product distributions. Overall, the findings implied that alternative oxidants could operate alongside Compound I in complex reaction mechanisms of enzymatic and synthetic iron porphyrinoid complexes.


Family Aggregation of HTLV-1 Infection Associated with FAS -670A/G Polymorphism: A Case Report.
Human T-lymphotropic virus 1 (HTLV-1) infection has been associated with ATL and inflammatory diseases but remains a neglected health problem. HTLV-1 associated diseases were originally described as sporadic entities, but family aggregations have been reported. Viral, genetic, immunological and behavioral factors were used to explain family clusters, but until now a clear explanation remains uncertain. In the present study we report, for the first time, a family cluster of diseased persons presenting the infection across three generations associated with FAS -670A/G polymorphism.


A furoviral replicase recruits host HSP70 to membranes for viral RNA replication.
Many host factors have been identified to be involved in viral infection. However, although furoviruses cause important diseases of cereals worldwide, no host factors have yet been identified that interact with furoviral genes or participate in the viral infection cycle. In this study, both TaHSP70 and NbHSP70 were up-regulated in Chinese wheat mosaic furovirus (CWMV)-infected plants. Their overexpression and inhibition were correlated with the accumulation of viral genomic RNAs, suggesting that the HSP70 genes could be necessary for CWMV infection. The subcellular distributions of TaHSP70 and NbHSP70 were significantly affected by CWMV infection or by infiltration of RNA1 alone. Further assays showed that the viral replicase encoded by CWMV RNA1 interacts with both TaHSP70 and NbHSP70 in vivo and vitro and that its region aa167-333 was responsible for the interaction. Subcellular assays showed that the viral replicase could recruit both TaHSP70 and NbHSP70 from the cytoplasm or nucleus to the granular aggregations or inclusion-like structures on the intracellular membrane system, suggesting that both HSP70s may be recruited into the viral replication complex (VRC) to promote furoviral replication. This is the first host factor identified to be involved in furoviral infection, which extends the list and functional scope of HSP70 chaperones.


The Effect of Temperature on the Properties of Hydrochars Obtained by Hydrothermal Carbonization of Waste Camellia oleifera Shells.
Hydrothermal carbonization (HTC) is a thermochemical conversion technique that can produce renewable solid biofuel by all types of waste. Waste Camellia oleifera shells (WCOSs) can be used to produce hydrochars via HTC. The effect of HTC temperature on the physicochemical properties and combustion behaviors of hydrochars was analyzed by varying from 150 to 300 °C. The mass yield of hydrochars decreased from 72.45% at 150 °C to 41.88% at 300 °C with the increase in temperature, and the higher heating value increased from 19.22 MJ/kg at 150 °C to 29.97 MJ/kg at 300 °C. The H/C and O/C values reduced from 1.30 and 0.66 of HTC150 to 0.77 and 0.27 of HTC300, respectively. Fourier transform infrared spectroscopy analysis indicated that the functional groups of hydrochar have changed because of the dehydration and decarboxylation reaction. The surface structure of hydrochars was rougher, and many pore structures were found at 240-300 °C by scanning electron microscopy analysis. The combustion behaviors of WCOSs and their hydochars are distinct via thermogravimetric analysis, and the stability of hydrochars was strengthened with the increase in HTC temperature.


Osteogenic Lineage Commitment of Adipose-Derived Stem Cells Is Predetermined by Three-Dimensional Cell Accumulation on Micropatterned Surface.
Lineage commitment of stem cells is mainly regulated by their microenvironments, which comprise soluble growth factors, extracellular matrix, mechanical forces, and cell density. Although numerous studies have investigated stem cell response to these factors in two-dimensional (2D) culture, little is known about that in 3D culture. Here, we studied effects of 3D cell accumulation levels on the differentiation behavior of mesenchymal stem cells (MSCs) by using a micropatterned surface. After induction of 3D-cultured MSCs on the surface, their osteogenic differentiation was significantly promoted, while adipogenic differentiation was not. This differentiation behavior of densely packed MSCs in 3D culture is unlike that in 2D culture. Moreover, to determine the contributing factor of this commitment, the relationship between 3D cell accumulation levels and their differentiation potential was studied before differentiation induction. A series of MSCs with varied 3D accumulation levels were constructed on the micropatterned surface, where the accumulated MSCs were not in hypoxic environment. Interestingly, with increasing 3D accumulation levels, MSCs enhanced their osteogenic potential but repressed adipogenic potential in the gene expression level. These results suggest that preconditioned 3D microenvironments with high cell accumulation levels promote osteogenic differentiation of MSCs and their accumulation levels help in regulating MSC differentiation.


A new trend in the HIV epidemic among men who have sex with men, San Francisco, 2004-2011.
In San Francisco, men who have sex with men (MSM) have historically comprised 90% of the HIV epidemic. It has been suggested that given the ongoing HIV transmission among this population, there is the possibility of a high-level endemic of HIV into the future. We report on the possibility of another phase in the HIV epidemic among MSM in San Francisco. Behavioral surveillance systems monitor HIV prevalence, HIV incidence, and behaviors among populations at high risk for HIV infection. Among MSM, time-location sampling is used to obtain samples for standardized behavioral surveys, HIV-antibody and incidence testing. We analyzed National HIV Behavioral Surveillance data from MSM sampled in 2004, 2008, and 2011. Three hundred eighty-six, 521, and 510 MSM were enrolled in each of the waves. Only slight changes were seen in demographics over time. We detected significant declines in unrecognized HIV infection and methamphetamine use, a significant increase in HIV testing in the past 6 months, and no changes in HIV prevalence, history of gonorrhea infection, or having multiple sex partners. Among HIV-infected men, current antiretroviral treatment (ART) use seems to have risen from 2008 to 2011. The trends of the last 7 years point to stable HIV prevalence as rising ART coverage results in improving survival coupled with decreasing incidence as ART use achieves viral load suppression at levels more than sufficient to offset ongoing sexual risk behavior. "Treatment as prevention" may be occurring among MSM in San Francisco.


A finite element model to predict the double hearing protector effect on an in-house acoustic test fixture.
The sound attenuation of double hearing protectors (DHPs), earplugs combined with earmuffs, generally falls short of the sum of each single protector's attenuation when used independently. This phenomenon, referred to as the DHP effect, is found to be related to structure-borne sound transmission involving the outer ear and can also be observed on acoustic test fixtures (ATFs). At present, it still remains not fully understood, and no available model can help demonstrate the associated sound transmission mechanisms. In this work, a finite element model is proposed to study the DHP effect on an ATF between 100 Hz and 5 kHz. Power balances are calculated with selected configurations of the ATF in order to (i) quantify the contribution of each sound path, and study the effects of (ii) the artificial skin and (iii) acoustic excitation on the ATF exterior boundaries. The DHP effect is shown to originate from the structure-borne sound power injected from the ATF boundaries and/or earmuff cushion. The important influence of earcanal wall vibration is highlighted when the skin is accounted for. The simulation results allow for gaining more insight into the sound transmission through a DHP/ATF system.


Human motor cortex activity during mental rotation.
The functional role of human premotor and primary motor cortex during mental rotation has been studied using functional MRI at 3 T. Fourteen young, male subjects performed a mental rotation task in which they had to decide whether two visually presented cubes could be identical. Exploratory Fuzzy Cluster Analysis was applied to identify brain regions with stimulus-related time courses. This revealed one dominant cluster which included the parietal cortex, premotor cortex, and dorsolateral prefrontal cortex that showed signal enhancement during the whole stimulus presentation period, reflecting cognitive processing. A second cluster, encompassing the contralateral primary motor cortex, showed activation exclusively after the button press response. This clear separation was possible in 3 subjects only, however. Based on these exploratory results, the hypothesis that primary motor cortex activity was related to button pressing only was tested using a parametric approach via a random-effects group analysis over all 14 subjects in SPM99. The results confirmed that the stimulus response via button pressing causes activation in the primary motor cortex and supplementary motor area while parietal cortex and mesial regions rostral to the supplementary motor area are recruited for the actual mental rotation process.


The agricultural dispersal-valley drift spray drift modeling system compared with pesticide drift data.
The coupling of the valley drift (VALDRIFT) atmospheric dispersion/deposition model with the agricultural dispersal (AGDISP) aircraft wake model generates a modeling system for predicting the off-target drift of pesticides sprayed in a mountain valley. The approach uses the AGDISP near-field spray model to estimate the mass fraction of pesticide remaining airborne after initial application, then the VALDRIFT complex terrain model to estimate the drift of pesticide from the target area. The modeling system inputs include detailed spray information, a measure (or estimate) of winds in the valley, and the valley topographic characteristics; the results are pesticide concentrations throughout the valley atmosphere and pesticide deposition to the valley surface. The AGDISP and VALDRIFT models are operated independently, with the results from AGDISP being used as input to VALDRIFT through user-created data files. The modeling system was evaluated using pesticide drift data from spray trials conducted in the Mill Creek Canyon of Utah's Wasatch Mountains, USA, during the late spring of 1993. The predicted deposition compared within a factor of three of the observations (70% of the time) at all sampling locations extending several kilometers down-valley from the spray treatment block. The overall average ratio of predicted-to-observed deposition was 0.9.


Encapsulation of chiral Fe(salan) in nanocages with different microenvironments for asymmetric sulfide oxidation.
The solid catalysts for asymmetric oxidation of sulfides were prepared by encapsulating a chiral iron salan complex [Fe(salan)] in the nanocages of mesoporous silicas. The microenvironment of nanocages was finely tuned using silylation reagents with different kinds of organic groups, such as propyl (C3), 1-butyl-3-propyl-4,5-dihydroimidazolium bromide (ILBr), N-propyl-N,N,N-tri-n-butylammonium chloride (TBNCl) and N-propyl-N,N,N-tri-n-butylammonium bromide (TBNBr), and investigated by water and benzene adsorption. Fe(salan) encapsulated in the amphiphilic nanocage shows much higher enantioselectivity and activity than that in hydrophobic or hydrophilic nanocage for the asymmetric oxidation of thioanisole using H(2)O(2) as oxidant. The TOF of Fe(salan) encapsulated in the nanocage modified with TBNBr can reach as high as 220 h(-1), even higher than homogeneous Fe(salan) with a TOF of 112 h(-1). The enhanced catalytic activity is mainly due to the fast diffusion of H(2)O(2) and sulfide in the amphiphilic nanocage. The above results suggest that the microenvironment modification of the nanocage is an efficient method to synthesize highly efficient solid catalysts for asymmetric catalysis.


Decreasing Workflow and Educational Interruptions in the Reading Room: Working Smarter, Not Harder.
Disruptions in image interpretation lead to interrupted education and inefficiency, and ultimately delay patient care. In the academic reading room, time can often be spent rerouting phone calls. The objective of this study was to evaluate resident perception of current workflow, decrease interruptions, and improve patient care and resident education by implementing a cost-effective automated centralized phone tree. Phone call records were obtained between January 25 and February 23, 2021 and May 3 and June 30, 2021 prior to implementation of an automated centralized phone tree within the Emergency Radiology reading room. Calls during weekday business hours were evaluated. Postimplementation phone records were obtained over 4 weeks (August 20-September 16, 2021). Residents on rotation were surveyed prior to and after phone tree implementation regarding the qualitative impact. The total number of phone calls decreased after phone tree implementation to 8 calls over a 19-day period from 100-200 phone calls over a 20-22 day period. There is a statistically significant difference (p-value < 0.017) in the median number of phone calls postimplementation for all compared preimplementation time points. Resident surveys also demonstrate a statistically significant improvement (p-value < 0.05) in the evaluated metrics. Data demonstrate a quantitative decrease in the number of calls arriving at the Emergency Radiology reading room as well as qualitative improvements in resident workplace satisfaction, feelings of burnout, and burden of interruptions. These data suggest that a self-directed triage system (eg, phone tree) could provide a cost-effective and simple means of decreasing interruptions.


The Correlation between Body Mass Index with the Occurrence of Skin Tag.
Skin tag is a benign tumour of the skin with a soft consistency which commonly occurs in the flexure area. Skin tag often found in individuals with middle and old age. Until now, there are many of theories have been proposed to explain the mechanism of the skin tag, one of the theory is obesity. To determine the body mass index (BMI) in patients with skin tag. This study is an analytic study with cross-sectional designs involving 32 subjects with skin tag and 32 controls. Diagnosis of skin tag was made based on anamnesis and clinical examination. All subjects underwent a physical examination (height and weight) to determine BMI (weight in kilogrammes divided by the square of height in meters). To analyse association between higher BMI with the occurrence of skin tag we use student t-test. The mean BMI in the skin tag group (28.1+ 3.9 kg/m^2) was higher compared with the control group (24.1 + 2.3 kg/m^2). Statistical analysis by Student t-test found the p-value < 0.05. We found a correlation between increased BMI with the occurrence of the skin tag.


Minimally invasive surgical therapies for atrial fibrillation.
Atrial fibrillation is the most common sustained arrhythmia and is associated with significant risks of thromboembolism, stroke, congestive heart failure, and death. There have been major advances in the management of atrial fibrillation including pharmacologic therapies, antithrombotic therapies, and ablation techniques. Surgery for atrial fibrillation, including both concomitant and stand-alone interventions, is an effective therapy to restore sinus rhythm. Minimally invasive surgical ablation is an emerging field that aims for the superior results of the traditional Cox-Maze procedure through a less invasive operation with lower morbidity, quicker recovery, and improved patient satisfaction. These novel techniques utilize endoscopic or minithoracotomy approaches with various energy sources to achieve electrical isolation of the pulmonary veins in addition to other ablation lines. We review advancements in minimally invasive techniques for atrial fibrillation surgery, including management of the left atrial appendage.


Annexins sense changes in intracellular pH during hypoxia.
The pH(i) (intracellular pH) is an important physiological parameter which is altered during hypoxia and ischaemia, pathological conditions accompanied by a dramatic decrease in pH(i). Sensors of pH(i) include ion transport systems which control intracellular Ca2+ gradients and link changes in pH(i) to functions as diverse as proliferation and apoptosis. The annexins are a protein family characterized by Ca2+-dependent interactions with cellular membranes. Additionally, in vitro evidence points to the existence of pH-dependent, Ca(2+)-independent membrane association of several annexins. We show that hypoxia promotes the interaction of the recombinant annexin A2-S100A10 (p11) and annexin A6 with the plasma membrane. We have investigated in vivo the influence of the pH(i) on the membrane association of human annexins A1, A2, A4, A5 and A6 tagged with fluorescent proteins, and characterized this interaction for endogenous annexins present in smooth muscle and HEK (human embryonic kidney)-293 cells biochemically and by immunofluorescence microscopy. Our results show that annexin A6 and the heterotetramer A2-S100A10 (but not annexins A1, A4 and A5) interact independently of Ca2+ with the plasma membrane at pH 6.2 and 6.6. The dimerization of annexin A2 within the annexin A2-S100A10 complex is essential for the pH-dependent membrane interaction at this pH range. The pH-induced membrane binding of annexins A6 and A2-S100A10 might have consequences for their functions as membrane organizers and channel modulators.


Person references, change in footing, and agency positioning in psychotherapeutic conversations.
This study contributes to the research on agency positioning in psychotherapy by looking at how clients and therapists, when discussing the client's difficulties, made use of two specific conversational practices, i.e., different grammatical forms of person reference and changes in footing, and what the consequences of this were for how the clients were positioned in relation to their problematic experiences. A data corpus of the first sessions of nine psychotherapies at a university training clinic in Finland was utilized. The uses of person references and changes in footing in therapists' initiative turns, clients' responses, and therapists' third position (recipient) actions were examined. The analysis showed that in initiative turns therapists usually used the second-person singular, as an invitation for the client to respond from his/her personal point of view, thus ascribing active agency to the client. When telling their problematic experiences, clients typically used so-called zero-person constructions, presenting such experiences as common to people in general, thus lessening their agency and inviting the therapist to share their experiential position. In recipient actions, therapists could use a combination of zero and active person reference which served to communicate an empathic stance and an invitation to the client to take an agentic observer position. Almost exclusively, only therapists used changes in footing. This could happen rapidly within single utterances and serve to express affiliation with the client's emotional experience and to invite or challenge the client to take an observer position. The study supplemented the CA change model with the DA and DSA notions of changes in agency positions as core elements in therapy talk and showed how variations in person references and changes in footing had a decisive influence on how different types of turns functioned within the overall conversational structure of the psychotherapy institution.


Susceptibility to upper respiratory tract infection and touching of the eyes or nose: a cross-sectional study of Japanese workers.
This study was a cross-sectional survey of Japanese workers regarding the relationship between touching the eyes or nose and susceptibility to URTI in workers. The survey respondents were 4,663 Japanese workers. Subjects were surveyed via a self-administered questionnaire regarding their susceptibility to URTI and how often they touched their eyes or nose. In addition, subjects were surveyed regarding their preventive behaviors and routine behaviors thought to be associated with URTIs. A multiple logistic regression model was used to assess the relationship between susceptibility to URTI and how often the eyes or nose are touched. Responses from 3,663 individuals who answered the self-administered questionnaire were analyzed. There were 1,590 individuals (42.9%) with a "frequent incidence of URTIs", defined as URTIs more than once a year. In terms of how often the eyes or nose are touched, the odds ratios (95% CI) for a frequent incidence of URTIs among the groups responding "sometimes" and "often" were 1.41 (1.21-1.63) and 1.96 (1.59-2.42) (trend test: p<0.001) compared with the groups responding "never" and "almost never". Multivariate-adjusted odds ratios adjusted for confounding factors, i.e., behaviors to prevent URTIs, routine behaviors associated with URTIs, age, sex and BMI, were 1.33 (1.14-1.54) and 1.69 (1.36-2.09) (trend test: p<0.001). The present cross-sectional study indicates that susceptibility to URTI and how often the eyes or nose are touched are significantly associated in Japanese workers, independent of preventive behaviors and routine behaviors associated with URTIs


Desorption corona beam ionization source for mass spectrometry.
A novel Desorption Corona Beam Ionization (DCBI) source for direct analysis of samples from surface in mass spectrometry is reported. The DCBI source can work under ambient conditions without time-consuming sample pretreatments. The source shares some common features with another ionization source - Direct Analysis in Real Time (DART), developed earlier. For example, helium was used as the discharge gas (although only corona discharge is involved in the present source), and heating of the discharge gas is required for sample desorption. However, the difference between the two sources is substantial. In the present source, a visible thin corona beam extending out around 1 cm can be formed by using a hollow needle/ring electrode structure. This feature would greatly facilitate localizing sampling areas and performing imaging/profiling experiments. The DCBI source is also capable of performing progressive temperature scans between room temperature and 450 degrees C in order to sequentially desorb samples from the surface and, therefore, to achieve a rough separation of the individual components in a complex mixture, resulting in less congestion in the mass spectrum acquired. Mass spectra for a broad range of compounds (pesticides, veterinary additives, OTC drugs, explosive materials) have been acquired using the DCBI source. For most of the compounds tested, the heater temperature required for efficient desorption is at least 150 degrees C. The molecular weight of the sample that can be desorbed/ionized is normally below 600 dalton even at the highest heater temperature, which is mainly limited by the volatility of the sample.


The effects of antihypertensive therapy on renal function.
Renal vascular resistance is increased in essential hypertension, with a consequent reduction in renal plasma flow together with a normal or slightly reduced glomerular filtration rate. Non-specific vasodilators may exacerbate this effect while loop diuretics, beta-blockers, angiotensin converting enzyme inhibitors and calcium antagonists may increase these renal hemodynamic parameters. We studied the effect of lacidipine, a new long-lasting calcium antagonist, on renal hemodynamics in 11 essential hypertensives. Lacidipine (4 mg once a day) acutely increased renal plasma flow without affecting the glomerular filtration rate. A transient, but non-significant, diuresis and natriuresis occurred. After 4 weeks of lacidipine treatment, all the parameters of renal function returned to basal levels. These results suggest that the well known renal effects of calcium antagonists are, at least in part, related to the onset of the antihypertensive effect being more pronounced with compounds such as nifedipine which have a rapid-onset, blood pressure-lowering effect.


The ectopic expression of the gastric inhibitory polypeptide receptor is frequent in adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia, but rare in unilateral tumors.
Control of cortisol secretion by the abnormal expression of the gastric inhibitory polypeptide receptor (GIP-R) have been observed in some rare cases of ACTH-independent, food-dependent Cushing's syndrome (FD-ACS) due to adrenal adenoma (AA) or bilateral macronodular hyperplasia (AIMAH). This study was performed to determine the prevalence of GIP-R ectopic expression in ACS and its correlation with fasting cortisol levels. GIP-R expression was studied by RT-PCR in 30 unilateral adrenal tumors [16 AA and 14 adrenocortical cancer (AC)] and 8 AIMAH tissues. Fasting and postprandial cortisol levels were assayed, respectively, at 0800 and 1200 h in AA, AC, and AIMAH, and 1 h after a morning standard meal in 6 AIMAH patients. Similar expression of 2 GIP-R isoforms was observed in 1 of 16 AA, 0 of 14 AC, and 4 of 8 AIMAH as well as in the 4 insulinomas used as positive controls. In vitro study of the GIP-R-expressing AA showed stimulation of cortisol secretion and cAMP production by GIP. The fasting 0800-h plasma cortisol level was above 276 nmol/liter in all patients except 1 AA case and 1 AIMAH case, both of whom expressed GIP-R. In the 3 additional AIMAH cases that expressed the GIP-R, fasting plasma cortisol levels were above 276 nmol/liter. This study demonstrates that ectopic expression of GIP-R is rare in AA and is usually associated with the low fasting plasma cortisol levels that characterize FD-ACS. In contrast, GIP-R expression is frequent in AIMAH and might not always be associated with a low fasting plasma cortisol level. This suggests that maintenance of hypercortisolemia in GIP-R- expressing AIMAH does not always depend solely on GIP-R, and that simultaneous abnormal expression of other membrane receptors might be present. The expression of GIP-R could not be observed during malignant transformation of the adrenal cortex. This study highlighted the major role of cAMP alterations secondary to GIP-R ectopic expression in the pathophysiology of AIMAH and in some rare cases of well differentiated benign adrenocortical tumors.


Molecular characterization of the HLA-linked steroid 21-hydroxylase B gene from an individual with congenital adrenal hyperplasia.
21-Hydroxylase deficiency which causes congenital adrenal hyperplasia is one of the most common defects of adrenal steroidogenesis. There are two 21-hydroxylase genes in man, A and B, and these have been mapped to the HLA class III region. Only the 21-hydroxylase B gene is thought to be active. To understand the molecular basis of congenital adrenal hyperplasia in a patient with the salt-wasting form of the disease, we cloned and characterized his single 21-hydroxylase B gene. The nucleotide sequence of this gene and a 21-hydroxylase B gene from a normal individual have been determined. Comparison of the two sequences has revealed 11 nucleotide alterations, of which two are in the 5' flanking region, four are in introns, one is in the 3' untranslated region and four are in exons. Two of the differences in exons cause codon changes, with Ser-269 and Asn-494 in the normal 21-hydroxylase B gene being converted to Thr and Ser, respectively. These amino acid substitutions may give an insight into those residues necessary for 21-hydroxylase enzymatic activity. We have also confirmed that the 21-hydroxylase A gene is a pseudogene due to three deleterious mutations in the exons. In addition, comparison of the 21-hydroxylase B gene sequence with other published sequences indicates that this microsomal cytochrome P-450 may be polymorphic.


Neurologic complications of 603 consecutive continuous spinal anesthetics using macrocatheter and microcatheter techniques. Perioperative Outcomes Group.
Recent case reports of cauda equina syndrome after continuous spinal anesthesia have led to a reevaluation of the indications and applications of this regional anesthetic technique. However, few large studies have formally investigated the frequency of neurologic complications using macro- and microcatheter (smaller than 24 gauge) techniques. This retrospective review examines 603 continuous spinal anesthetics, including 127 administered through a 28-gauge microcatheter, performed between June 1987 and May 1992. The surgical procedure was orthopedic in 397 of 476 (83.4%) macrocatheter patients. All microcatheter patients were parturients. Three patients reported pain (persistent paresthesia) postoperatively. In two patients, the symptoms resolved in 4 days; the other patient was discharged 8 days postoperatively with residual foot pain. There was also one patient with aseptic meningitis and one patient with a sensory cauda equina syndrome (still present after 15 mo). There were 58 (9.6%) patients with a postdural puncture headache (PDPH), including 42 of 127 (33.1%) patients in the microcatheter group. An epidural blood patch was performed in 41 (6.8%) patients. The frequency of neurologic complications, excluding PDPH, is similar to those in published reviews. However, PDPH in microcatheter patients is more frequent than previously reported.


Chiral hemicucurbit[8]uril as an anion receptor: selectivity to size, shape and charge distribution.
A novel eight-membered macrocycle of the hemicucurbit[n]uril family, chiral (all-R)-cyclohexanohemicucurbit[8]uril (cycHC[8]) ‡The name cyclohexylhemicucurbituril, previously used for these macrocycles, is changed in accordance with the IUPAC nomenclature for fused cycles, as the cyclohexane substituents are fused with the parent hemicucurbituril. binds anions in a purely protic solvent with remarkable selectivity. The cycHC[8] portals open and close to fully encapsulate anions in a 1 : 1 ratio, resembling a molecular Pac-Man™. Comprehensive gas, solution and solid phase studies prove that the binding is governed by the size, shape and charge distribution of the bound anion. Gas phase studies show an order of SbF6- ≈ PF6- > ReO4- > ClO4- > SCN- > BF4- > HSO4- > CF3SO3- for anion complexation strength. An extensive crystallographic study reveals the preferred orientations of the anions within the octahedral cavity of cycHC[8] and highlights the importance of the size- and shape-matching between the anion and the receptor cavity. The solution studies show the strongest binding of the ideally fitting SbF6- anion, with an association constant of 2.5 × 105 M-1 in pure methanol. The symmetric, receptor cavity-matching charge distribution of the anions results in drastically stronger binding than in the case of anions with asymmetric charge distribution. Isothermal titration calorimetry (ITC) reveals the complexation to be exothermic and enthalpy-driven. The DFT calculations and VT-NMR studies confirmed that the complexation proceeds through a pre-complex formation while the exchange of methanol solvent with the anion is the rate-limiting step. The octameric cycHC[8] offers a unique example of template-controlled design of an electroneutral host for binding large anions in a competitive polar solvent.


Reaction mechanism of pyridoxal 5'-phosphate synthase. Detection of an enzyme-bound chromophoric intermediate.
Vitamin B6 is an essential metabolite in all organisms. De novo synthesis of the vitamin can occur through either of two mutually exclusive pathways referred to as deoxyxylulose 5-phosphate-dependent and deoxyxylulose 5-phosphate-independent. The latter pathway has only recently been discovered and is distinguished by the presence of two genes, Pdx1 and Pdx2, encoding the synthase and glutaminase subunit of PLP synthase, respectively. In the presence of ammonia, the synthase alone displays an exceptional polymorphic synthetic ability in carrying out a complex set of reactions, including pentose and triose isomerization, imine formation, ammonia addition, aldol-type condensation, cyclization, and aromatization, that convert C3 and C5 precursors into the cofactor B6 vitamer, pyridoxal 5'-phosphate. Here, employing the Bacillus subtilis proteins, we demonstrate key features along the catalytic path. We show that ribose 5-phosphate is the preferred C5 substrate and provide unequivocal evidence that the pent(ul)ose phosphate imine occurs at lysine 81 rather than lysine 149 as previously postulated. While this study was under review, corroborative crystallographic evidence has been provided for imine formation with the corresponding lysine group in the enzyme from Thermotoga maritima (Zein, F., Zhang, Y., Kang, Y.-N., Burns, K., Begley, T. P., and Ealick, S. E. (2006) Biochemistry 45, 14609-14620). We have detected an unanticipated covalent reaction intermediate that occurs subsequent to imine formation and is dependent on the presence of Pdx2 and glutamine. This step most likely primes the enzyme for acceptance of the triose sugar, ultimately leading to formation of the pyridine ring. Two alternative structures are proposed for the chromophoric intermediate, both of which require substantial modifications of the proposed mechanism.