The diagnosis and management of central hypothyroidism in 2018.
Central hypothyrodism (CeH) is a hypothyroid state caused by an insufficient stimulation by thyrotropin (TSH) of an otherwise normal thyroid gland. Several advancements, including the recent publication of expert guidelines for CeH diagnosis and management, have been made in recent years thus increasing the clinical awareness on this condition. Here, we reviewed the recent advancements and give expert opinions on critical issues. Indeed, CeH can be the consequence of various disorders affecting either the pituitary gland or the hypothalamus. Recent data enlarged the list of candidate genes for heritable CeH and a genetic origin may be the underlying cause for CeH discovered in pediatric or even adult patients without apparent pituitary lesions. This raises the doubt that the frequency of CeH may be underestimated. CeH is most frequently diagnosed as a consequence of the biochemical assessments in patients with hypothalamic/pituitary lesions. In contrast with primary hypothyroidism, low FT4 with low/normal TSH levels are the biochemical hallmark of CeH, and adequate thyroid hormone replacement leads to the suppression of residual TSH secretion. Thus, CeH often represents a clinical challenge because physicians cannot rely on the use of the 'reflex TSH strategy' for screening or therapy monitoring. Nevertheless, in contrast with general assumption, the finding of normal TSH levels may indicate thyroxine under-replacement in CeH patients. The clinical management of CeH is further complicated by the combination with multiple pituitary deficiencies, as the introduction of sex steroids or GH replacements may uncover latent forms of CeH or increase the thyroxine requirements.


Assessment of Generative Adversarial Networks Model for Synthetic Optical Coherence Tomography Images of Retinal Disorders.
To assess whether a generative adversarial network (GAN) could synthesize realistic optical coherence tomography (OCT) images that satisfactorily serve as the educational images for retinal specialists, and the training datasets for the classification of various retinal disorders using deep learning (DL). The GANs architecture was adopted to synthesize high-resolution OCT images trained on a publicly available OCT dataset, including urgent referrals (37,206 OCT images from eyes with choroidal neovascularization, and 11,349 OCT images from eyes with diabetic macular edema) and nonurgent referrals (8617 OCT images from eyes with drusen, and 51,140 OCT images from normal eyes). Four hundred real and synthetic OCT images were evaluated by two retinal specialists (with over 10 years of clinical retinal experience) to assess image quality. We further trained two DL models on either real or synthetic datasets and compared the performance of urgent versus nonurgent referrals diagnosis tested on a local (1000 images from the public dataset) and clinical validation dataset (278 images from Shanghai Shibei Hospital). The image quality of real versus synthetic OCT images was similar as assessed by two retinal specialists. The accuracy of discrimination of real versus synthetic OCT images was 59.50% for retinal specialist 1 and 53.67% for retinal specialist 2. For the local dataset, the DL model trained on real (DL_Model_R) and synthetic OCT images (DL_Model_S) had an area under the curve (AUC) of 0.99, and 0.98, respectively. For the clinical dataset, the AUC was 0.94 for DL_Model_R and 0.90 for DL_Model_S. The GAN synthetic OCT images can be used by clinicians for educational purposes and for developing DL algorithms. The medical image synthesis based on GANs is promising in humans and machines to fulfill clinical tasks.


Disclosure of information and informed consent: ethical and practical considerations.
Disclosure of information and informed consent are relatively new concepts in the patient-physician relationship. They are based primarily on the principle of autonomy and they have many favorable practical advantages. However, the practical implementation of these requirements is fraught with difficulties, some of which can cause harm to the patient or be obstacles in fulfilling the moral obligation of beneficence. This is particularly true when disclosure of information and informed consent are done by physicians in a defensive way for fear of malpractice suits. The most ethically defensible approach is to tailor and navigate the information according to the needs and desires of each individual patient in a sensitive and empathic manner. The informed consent should be a process of mutually shared responsibility by the patient and the physician, ensuring adequate and relevant information that is well comprehended by the individual patient, and is used correctly for his or her decision making.


Medium-term follow-up series using a modular distal fixation prosthesis to address proximal femoral bone deficiency in revision total hip arthroplasty. A 5- to 9-year follow-up study.
We reviewed a series of 39 patients (40 cases) receiving the Link MP stem in revision hip arthroplasty. Average follow-up was 68 months (range 60-115 months). Proximal femoral defects were classified using the Endo-Klinik and Paprosky classifications. Indications included: osteolysis 13 cases; septic loosening 8 cases; periprosthetic fractures 18 cases; metastatic bone disease 1 case. We found 92.5% overall survival rate, average Harris Hip Score past two years of 67 and average Oxford Hip Score past five years of 43. We found no implant failure or loosening. Complications included: 4 deep infections (2 revised to excision arthroplasty), 5 dislocations (1 revision of the proximal modular segment for impingement). We concluded that revision was successful in cases of peri-prosthetic fractures, septic and aseptic loosening. We advocate use of cerclage wires to prevent peri-operative fractures and use of proximal modular segments with CCD angle of 126 to avoid dislocation.


Little change in markers of protein breakdown and oxidative stress in humans in immobilization-induced skeletal muscle atrophy.
A number of studies in rodents suggest that disuse atrophy results from a large increase in proteolysis affected by, or accompanying, increased oxidative stress. Little information is available, however, about the effects of immobilization on markers of muscle protein breakdown and oxidative stress in humans. Therefore, the purpose of this investigation was to measure markers of breakdown or oxidative stress in subjects who underwent 14 days of knee-brace-mediated immobilization. Vastus lateralis samples taken from 21 young subjects before, and 2 days and 14 days after, single leg immobilization were measured for ubiquitin-protein conjugates, caspase 3/7 activity, the 14-kDa caspase-3 cleaved actin fragment, 4-hydroxy-2-nonenal (4-HNE) adducts, and protein carbonyls. Quadriceps cross-sectional area decreased by 5.7% +/- 1.1% (p < 0.0001) following immobilization. Ubiquitin-protein conjugates were elevated at 2 days of immobilization (12%, p < 0.05) but were not different from baseline at 14 days. Levels of the 14-kDa actin fragment and caspase 3/7 activity did not change over the immobilization period. The oxidative stress markers, 4-HNE adducts and protein carbonyls, did not change at any time point. These static measures of breakdown and oxidative modification suggest that a small increase in protein ubiquitination occurs early (2 days), but elevations in ubiquitinated or oxidatively modified proteins are not sustained during the later phase (14 days) of uncomplicated disuse atrophy in humans, suggesting that these pathways are not playing a major role in simple disuse-induced atrophic loss of protein mass.


Thermosensitive liposomes modified with poly(N-isopropylacrylamide-co-propylacrylic acid) copolymers for triggered release of doxorubicin.
A novel polymer-modified thermosensitive liposome (pTSL) was developed for the delivery of Doxorubicin (DOX) for cancer therapy. Copolymers containing temperature-responsive N-isopropylacrylamide (NIPAAm) and pH-responsive propylacrylic acid (PAA) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, yielding copolymers with dual pH/temperature-dependent phase transition properties. When attached to liposomes, these copolymers were membrane-disruptive in a pH/temperature-dependent manner. pTSL demonstrated enhanced release profile and significantly lower thermal dose threshold when compared to traditional thermosensitive formulations and were stable in serum with minimal drug leakage over time. These liposomes thus have the potential to dramatically reduce the risk of damage to healthy tissues that is normally associated with liposomal cancer therapy.


Benzylfumaric, benzylmaleic, and Z- and E-phenylitaconic acids: synthesis, characterization, and correlation with a metabolite generated by Azoarcus tolulyticus Tol-4 during anaerobic toluene degradation.
E-Phenylitaconic acid has been isolated as a metabolite generated by Azoarcus tolulyticus Tol-4 along with benzylsuccinic acid during anaerobic degradation of toluene. Strain Tol-4 converted 1 to 2% of toluene carbon to E-phenylitaconate and benzylsuccinate (10:1). The identification of E-phenylitaconic acid was based on 1H nuclear magnetic resonance (NMR) characterization of degradation products derived from 13C-labeled toluene followed by comparison of spectroscopic and chromatographic data for the isolated, unlabeled metabolite with those for chemically synthesized benzylfumaric acid, benzylmaleic acid, E-phenylitaconic acid, and Z-phenylitaconic acid. Spectroscopic comparisons included 1H NMR, 13C NMR, and nuclear overhauser effect correlations. High-pressure liquid chromatography (HPLC) retention times and HPLC coinjections with synthetic dioic acids provided another reliable line of evidence for structure assignment. The formation of E-phenylitaconic acid differs from previous reports of benzylfumaric acid generation along with benzylsuccinic acid during anaerobic microbial degradation of toluene. This has important implications relevant to elaboration of the metabolic route for anaerobic toluene degradation by strain Tol-4 and related organisms. Similar amounts of E-phenylitaconic acid were also produced by seven other strains of A. tolulyticus.


MicroRNA-139-3p suppresses growth and metastasis of glioblastoma via inhibition of NIN1/RPNI2 binding protein 1 homolog.
This study aimed to investigate the role of microRNA-139-3p (miR-139-3p) in glioblastoma, and further explored the underlying molecular mechanism. Gene Expression Omnibus (GEO) dataset (accession code GSE90603) was selected to identify differentially expressed microRNAs in glioblastoma. The level of miR-139-3p in glioblastoma tissues and cell lines was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), colony formation, wound healing, and transwell invasion assays were applied to assess the role of miR-139-3p in glioblastoma cells growth and aggressiveness. The direct target of miR-139-3p was confirmed using luciferase reporter assay. NIN1/RPNI2 binding protein 1 homolog (NOB1), specific short hairpin RNA (shRNA), and lentiviral vector encoding NOB1 stable transfections were done. The expression levels of NOB1 were detected by Western blotting and qRT-PCR. Glioblastoma cells were subcutaneously implanted into nude mice to determine the role of miR-139-3p in tumor growth and metastasis in vivo. miR-139-3p was remarkably down-expressed in glioblastoma tissue compared to control normal tissue. Overexpression of miR-139-3p suppressed the growth and metastasis of glioblastoma cells. Moreover, miR-139-3p inhibited glioblastoma growth and lung metastasis in vivo, whereas under-expression of miR-139-3p caused an opposite outcome. Furthermore, our work revealed that NOB1 expression was negatively associated with miR-139-3p, and NOB1 knock-down mimicked the inhibitory effect of miR-139-3p on glioblastoma cell proliferation and mobility phenotypes. Finally, overexpression of NOB1 neutralized the inhibition of miR-139-3p in glioblastoma cells. Our findings indicated that miR-139-3p played a vital role in inhibiting glioblastoma growth and metastasis by targeting NOB1.


Serum HCG beta-core fragment is masked by associated macromolecules.
To determine if beta-core fragment is present in serum from individuals with pregnancy and choriocarcinoma, samples were analyzed by gel filtration and fractions assessed by immunoassays (Mr = 15,000). In agreement with published reports, only minute amounts of beta-core fragment were detected (less than 0.1% of hCG level). A small amount of beta-core fragment activity was identified near the void volume of the column (Mr greater than 60,000). This high molecular weight material was pooled and dissociated with 3M ammonium thiocyanate, and gel filtration repeated. A much more significant beta-core fragment peak was then detected (Mr = 15,000). After dissociation, beta-core fragment was 18% (mol/mol) of the hCG level in early pregnancy serum, 91% in mid-pregnancy serum, 50% in term pregnancy serum, but only 1.3% in choriocarcinoma serum, pre-therapy. We conclude that the major form of beta-core fragment found in serum is associated with other macromolecules, which mask the beta-core fragment epitope to existing hCG beta antibodies. Measurements made on the dissociated beta-core fragment complex are much more in keeping with pregnancy levels found in urine.


Ga-68 DOTATOC PET, endoscopic ultrasonography, and multidetector CT in the diagnosis of duodenopancreatic neuroendocrine tumors: a single-centre retrospective study.
In this report, we compared endoscopic ultrasonography (EUS), multidetector CT (MDCT), and Ga-68 DOTATOC PET/CT in patients with neuroendocrine tumors (NETs). We report our experience with use of these methods in patients suspected to have duodenopancreatic primitive NET. Nineteen consecutive patients (mean age, 56; 21-80), who underwent both Ga-68 DOTATOC PET/CT and EUS between March 2007 and November 2008 were retrospectively included in the study (16 underwent MDCT). Suspicion of NET was confirmed by EUS-FNA and/or surgery. Operative characteristics of PET, EUS, and MDCT were compared. Twenty-three neuroendocrine lesions were diagnosed in 13/19 patients. EUS, PET, and MDCT correctly identified as affected 13/13 (100%), 12/13 (92%), and 10/11 (91%) patients, respectively. On a lesion basis, EUS, PET, and MDCT identified correctly as NETs 22/23 (96%), 20/23 (87%), and 13/18 (72%) lesions (P = 0.08 EUS vs. CT). Both on a patient and on a lesion basis, specificity was 67%, 83%, and 80% for EUS, PET, and MDCT, respectively. EUS, Ga-68 DOTATOC PET, and MDCT seem to have comparable accuracy in diagnosis of duodenopancreatic NET and their combination may allow an optimal preoperative diagnosis.


Extra Ocular Muscle Fenestration as a Weakening Maneuver for Surgical Management of Strabismus: A Randomized Pilot Clinical Trial.
This study aimed to evaluate the efficacy and safety of fenestration in comparison to the classic muscle recession as a weakening maneuver to horizontal and vertical extra ocular muscles in the surgical management of strabismus. This is a pilot single blind parallel group randomized controlled trial with 1:1 allocation ratio. Male or female patients aged 1- to 60-years-old who were admitted to the Pediatric Ophthalmology and Strabismus Department for surgical correction of horizontal or vertical strabismus. Patients were randomly allocated by the envelop method to either group 1 (muscle fenestration, N=9) or group 2 (classic muscle recession, N=9). All participants were assessed at the first post operative day, at one week, and one month after the surgery for the outcomes. Postoperative ocular alignment evaluated at the first day, one week, and one month following the operation showed comparable results with no significant differences between both groups (p>0.05). The median postoperative pain score evaluated at the first day following the operation was significantly higher in fenestration group than recession group (the medians were 2.0 and 1.0, respectively, p=0.014). Alternatively, the medians of the pain score were equal in both groups at one week and one month postoperatively (p>0.999). One patient in the fenestration group developed progressive subconjunctival hemorrhage. In contrast, there was no postoperative complications in the recession group (p>0.999). Efficacy and safety of muscle fenestration for correcting horizontal or vertical strabismus was comparable to the classic muscle recession.


Healthcare expenditure and its predictors in a cohort of Australians living with sciatica.
To estimate the healthcare resource utilisation of an Australian cohort of people with sciatica and explore individual-level factors associated with expenditure. Healthcare utilisation (services and medication) data from a randomised, double-blind, placebo-controlled trial of pregabalin in patients with sciatica (n = 185) were analysed to estimate healthcare expenditure of participants over 12 months. Associations between key baseline socio-economic, pain and quality of life characteristics and healthcare expenditure were examined using generalised linear imputation models. On average, participants accessed AUD$1,134 of healthcare over the year, predominantly made up of $114 of medication and $914 of health services, which included $418 of physiotherapy services. Participants randomised to receive pregabalin incurred higher expenditure ($1,263 compared to $1,001 for placebo), which was largely driven by pregabalin ($158) and greater health services ($107). Healthcare expenditure was significantly higher for participants prescribed pregabalin, earning greater than $1,700 per week ($88,400 per year) and reporting poorer quality of life (physical and mental). Our results suggest inefficiency in the use of healthcare resources due to increased healthcare resource utilisation in people with sciatica treated with pregabalin, compared to placebo. Costs of treating sciatica varied based on individual quality of life and socio-economic characteristics.


Neutrophil phenotypes implicated in the pathophysiology of post-traumatic sepsis.
The disruption of immune homeostasis after trauma is a major cause of post-traumatic organ dysfunction and/or sepsis. Recently, a variety of neutrophil phenotypes with distinct functions have been identified and suggested as involved in various clinical conditions. The association between neutrophil phenotypes and post-traumatic immunodeficiency has also been reported, yet the specific neutrophil phenotypes and their functional significance in post-traumatic sepsis have not been fully clarified. Therefore, we sought to investigate neutrophil phenotypic changes in a murine model, as these may hold prognostic value in post-traumatic sepsis. Third-degree burns affecting 25% of the body surface area were used to establish trauma model, and sepsis was induced 24 h later through cecal ligation and puncture (CLP). The Burn/CLP post-traumatic sepsis model and the Sham/CLP control model were established to assess the immunological status after trauma. Histopathological evaluation was performed on the spleen, liver, kidneys, and lung tissues. Immunological evaluation included the assessment of neutrophil markers using mass cytometry as well as cytokine measurements in serum and ascitic fluid through multiplex analysis using LUMINEX®. The Burn/CLP group had a lower survival rate than the Sham/CLP group. Histopathological examination revealed an impaired immune response and more advanced organ damage in the Burn/CLP group. Furthermore, the Burn/CLP group exhibited higher levels of transforming growth factor-beta 1 in the blood and generally lower levels of cytokines than the Sham/CLP group. CD11b, which is involved in neutrophil adhesion and migration, was highly expressed on neutrophils in the Burn/CLP group. The expression of CD172a, which is related to the inhibition of phagocytosis, was also upregulated on neutrophils in the Burn/CLP group. The expression of sialic acid-binding lg-like lectin F and CD68 also differed between the two groups. Different neutrophil phenotypes were observed between Burn/CLP and Sham/CLP groups, suggesting that neutrophils are implicated in the immune imbalance following trauma. However, further studies are needed to prove the causal relationships between neutrophil phenotypes and outcomes, including survival rate and organ dysfunction.


Heat-moisture treated waxy highland barley starch: Roles of starch granule-associated surface lipids, temperature and moisture.
Roles of temperature, moisture and starch granule-associated surface lipids (SGASL) during heat-moisture treatment (HMT) of waxy highland barley starch were elucidated. Starch without SGASL showed a higher increase in ratio (1016/993 cm-1) (0.095-0.121), lamellar peak area (88), radius of gyration (Rg1, 0.9-1.8 nm) and power-law exponents (0.19-0.42) than native starch (0.038-0.047, 46, 0.1-0.6 nm, 0.04-0.14), upon the same increase in moisture or temperature. Thus, removing SGASL promoted HMT. However, after HMT (30 % moisture, 120 °C), native starch showed lower relative crystallinity (RC, 11.67 %) and lamellar peak area (165.0), longer lamellar long period (L, 14.99 nm), and higher increase in peak gelatinization temperature (9.2-13.3 °C) than starch without SGASL (12.04 %, 399.2, 14.52 nm, 4.7-6.1 °C). This suggested that the resulting SGASL-amylopectin interaction further destroyed starch structure. Starch with and without SGASL showed similar trends in RC, lamellar peak area, L and Rg1 with increasing temperature, but different trends with increasing moisture, suggesting that removing SGASL led to more responsiveness to the effects of increasing moisture. Removing SGASL resulted in similar trends (RC and lamellar peak area) with increasing moisture and temperature, suggesting that the presence of SGASL induced different effects on moisture and temperature.


Intra-individual variation and estimates of usual physical activity.
The magnitude of intra-individual variation, as determined by three methods of physical activity (PA) assessment, was estimated to determine the optimal number of repeated measures needed to reliably measure an individual's usual PA habits. Data were obtained from 77 healthy adults enrolled in the Survey of Activity, Fitness, and Exercise (SAFE). PA was measured by: 1) Caltrac accelerometers worn 48-hours every 26 days for one year; 2) concurrent 48-hour PA records (PARs); and 3) a corresponding series of four-week PA histories (FWH). Repeated measures regression analyses were used to analyze the data. PA tended to be slightly higher in the summer months as compared with the winter months, but this seasonality explained little of the intra-individual variation. The intra-individual standard deviation (SD) estimated for the FWH (180 MET-min(d(-1))) was 39% of the mean annual MET-min(d(-1)), as compared with the Caltrac (163 MET-mind(d(-1)) or 9%) and PAR (259 MET-min(d(-1)) or 11%). Given the intra-individual variation, three repeated observations of the FWH, six Caltrac, or nine PAR over the course of the year were needed to achieve 80% reliability in estimation of mean annual PA. Intra-individual variation in PA is substantial and must be accounted for in estimates of usual PA.


SARS-CoV-2 and mitochondrial health: implications of lifestyle and ageing.
Infection with SARs-COV-2 displays increasing fatality with age and underlying co-morbidity, in particular, with markers of the metabolic syndrome and diabetes, which seems to be associated with a "cytokine storm" and an altered immune response. This suggests that a key contributory factor could be immunosenescence that is both age-related and lifestyle-induced. As the immune system itself is heavily reliant on mitochondrial function, then maintaining a healthy mitochondrial system may play a key role in resisting the virus, both directly, and indirectly by ensuring a good vaccine response. Furthermore, as viruses in general, and quite possibly this new virus, have also evolved to modulate immunometabolism and thus mitochondrial function to ensure their replication, this could further stress cellular bioenergetics. Unlike most sedentary modern humans, one of the natural hosts for the virus, the bat, has to "exercise" regularly to find food, which continually provides a powerful adaptive stimulus to maintain functional muscle and mitochondria. In effect the bat is exposed to regular hormetic stimuli, which could provide clues on how to resist this virus. In this paper we review the data that might support the idea that mitochondrial health, induced by a healthy lifestyle, could be a key factor in resisting the virus, and for those people who are perhaps not in optimal health, treatments that could support mitochondrial function might be pivotal to their long-term recovery.


Topography of genetic loci in tissue samples: towards new diagnostic tool using interphase FISH and high-resolution image analysis techniques.
Using single and dual colour fluorescence in situ hybridisation (FISH) combined with image analysis techniques the topographic characteristics of genes and centromeres in nuclei of human colon tissue cells were investigated. The distributions of distances from the centre-of-nucleus to genes (centromeres) and from genes to genes (centromeres to centromeres) were studied in normal colon tissue cells found in the neighbourhood of tumour samples, in tumour cell line HT-29 and in promyelocytic HL-60 cell line for comparison. Our results show that the topography of genetic loci determined in 3D-fixed cell tissue corresponds to that obtained for 2D-fixed cells separated from the tissue. The distributions of the centre-of-nucleus to gene (centromere) distances and gene to gene (centromere to centromere) distances and their average values are different for various genetic loci but similar for normal colon tissue cells, HT-29 colon tumour cell line and HL-60 promyelocytic cell line. It suggests that the arrangement of genetic loci in cell nucleus is conserved in different types of human cells. The investigations of trisomic loci in HT-29 cells revealed that the location of the third genetic element is not different from the location of two homologues in diploid cells. We have shown that the topographic parameters used in our experiments for different genetic elements are not tissue or tumour specific. In order to validate high-resolution cytometry for oncology, further investigations should include more precise parameters reflecting the state of chromatin in the neighbourhood of critical oncogenes or tumour suppresser genes.


Angiotensin-converting enzyme insertion/deletion gene polymorphism in general population of west Azarbaijan, Iran.
Angiotensin-converting enzyme (ACE) gene polymorphisms have been studied in different ethnic populations. We assessed the ACE gene insertion/deletion alleles frequencies and genotype distributions in a group of individuals from among the general population of west Azarbaijan, Iran, in order to determine the prevalence of deletion/deletion (D/D), deletion/insertion (D/I) and insertion/insertion (I/I) genotypes. In a cross-sectional study, 167 healthy individuals were enrolled in a randomized fashion. They were selected from the general population of west Azerbaijan, Iran. Polymerase chain reaction was carried out to determine the ACE D/D, D/I and I/I genotypes. The ACE alleles were D and I in 59.7% and 40.3% of the women, 59.3% and 40.7% of the men and 59.6% and 40.4% of all of the participants, respectively. The D/D, D/I, and I/I genotypes were observed in 22 (40.7%), 20 (37%), and 12 (22.2%) men, 41 (36.3%), 53 (46.9%), and 19 (16.8%) women, and 63 (37.7%), 73 (43.7%), and 31 (18.6%) participants, respectively. Statistical analysis showed that differences in ACE D and I alleles and genotype frequencies were not significant between the men and the women. In this study on the general population of west Azarbaijan, the frequencies of the ACE D and I alleles were 59.6% and 40.4%. The ACE D/D, D/I and I/I genotypes were seen in 37.7%, 43.7%, and 18.6% of the studied population, respectively.


Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane.
To determine the effects of constant rate infusion of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine (MLK) combination on end-tidal isoflurane concentration (ET-Iso) and minimum alveolar concentration (MAC) in dogs anesthetized with isoflurane and monitor depth of anesthesia by use of the bispectral index (BIS). 6 adult dogs. Each dog was anesthetized with isoflurane on 5 occasions, separated by a minimum of 7 to 10 days. Individual isoflurane MAC values were determined for each dog. Reduction in isoflurane MAC, induced by administration of morphine (3.3 microg/kg/min), lidocaine (50 microg/kg/min), ketamine (10 microg/kg/min), and MLK, was determined. Heart rate, mean arterial blood pressure, oxygen saturation as measured by pulse oximetry (Spo2), core body temperature, and BIS were monitored. Mean +/- SD isoflurane MAC was 1.38 +/- 0.08%. Morphine, lidocaine, ketamine, and MLK significantly lowered isoflurane MAC by 48, 29, 25, and 45%, respectively. The percentage reductions in isoflurane MAC for morphine and MLK were not significantly different but were significantly greater than for lidocaine and ketamine. The Spo2, mean arterial pressure, and core body temperature were not different among groups. Heart rate was significantly decreased at isoflurane MAC during infusion of morphine and MLK. The BIS was inversely related to the ET-Iso and was significantly increased at isoflurane MAC during infusions of morphine and ketamine, compared with isoflurane alone. Low infusion doses of morphine, lidocaine, ketamine, and MLK decreased isoflurane MAC in dogs and were not associated with adverse hemodynamic effects. The BIS can be used to monitor depth of anesthesia.


[A Case of Resection of Para-Aortic Lymph Node Recurrence Three Years after Curative Surgery for Ascending Colon Cancer].
A79 -year-old woman underwent right hemicolectomy and D3 dissection for ascending colon cancer. Pathologically, the tumor was diagnosed as moderately differentiated adenocarcinoma, pSS, ly1, v1, pPM0, pDM0, pRM0, pN1(3/19), M0, pStage III a. Adjuvant chemotherapy using UFT/UZEL was administered. One and a half years after surgery, PET-CT showed para-aortic lymph node swelling with high FDG uptake. Chemotherapy administration(capecitabine plus bevacizumab)was started and the lymph node swelling reduced. However, 1 year after chemotherapy, the node was swollen again. Para-aortic lymphadenectomy was performed. Pathological examination of the resected specimen showed metastatic adenocarcinoma. No adjuvant chemotherapy was administered. Three years after the last surgery, the patient is alive without any sign of recurrence. In this case, surgical treatment for para-aortic lymph node metastasis of colon cancer resulted in excellent QOL maintenance. We recommend para-aortic lymphadenectomy if the metastasis is localized.


Toxicological impact of waterpipe smoking and flavorings in the oral cavity and respiratory system.
Waterpipe smoking (WS), an emerging trend has major health concerns. It is prevalent worldwide as a recreational activity both indoors and outdoors. The aim of this review was to assess the impact of waterpipe smoke on the oral and respiratory system (oral cavity and pulmonary tissues). A number of studies have shown that periodontal health status is compromised in waterpipe smokers when compared with nonsmokers. Some studies have associated WS with oral premalignant and malignant lesions; however, due to the poor quality of these studies, the presented outcomes should be interpreted with caution. Although cigarette smoking has been considered as a potential risk factor for dental caries; there are no studies in indexed literature that have shown an association to exist between dental caries and WS. Inhaled waterpipe smoke imposes oxidative stress and inflammatory responses and compromises the ventilatory capacity of the lungs and may lead to an increased risk of decline in lung function. WS may cause oral and pulmonary diseases, such as periodontal disease and chronic obstructive airway disease, respectively. The association between WS and development of dental caries and oral pre-cancer and their relationships with chronic airways disease requires investigations. This review discusses the current evidence of waterpipe smoke effects on the oral health and respiratory system based on basic and clinical science and provides future directions for research and regulatory science on how WS can affect the oral cavity and the respiratory/pulmonary system.


Platinum nanoparticle-facilitated reflective surfaces for non-contact temperature control in microfluidic devices for PCR amplification.
The polymerase chain reaction (PCR) is critical for amplification of target sequences of DNA or RNA that have clinical, biological or forensic relevance. While extrinsic Fabry-Perot interferometry (EFPI) has been shown to be adequate for non-contact temperature sensing, the difficulty in defining a reflective surface that is semi-reflective, non-reactive for PCR compatibility and adherent for thermal bonding has limited its exploitation. Through the incorporation of a reflective surface fabricated using a thermally driven self-assembly of a platinum nanoparticle monolayer on the surface of the microfluidic chamber, an enhanced EFPI signal results, allowing for non-contact microfluidic temperature control instrumentation that uses infrared-mediated heating, convective forced-air cooling, and interferometic temperature sensing. The interferometer is originally calibrated with a miniature copper-constantan thermocouple in the PCR chamber resulting in temperature sensitivities of -22.0 to -32.8 nm·°C(-1), depending on the chamber depth. This universal calibration enables accurate temperature control in any device with arbitrary dimensions, thereby allowing versatility in various applications. Uniquely, this non-contact temperature control for PCR thermocycling is applied to the amplification of STR loci for human genetic profiling, where nine STR loci are successfully amplified for human identification using the EFPI-based non-contact thermocycling.


Photonuclear fission from high energy electrons from ultraintense laser-solid interactions
A new regime of laser-matter interactions in which the quiver motion of plasma electrons is fully relativistic, with energies extending well above the threshold for nuclear processes, is studied using a petawatt laser system. In solid target experiments with focused intensities exceeding 10(20) W/cm(2), high energy electron generation, hard bremsstrahlung, and nuclear phenomena have been observed. We report here a quantitative comparison of the high energy electrons and the bremsstrahlung spectrum, as measured by photonuclear reaction yields, including the photoinduced fission of 238U.


Biogeography of actinomycete communities and type II polyketide synthase genes in soils collected in New Jersey and Central Asia.
Soil microbial communities are believed to be comprised of thousands of different bacterial species. One prevailing idea is that "everything is everywhere, and the environment selects," implying that all types of bacteria are present in all environments where their growth requirements are met. We tested this hypothesis using actinomycete communities and type II polyketide synthase (PKS) genes found in soils collected from New Jersey and Uzbekistan (n = 91). Terminal restriction fragment length polymorphism analysis using actinomycete 16S rRNA and type II PKS genes was employed to determine community profiles. The terminal fragment frequencies in soil samples had a lognormal distribution, indicating that the majority of actinomycete phylotypes and PKS pathways are present infrequently in the environment. Less than 1% of peaks were detected in more than 50% of samples, and as many as 18% of the fragments were unique and detected in only one sample. Actinomycete 16S rRNA fingerprints clustered by country of origin, indicating that unique populations are present in North America and Central Asia. Sequence analysis of type II PKS gene fragments cloned from Uzbek soil revealed 35 novel sequence clades whose levels of identity to genes in the GenBank database ranged from 68 to 92%. The data indicate that actinomycetes are patchily distributed but that distinct populations are present in North American and Central Asia. These results have implications for microbial bioprospecting and indicate that the cosmopolitan actinomycete species and PKS pathways may account for only a small proportion of the total diversity in soil.


Deformation of transcatheter heart valves with mitral valve-in-valve.
The use of oversizing in mitral valve-in-valve (MViV) procedures can lead to non-uniform expansion of transcatheter heart valves (THV). This may have implications for THV durability. The objective of this study was to assess the extent and predictors of THV deformation in MViV procedures. We examined 33 patients who underwent MViV with SAPIEN prostheses. The extent of THV deformation (deformation index, eccentricity, neosinus volume, asymmetric leaflet expansion and vertical deformation) and hypoattenuating leaflet thickening (HALT) were assessed using cardiac computed tomography (CT), performed prospectively at 30 days post-procedure. For descriptive purposes, the THV deformation index was calculated, with values >1.00 representing a more hourglass shape. Non-uniform underexpansion of THV was common after MViV implantation, with a median expansion area of 74.0% (interquartile range 68.1-84.1) at the narrowest level and a THV deformation index of 1.21 (1.13-1.29), but circularity was maintained with eccentricity ranging from 0.24 to 0.28.The degree of oversizing was a key factor associated with greater underexpansion and a higher deformation index (β=-0.634; p<0.001; β=0.594; p<0.001, respectively). Overall, the incidence of HALT on the 30-day postprocedural CT was 27.3% (9 of 33). Most patients (32 of 33) were on anticoagulation therapy, but the prothrombin time and international normalised ratio (PT-INR) at the time of the CT scan was <2.5 in 23 of 32 patients. Among patients with a PT-INR of <2.5, HALT was predominantly observed with a high THV deformation index of ≥1.18. THV deformation, i.e., underexpansion and an hourglass shape, commonly occurs after MViV implantation and is negatively affected by excessive oversizing. Optimising THV expansion during MViV could potentially prevent HALT.


Accurate detection of subclonal single nucleotide variants in whole genome amplified and pooled cancer samples using HaloPlex target enrichment.
Target enrichment and resequencing is a widely used approach for identification of cancer genes and genetic variants associated with diseases. Although cost effective compared to whole genome sequencing, analysis of many samples constitutes a significant cost, which could be reduced by pooling samples before capture. Another limitation to the number of cancer samples that can be analyzed is often the amount of available tumor DNA. We evaluated the performance of whole genome amplified DNA and the power to detect subclonal somatic single nucleotide variants in non-indexed pools of cancer samples using the HaloPlex technology for target enrichment and next generation sequencing. We captured a set of 1528 putative somatic single nucleotide variants and germline SNPs, which were identified by whole genome sequencing, with the HaloPlex technology and sequenced to a depth of 792-1752. We found that the allele fractions of the analyzed variants are well preserved during whole genome amplification and that capture specificity or variant calling is not affected. We detected a large majority of the known single nucleotide variants present uniquely in one sample with allele fractions as low as 0.1 in non-indexed pools of up to ten samples. We also identified and experimentally validated six novel variants in the samples included in the pools. Our work demonstrates that whole genome amplified DNA can be used for target enrichment equally well as genomic DNA and that accurate variant detection is possible in non-indexed pools of cancer samples. These findings show that analysis of a large number of samples is feasible at low cost, even when only small amounts of DNA is available, and thereby significantly increases the chances of indentifying recurrent mutations in cancer samples.


Small heterodimer partner interacts with NLRP3 and negatively regulates activation of the NLRP3 inflammasome.
Excessive activation of the NLRP3 inflammasome results in damaging inflammation, yet the regulators of this process remain poorly defined. Herein, we show that the orphan nuclear receptor small heterodimer partner (SHP) is a negative regulator of NLRP3 inflammasome activation. NLRP3 inflammasome activation leads to an interaction between SHP and NLRP3, proteins that are both recruited to mitochondria. Overexpression of SHP competitively inhibits binding of NLRP3 to apoptosis-associated speck-like protein containing a CARD (ASC). SHP deficiency results in increased secretion of proinflammatory cytokines IL-1β and IL-18, and excessive pathologic responses typically observed in mouse models of kidney tubular necrosis and peritoneal gout. Notably, the loss of SHP results in accumulation of damaged mitochondria and a sustained interaction between NLRP3 and ASC in the endoplasmic reticulum. These data are suggestive of a role for SHP in controlling NLRP3 inflammasome activation through a mechanism involving interaction with NLRP3 and maintenance of mitochondrial homeostasis.


Unilateral Autologous Breast Reconstruction with Bi-pedicled, Conjoined Deep Inferior Epigastric Perforator Flaps.
The abdomen remains the most popular and reliable donor site for autologous breast reconstruction. Some patients, however, lack sufficient tissue to recreate an aesthetic breast mound using a single-pedicle, deep inferior epigastric perforator (DIEP) flap, particularly when matching a contralateral native breast. The amount of abdominal skin and/or soft tissue reliably supplied by one vascular pedicle is frequently insufficient to adequately restore the breast skin envelope and "footprint." This study summarizes our experience with using bipedicled DIEP flaps to improve the aesthetic results of unilateral breast reconstruction in such patients. Consecutive patients undergoing unilateral breast reconstruction with bi-pedicled, conjoined DIEP flaps over a 4-year period were retrospectively reviewed. Primary and secondary flap microvascular anastomoses were performed to the antegrade internal mammary (IM) vessels and to either the retrograde IM vessels or a primary DIEP pedicle side branch, respectively. Clinical characteristics and outcomes were recorded. Sixty-three patients underwent immediate (n = 29) or delayed (n = 34) reconstruction, with age and body mass index of 54.1 ± 8.4 years and 26.6 ± 4.7, respectively. Mean follow-up was 14.1 months. Twenty-eight (44.4%) patients received prereconstruction radiation therapy. All patients had preoperative abdominal imaging, including 57 (90.5%) using magnetic resonance angiography. There were no flap losses with three operative interventions for flap salvage. Unilateral breast reconstruction with bipedicled, conjoined DIEP flaps is safe and reliable. These procedures can be performed with a complication profile similar to single-pedicle DIEP flaps. The additional skin and soft tissue available with bi-pedicled flaps allows for greater flexibility in matching the shape and projection of a woman's contralateral breast, and in some cases is necessary to achieve an aesthetically acceptable reconstruction. With growing expectations among breast reconstruction patients, conjoined bi-pedicled flaps represent a tool for meeting their reconstructive needs and exceeding the status quo for aesthetic outcomes.


Patterns of Contraceptive Consistency among Young Adult Women in Southeastern Michigan: Longitudinal Findings Based on Journal Data.
We aimed to determine patterns of contraceptive consistency among heterosexually active, young adult women who do not desire pregnancy, and to identify factors associated with these patterns. We analyzed longitudinal data from a population-based study of young adult women aged 18 and 19 who were representative of a single county in southeastern Michigan. Using multinomial logistic regression, we identified associations between contraceptive consistency (dependent outcome) and sociodemographic characteristics and personal factors. We categorized women into three patterns of contraceptive consistency: 1) always consistent (40%; reference group), 2) sometimes consistent (49%), 3) never consistent (11%). Not being employed was associated with increased odds of being sometimes consistent (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.1-2.2) and never consistent (OR, 1.9; 95% CI, 1.1-3.4). Those who reported a grade point average of 3.0 or less were more likely to be never consistent (OR, 2.5; 95% CI, 1.2-5.3). Women in a serious relationship had a two times greater odds of being sometimes consistent. Among always consistent users, the oral contraceptive pill was most often used (55%); only 4% used the intrauterine device or implant. Sometimes consistent and never consistent users most frequently relied on condoms (35%) and withdrawal (68%), respectively. This analysis of longitudinal data revealed that the majority of young adult women inconsistently used short-acting or coital-specific methods; few used the most effective, long-acting methods. Interventions to improve contraceptive consistency among young adult women should include periodic assessments of personal factors (i.e., work, school, relationships) and promotion of long-acting reversible contraceptive methods when appropriate.


Pseudocholinesterase variation in southern African populations.
Genetic variation at both the E1 and E2 loci of pseudocholinesterase was studied in 7 southern African populations. In the Ashkenazim and Afrikaners, E1 locus variation was observed and the frequency of the E1a or 'atypical' allele was found to be 0.017 in the Ashkenazim and 0.016 in the Afrikaans-speaking population, similar to those observed in other caucasoid populations. The E1s, or 'silent' allele, was found to occur in the Afrikaans-speaking population at a frequency 2-3 times greater than in other Caucasians, giving an increased risk of scoline-sensitivity. The rarity of the E1a in the Negro and Khoisan populations was confirmed. All 7 populations showed variation at the E2 locus with high frequencies of the E2+ allele in the Caucasians and San, while Negroes showed relatively low frequencies. Coloureds showed intermediate frequencies, consistent with their historical origins.


Some factors affecting mutant numbers in the Salmonella/microsome assay.
An examination has been made of some of the parameters which can affect mutant numbers in the Salmonella/microsome assay. The type of minimal media plates used for the assay and the concentration of glucose-6-phosphate, one of the co-factors necessary for mono-oxygenase action, had no effect on mutant numbers. Increases in mutated bacteria resulted from the use of (1) log-phase bacteria, (2) higher NADP concentrations than those normally recommended, and (3) higher phosphate buffer concentrations. Six mutagens, i.e., 2-acetylaminofluorene (AAF), 3,3'-dichlorobenzidine (3,3'-DCB), cyclophosphamide (CY), aflatoxin B1 (AFB1), 3-methylcholanthrene (3MC) and benzo[a]pyrene (BP), all requiring mono-oxygenase activation, were studied with two Salmonella typhimurium strains, TA98 and TA100, and liver preparations from rats given different inducing agent treatments using optimum conditions. Phenobarbitone induction was generally superior to Aroclor-1254 in converting these substrates to mutagens except for the polycyclic hydrocarbon substrates. A comparison of 3-methylcholanthrene, Aroclor-1254, beta-naphthoflavone or phenobarbitone as inducing agents revealed the first three of these to be equally effective in activating BP or 3MC to mutagens, whereas phenobarbitone was less active. Dual administration of 3-methylcholanthrene and phenobarbitone to rats did not result in an additive mutagenic effect using AAF, AFB1 or 3,3'-DCB as substrates, the numbers of mutant bacteria obtained being only equal to that seen with 3-methylcholanthrene alone. These differences were not due to there being different liver protein optima for the various inducing agent treatments. The foregoing results are discussed in relation to attempts to draw up a rigid protocol for mutagenicity testing.


Amylose-like polysaccharide accumulation and hyphal cell-surface structure in relation to citric acid production by Aspergillus niger in shake culture.
When 120 mg glucose/ml was used as a carbon source, in shake culture Aspergillus niger Yang no. 2 maximally produced only 15.4 mg citric acid/ml but accumulated 3.0 mg extracellular polysaccharide/ml. The polysaccharide secreted by mycelia of Yang no. 2 in shake culture was confirmed to be an amylose-like alpha-1,4-glucan by hydrolysis analysis with acid, amylase and glucoamylase. However, in static cultures, such as semisolid and surface cultures free from physical stresses caused by shaking damage, Yang no. 2 produced more citric acid but did not accumulate the polysaccharide. With cultivation time in shake culture, the amount of extracellular polysaccharide and the viscosity of the culture broth increased. The increase of shaking speed caused a remarkable increase in the accumulation of extracellular polysaccharide, e.g. 11.2 mg extracellular polysaccharide/ml was accumulated in the medium at a shaking speed of 200 rpm. The addition of 2.0 mg carboxymethylcellulose (CMC)/ml as a viscous additive to the medium reduced drastically the amount of extracellular polysaccharide accumulated to 1.5 mg/ml, but increased the citric acid produced to 52.0 mg/ml. However, intracellular polysaccharide accumulation kept up a steady rate of 0.26 microgram/mg dried mycelium through the entire period of cultivation. The addition of 3.0 mg polysaccharide/ml purified from the culture broth to the medium at the start of a culture resulted in a decrease of extracellular polysaccharide accumulation but an increase of citric acid accumulation. From electronmicroscopic observation, cell surfaces of hyphae cultivated with CMC were smooth, while hyphae cultivated without CMC had fibrous and granular polysaccharide on the cell surface. These results suggested that Yang no. 2 secreted the polysaccharide on the cell surface as a viscous substance and/or a shock absorber to protect itself from physical stresses caused by shaking damage in shake culture.


The thylakoid lumen of chloroplasts. Isolation and characterization.
The chloroplast compartment enclosed by the thylakoid membrane, the "lumen," is poorly characterized. The major aims of this work were to design a procedure for the isolation of the thylakoid lumen which could be generally used to characterize lumenal proteins. The preparation was a stepwise procedure in which thylakoid membranes were isolated from intact chloroplasts. Loosely associated thylakoid surface proteins were removed, and following Yeda press fragmentation the lumenal content was recovered in the supernatant following centrifugation. The purity and yield of lumenal proteins were determined using appropriate marker proteins specific for the different chloroplast compartments. Quantitative immunoblot analyses showed that the recovery of soluble lumenal proteins was 60-65% (as judged by the presence of plastocyanin), whereas contamination with stromal enzymes was less than 1% (ribulose-bisphosphate carboxylase) and negligible for thylakoid integral membrane proteins (D1 protein). Approximately 25 polypeptides were recovered in the lumenal fraction, of which several were identified for the first time. Enzymatic measurements and/or amino-terminal sequencing revealed the presence of proteolytic activities, violaxanthin de-epoxidase, polyphenol oxidase, peroxidase, as well as a novel prolyl cis/trans-isomerase.


Malaria surveillance--United States, 2006.
Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium (i.e., P. falciparum, P. vivax, P. ovale, and P. malariae). These parasites are transmitted by the bite of an infective female Anopheles species mosquito. The majority of malaria infections in the United States occur among persons who have traveled to areas with ongoing malaria transmission. In the United States, cases can occur through exposure to infected blood products, congenital transmission, or local mosquitoborne transmission. Malaria surveillance is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers. This report summarizes cases in persons with onset of illness in 2006 and summarizes trends during previous years. Malaria cases confirmed by blood film or polymerase chain reaction (PCR) are mandated to be reported to local and state health departments by health-care providers or laboratory staff members. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS), National Notifiable Diseases Surveillance System (NNDSS), and direct CDC consultations. Data from these reporting systems serve as the basis for this report. CDC received reports of 1,564 cases of malaria among persons in the United States with onset of symptoms in 2006, six of which were fatal. This is an increase of 2.4% from the 1,528 cases reported for 2005. P. falciparum, P. vivax, P. malariae, and P. ovale were identified in 39.2%, 17.6%, 2.9%, and 3.0% of cases, respectively. Ten patients (0.6%) were infected by two or more species. The infecting species was unreported or undetermined in 36.6% of cases. Compared with 2005, the largest increases in cases were from Asia (16.0%). Based on estimated volume of travel, the highest estimated relative case rates of malaria among travelers occurred among those returning from West Africa. Of 602 U.S. civilians who acquired malaria abroad and for whom chemoprophylaxis information was known, 405 (67.3%) reported that they had not followed a chemoprophylactic drug regimen recommended by CDC for the area to which they had traveled. Seventeen cases were reported in pregnant women, among whom only one reported taking chemoprophylaxis precautions. Six deaths were reported; five of the persons were infected with P. falciparum and one with P. malariae. Despite the 2.4% increase in cases from 2005 to 2006, the numbers of malaria cases remained relatively stable during 2001--2006. No change was detected in the proportion of cases by species responsible for infection. U.S. civilians traveling to West Africa had the highest estimated relative case rates. In the majority of reported cases, U.S. civilians who acquired infection abroad had not adhered to a chemoprophylaxis regimen that was appropriate for the country in which they acquired malaria. Additional investigations were conducted of the six fatal cases that occurred in the United States. Persons traveling to a malarious area should take one of the recommended chemoprophylaxis regimens appropriate for the region of travel and use personal protection measures to prevent mosquito bites. Any person who has been to a malarious area and who subsequently has a fever or influenza-like symptoms should seek medical care immediately and report their travel history to the clinician; investigation should always include blood-film tests for malaria, with results made available immediately. Malaria infections can be fatal if not diagnosed and treated promptly. CDC recommendations concerning malaria prevention are available at http://wwwn. cdc.gov/travel/contentdiseases.aspx#malaria or by calling the CDC Malaria Branch on weekdays (telephone: 770-488-7788; Monday--Friday, 8:00 A.M.--4:30 P.M. EST); during evenings, weekends, and holidays, call the CDC Director's Emergency Operations Center (telephone: 770-488-7100), and ask to page the person on call for the Malaria Branch. Recommendations concerning malaria treatment are available at http://www.cdc.gov/malaria/diagnosis_treatment/treatment.htm or by calling the CDC Malaria Hotline.


Investigating the transition from recent to remote memory using advanced tools.
Remote memories, weeks to decades long, are usually the ones most important to the organism, as the longevity of a memory is tightly connected to its significance. Retrograde amnesia studies in human patients as well as lesions and immediate early gene expression investigation in animal models, suggested that the hippocampus has a time dependent role in memory consolidation. Namely, that as a memory matures it becomes independent of the hippocampus and instead depends on extra-hippocampal areas. However, accumulating evidence implies that this temporal segregation is not as rigid as originally proposed. In this review we will focus on the integration of new methods, such as chemogenetics, optogenetics and calcium imaging, which enable genetic specificity as well as high temporal and spatial resolution. Using these methods, recent studies have started to resolve the inconsistencies of past findings by observing and manipulating neural ensembles in different brain regions. We then discuss how these techniques can be applied to investigate the cellular underpinnings of memory across multiple time points, and employed to study the contribution of various cell types to remote memory.


Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases.
Toll-like receptor 7 (TLR7) senses microbial-derived RNA but can also potentially respond to self-derived RNA. To prevent autoimmune responses, TLR7 is thought to localize in endolysosomes. Contrary to this view, we show here that TLR7 is present on the cell surface of immune cells and that TLR7 responses can be inhibited by an anti-TLR7 antibody. The anti-TLR7 antibody is internalized with TLR7 and accumulates in endolysosomes as an immune complex. TLR7 responses in dendritic cells, macrophages and B cells are all inhibited by the anti-TLR7 antibody. Furthermore, the anti-TLR7 antibody inhibits in vivo cytokine production induced by a TLR7 ligand. Spontaneous TLR7 activation in Unc93b1(D34A/D34A) mice causes lethal inflammation. Progressive inflammation such as splenomegaly, thrombocytopenia and chronic active hepatitis are ameliorated by anti-TLR7 antibody treatment. These results demonstrate that cell surface TLR7 is a promising target for therapeutic intervention in autoimmune diseases.


Nanostructured metal sulfides for energy storage.
Advanced electrodes with a high energy density at high power are urgently needed for high-performance energy storage devices, including lithium-ion batteries (LIBs) and supercapacitors (SCs), to fulfil the requirements of future electrochemical power sources for applications such as in hybrid electric/plug-in-hybrid (HEV/PHEV) vehicles. Metal sulfides with unique physical and chemical properties, as well as high specific capacity/capacitance, which are typically multiple times higher than that of the carbon/graphite-based materials, are currently studied as promising electrode materials. However, the implementation of these sulfide electrodes in practical applications is hindered by their inferior rate performance and cycling stability. Nanostructures offering the advantages of high surface-to-volume ratios, favourable transport properties, and high freedom for the volume change upon ion insertion/extraction and other reactions, present an opportunity to build next-generation LIBs and SCs. Thus, the development of novel concepts in material research to achieve new nanostructures paves the way for improved electrochemical performance. Herein, we summarize recent advances in nanostructured metal sulfides, such as iron sulfides, copper sulfides, cobalt sulfides, nickel sulfides, manganese sulfides, molybdenum sulfides, tin sulfides, with zero-, one-, two-, and three-dimensional morphologies for LIB and SC applications. In addition, the recently emerged concept of incorporating conductive matrices, especially graphene, with metal sulfide nanomaterials will also be highlighted. Finally, some remarks are made on the challenges and perspectives for the future development of metal sulfide-based LIB and SC devices.


Perivenular brain lesions in a primate multiple sclerosis model at 7-tesla magnetic resonance imaging.
BACKGROUND Magnetic resonance imaging (MRI) can provide in vivo assessment of tissue damage, allowing evaluation of multiple sclerosis (MS) lesion evolution over time--a perspective not obtainable with postmortem histopathology. Relapsing-remitting experimental autoimmune encephalomyelitis (EAE) is an experimental model of MS that can be induced in the common marmoset, a small new world primate, and that causes perivenular white matter (WM) lesions similar to those observed in MS. METHODS Brain lesion development and evolution were studied in vivo and postmortem in four marmosets with EAE through serial T2- and T2*-weighted scans at 7-tesla. Supratentorial WM lesions were identified and characterized. RESULTS Of 97 lesions observed, 86 (88%) were clearly perivenular, and 62 (72%) developed around veins that were visible even prior to EAE induction. The perivenular configuration was confirmed by postmortem histopathology. Most affected veins, and their related perivascular Virchow-Robin spaces, passed into the subarachnoid space rather than the ventricles. CONCLUSION As in human MS, the intimate association between small veins and EAE lesions in the marmoset can be studied with serial in vivo MRI. This further strengthens the usefulness of this model for understanding the process of perivenular lesion development and accompanying tissue destruction in MS.


Management of blood transfusion in aortic valve surgery: impact of a blood conservation strategy.
There are limited data in the literature concerning the effect of a blood conservation strategy (BCS) on aortic valve replacement (AVR) patients. From 2007 to 2011, 778 patients underwent AVR at a single institution. During this period, a multidisciplinary BCS was initiated with emphasis on limiting intraoperative hemodilution, tolerance of perioperative anemia, and blood management education for the cardiac surgery care providers. Mortality was 3.0% (23 of 778) overall and 1.7% (9 of 522) for isolated first-time AVR. There was no difference in rates of mortality (p = 0.5) or major complications (p = 0.4) between the pre-BCS and post-BCS groups; however, the BCS was associated with a lower risk of major complications (odds ratio, 1.7; p = 0.046) by multivariable analysis. The incidence of red blood cell (RBC) transfusion decreased from 82.9% (324 of 391) to 68.0% (263 of 387; p < 0.01). Of those patients who did not receive any day-of-operation RBC transfusions, 64.5% (191 of 296) did not receive any postoperative RBC transfusions. Lower risk of RBC transfusion was associated with isolated AVR (p < 0.01), a minimally invasive approach (p < 0.01), and BCS (p < 0.01), whereas a greater risk of RBC transfusion was associated with older age (p < 0.01), prior cardiac operation (p = 0.01), female sex (p < 0.01), and smaller body surface area (p < 0.01). Day-of-operation RBC transfusion of 2 units or more was associated with increased deaths (p = 0.01), prolonged intubation (p < 0.01), postoperative renal failure (p = 0.01), and increased incidence of any complication (p < 0.01). Perioperative BCS reduced RBC transfusion in AVR patients without an increase in mortality or morbidity. Guidelines for BCS in routine cardiac operations should be extended to AVR patients.


Specific humoral immunity versus polyclonal B cell activation in Trypanosoma cruzi infection of susceptible and resistant mice.
The etiologic agent of Chagas Disease is Trypanosoma cruzi. Acute infection results in patent parasitemia and polyclonal lymphocyte activation. Polyclonal B cell activation associated with hypergammaglobulinemia and delayed specific humoral immunity has been reported during T. cruzi infection in experimental mouse models. Based on preliminary data from our laboratory we hypothesized that variances in susceptibility to T. cruzi infections in murine strains is related to differences in the ability to mount parasite-specific humoral responses rather than polyclonal B cell activation during acute infection. Relatively susceptible Balb/c and resistant C57Bl/6 mice were inoculated with doses of parasite that led to similar timing and magnitude of initial parasitemia. Longitudinal analysis of parasite-specific and total circulating antibody levels during acute infection demonstrated that C57Bl/6 mice developed parasite-specific antibody responses by 2 weeks post-infection with little evidence of polyclonal B cell activation. The humoral response in C57Bl/6 mice was associated with differential activation of B cells and expansion of splenic CD21(high)CD23(low) Marginal Zone (MZ) like B cells that coincided with parasite-specific antibody secreting cell (ASC) development in the spleen. In contrast, susceptible Balb/c mice demonstrated early activation of B cells and early expansion of MZ B cells that preceded high levels of ASC without apparent parasite-specific ASC formation. Cytokine analysis demonstrated that the specific humoral response in the resistant C57Bl/6 mice was associated with early T-cell helper type 1 (Th1) cytokine response, whereas polyclonal B cell activation in the susceptible Balb/c mice was associated with sustained Th2 responses and delayed Th1 cytokine production. The effect of Th cell bias was further demonstrated by differential total and parasite-specific antibody isotype responses in susceptible versus resistant mice. T cell activation and expansion were associated with parasite-specific humoral responses in the resistant C57Bl/6 mice. The results of this study indicate that resistant C57Bl/6 mice had improved parasite-specific humoral responses that were associated with decreased polyclonal B cell activation. In general, Th2 cytokine responses are associated with improved antibody response. But in the context of parasite infection, this study shows that Th2 cytokine responses were associated with amplified polyclonal B cell activation and diminished specific humoral immunity. These results demonstrate that polyclonal B cell activation during acute experimental Chagas disease is not a generalized response and suggest that the nature of humoral immunity during T. cruzi infection contributes to host susceptibility.


Novel TGM5 mutations in acral peeling skin syndrome.
Acral peeling skin syndrome (APSS, MIM #609796) is a rare autosomal recessive disorder characterized by superficial exfoliation and blistering of the volar and dorsal aspects of hands and feet. The level of separation is at the junction of the stratum granulosum and stratum corneum. APSS is caused by mutations in the TGM5 gene encoding transglutaminase-5, which is important for structural integrity of the outermost epidermal layers. The majority of patients originate from Europe and carry a p.(Gly113Cys) mutation in TGM5. In this study, we report both European and non-European families carrying other mutations in the TGM5 gene. In 5 patients, we found 3 novel mutations: c.1001+2_1001+3del, c.1171G>A and c.1498C>T. To confirm their pathogenicity, we performed functional analyses with a transglutaminase activity assay, determined alternative splicing by reverse-transcribed PCR analysis and used databases and in silico prediction tools.


[Efficacy of percutaneous atrial septal defect closure guided by transesophageal echocardiography in children].
To compare the efficacy of percutaneous atrial septal defect (ASD) closure guided by transesophageal echocardiography (TEE) or guided by fluoroscopy in pediatric patients. Medical records of patients who underwent percutaneous ASD closure in the Children's Hospital, Zhejiang University School of Medicine from January 2017 to March 2018 were reviewed. There were 120 patients whose procedures were guided by TEE (TEE group), and 125 patients who had their procedures guided by fluoroscopy (fluoroscopy group). The performance of surgery, efficacy and postoperative complications were compared between two groups. Percutaneous ASD closure was successful in all patients. The operation time was shorter in the TEE group than that in fluoroscopy group[(20±14) min vs. (29±11) min, t=-7.939, P<0.05]. The size of the defect was larger in the TEE group than that of fluoroscopy group[(11±4) mm vs. (9±4) mm, t=2.512, P<0.05], but there was no significant difference in the sizes of occluder and occluder sheath between two groups (all P>0.05). No residual shunt, occluder shedding or displacement, severe arrhythmia or pericardial effusion were observed in either group. The incidence rates of fever, cough and diarrhea were not statistically different between two groups (all P>0.05). There was no significant difference in the outcome of percutaneous ASD closure guided by TEE or by fluoroscopy, but the procedure guided by TEE may reduce the operation time and can evaluate the size of ASD more accurately without involving radiation exposure, contrast agents use and large digital subtraction equipment.


Surface-modified bacterial nanofibrillar PHB scaffolds for bladder tissue repair.
The aim of the study is in vitro investigation of the feasibility of surface-modified bacterial nanofibrous poly [(R)-3-hydroxybutyrate] (PHB) graft for bladder reconstruction. In this study, the surface of electrospun bacterial PHB was modified with PEG- or EDA via radio frequency glow discharge method. After plasma modification, contact angle of EDA-modified PHB scaffolds decreased from 110 ± 1.50 to 23 ± 0.5 degree. Interestingly, less calcium oxalate stone deposition was observed on modified PHB scaffolds compared to that of non-modified group. Results of this study show that surface-modified scaffolds not only inhibited calcium oxalate growth but also enhanced the uroepithelial cell viability and proliferation.


In Vitro and In Vivo Metabolite Identification Studies for the New Synthetic Opioids Acetylfentanyl, Acrylfentanyl, Furanylfentanyl, and 4-Fluoro-Isobutyrylfentanyl.
New fentanyl analogs have recently emerged as new psychoactive substances and have caused numerous fatalities worldwide. To determine if the new analogs follow the same metabolic pathways elucidated for fentanyl and known fentanyl analogs, we performed in vitro and in vivo metabolite identification studies for acetylfentanyl, acrylfentanyl, 4-fluoro-isobutyrylfentanyl, and furanylfentanyl. All compounds were incubated at 10 μM with pooled human hepatocytes for up to 5 h. For each compound, four or five authentic human urine samples from autopsy cases with and without enzymatic hydrolysis were analyzed. Data acquisition was performed in data-dependent acquisition mode during liquid chromatography high-resolution mass spectrometry analyses. Data was analyzed (1) manually based on predicted biotransformations and (2) with MetaSense software using data-driven search algorithms. Acetylfentanyl, acrylfentanyl, and 4-fluoro-isobutyrylfentanyl were predominantly metabolized by N-dealkylation, cleaving off the phenethyl moiety, monohydroxylation at the ethyl linker and piperidine ring, as well as hydroxylation/methoxylation at the phenyl ring. In contrast, furanylfentanyl's major metabolites were generated by amide hydrolysis and dihydrodiol formation, while the nor-metabolite was minor or not detected in case samples at all. In general, in vitro results matched the in vivo findings well, showing identical biotransformations in each system. Phase II conjugation was observed, particularly for acetylfentanyl. Based on our results, we suggest the following specific and abundant metabolites as analytical targets in urine: a hydroxymethoxy and monohydroxylated metabolite for acetylfentanyl, a monohydroxy and dihydroxy metabolite for acrylfentanyl, two monohydroxy metabolites and a hydroxymethoxy metabolite for 4-fluoro-isobutyrylfentanyl, and a dihydrodiol metabolite and the amide hydrolysis metabolite for furanylfentanyl.


In utero arsenic exposure and infant infection in a United States cohort: a prospective study.
Arsenic (As), a ubiquitous environmental toxicant, has recently been linked to disrupted immune function and enhanced infection susceptibility in highly exposed populations. In drinking water, as levels above the EPA maximum contaminant level occur in our US study area and are a particular health concern for pregnant women and infants. As a part of the New Hampshire Birth Cohort Study, we investigated whether in utero exposure to As affects risk of infant infections. We prospectively obtained information on 4-month-old infants (n=214) using a parental telephone survey on infant infections and symptoms, including respiratory infections, diarrhea and specific illnesses, as well as the duration and severity of infections. Using logistic regression and Poisson models, we evaluated the association between maternal urinary As during pregnancy and infection risks adjusted for potentially confounding factors. Maternal urinary As concentrations were related to total number of infections requiring a physician visit (relative risk (RR) per one-fold increase in As in urine=1.5; 95% confidence interval (CI)=1.0, 2.1) or prescription medication (RR=1.6; 95% CI=1.1, 2.4), as well as lower respiratory infections treated with prescription medication (RR=3.3; 95% CI=1.2, 9.0). Associations were observed with respiratory symptoms (RR=4.0; 95% CI=1.0, 15.8), upper respiratory infections (RR=1.6; 95% CI=1.0, 2.5), and colds treated with prescription medication (RR=2.3; 95% CI=1.0, 5.2). Our results provide initial evidence that in utero As exposure may be related to infant infection and infection severity and provide insight into the early life impacts of fetal As exposure.


The effect of acute opioid administration on the phosphorylation of rat striatal synaptic membrane proteins.
The acute administration of morphine, methadone, etorphine, methionine-enkephalin, leucine-enkephalin and some related pharmacologically active peptides to rats produces biphasic effects on the degree of phosphorylation of striatal synaptic plasma membrane (SPM) proteins by endogenous protein kinases in the membranes. At 1 to 5 min after opioid administration, the phosphorylation of several SPM proteins is enhanced, followed at 10 to 20 min by a severe reduction in the rate of phosphorylation of the same proteins. Multiphasic responses follow the initial biphasic response after the injection of some opioids. Naloxone is able to block the agonist effects. The injection of saline or an inactive narcotic isomer has no effect on the phosphorylation of striatal SPM proteins. The administration of other psychoactive drugs such as clonidine or haloperidol also produces changes in phosphorylation, although the patterns of change are distinctly different from those produced by opioids. The proteins affected by opioid administration resemble those susceptible to stimulation of phosphorylation in the presence of Ca++/calmodulin. The role of Ca++/calmodulin-regulated reactions in the mechanisms of action of opioids has been evaluated by the addition of these modulators to the assays of preparation from opioid-treated rats. Neither modulators, added separately or together to the assay, was able to restore a depressed phosphorylation to normal levels, although each modulator was effective in stimulating the phosphorylation of many SPM proteins.


Healing architecture and psychiatric practice: (re)ordering work and space in an in-patient ward in Denmark.
Healing architecture is a defining feature of contemporary hospital design in many parts of the world, with psychiatric in-patient facilities in Denmark at the forefront of this innovation. The approach rests on the contention that designed clinical spaces and the particular dispositions they express may promote patient recovery. Although the idea that health may be spatially mediated is well-established, the means of this mediation are far from settled. This article contributes to this debate by analysing medical encounters in the context of a new purpose-built psychiatric hospital opened in Slagelse, Denmark in late 2015 as an example of healing architecture for the region. Grounded in qualitative research conducted in two wards between 2016 and 2017, we explore the key material and social effects of the hospital's healing architecture, and the spaces and practices it enacts. Following the work of Michael Lynch, we consider both the designed 'spatial order' of the in-patient wards and the 'spatial orderings' unfolding therein with a particular interest in how order is accomplished in psychiatric work. With much of the existing discussion of healing architectures focusing on their impacts on patient wellbeing, we consider how healing architectures may also be transforming psychiatric work.


Applying activity-based costing to healthcare settings.
Activity-based costing (ABC) focuses on processes that drive cost. By tracing healthcare activities back to events that generate cost, a more accurate measurement of financial performance is possible. This article uses ABC principles and techniques to determine costs associated with the x-ray process in a midsized outpatient clinic. The article also provides several tips for initiating an ABC cost system for an entire healthcare organization.


Influence of the land use pattern on the concentrations and fluxes of priority pollutants in urban stormwater.
This paper presents the results of the concentrations (μg/L) and fluxes (g/ha) of priority substances in stormwater from three watersheds with different land use patterns (namely, residential, urban dense, high urban density). Samples were collected at the outlet of these watersheds. Thirteen chemical groups were investigated corresponding to 88 individual substances before treatment. Results showed that stormwater discharges contained 55 substances, among them some metals, organotins, PAHs, PCBs, alkylphenols, pesticides, phthalates, cholorophenols and volatile organic compounds. Therefore, stormwater was highly contaminated. However, this contamination was often comparable from site to site, since no significant difference of the pollutant load was observed between the land use patterns.


[Experimental study of the antimicrobial effect of lysozyme in combination with antibiotics].
A synergistic effect of the antibacterial action of the lysozyme combination with various antibiotics against gram-positive and gram-negative microorganisms was found. The intensifying effect of lysozyme on its combination with antibiotics was more evident with respect to gram-positive microbes and less evident with respect to gram-negative organisms. The combinations os lysozyme with methicillin, lincomycin, oleandomycin or erythromycin proved to be most active against staphylococci. A high synergistic effect against streptococci was observed with the use of the lysozyme combination with benzylpenicillin, morphocycline, oleandomycin, ceporin or monomycin. The combination of lysozyme with macrolides had a maximum inhibitory effect on Coli bacteria.


Stored blood purification on activated charcoals.
The application of the hemosorption technique for storage, preservation and transfusion of the donor blood will result in a substantial increase in effectiveness of its application in numerous practically important situations, including even such as massive and exchange transfusion, or in patients with renal or liver insufficiency. Especially the metabolism of the erythrocytes, the intra- and extracellularic electrolyte supply of the blood and the pH level of the blood will be corrected according to the norm. Harmful products of the metabolism, microclots and impaired cells will also be reduced. The osmotic resistance of the erythrocytes rises significantly, the viscosity of the blood and the HBS-antigen level decrease.


Look before you reach: Fixation-reach latencies predict reaching kinematics in toddlers.
Research on infant and toddler reaching has shown evidence for motor planning after the initiation of the reaching action. However, the reach action sequence does not begin after the initiation of a reach but rather includes the initial visual fixations onto the target object occurring before the reach. We developed a paradigm that synchronizes head-mounted eye-tracking and motion capture to determine whether the latency between the first visual fixation on a target object and the first reaching movement toward the object predicts subsequent reaching behavior in toddlers. In a corpus of over one hundred reach sequences produced by 17 toddlers, we found that longer fixation-reach latencies during the pre-reach phase predicted slower reaches. If the slowness of an executed reach indicates reach difficulty, then the duration of pre-reach planning would be correlated with reach difficulty. However, no relation was found with pre-reach planning duration when reach difficulty was measured by usual factors and independent of reach duration. The findings raise important questions about the measurement of reach difficulty, models of motor control, and possible developmental changes in the relations between pre-planning and continuously unfolding motor plans throughout an action sequence.


[Multifunctional protein complex NAC (nascent polypeptide associated complex].
The functions of the evolutionary conservative complex NAC (Nascent polypepetide Associated Complex) and its subunits are discussed. The heterodimeric NAC protein contains alpha- and beta-subunits and is found to be reversibly bounded to the ribosome in all eukaryotes, from yeast to humans. NAC contacts the nascent polypeptide and protects it from proteolysis. NAC participates in polypeptide chain folding and modulates protein secretion and transmembrane protein formation. Mutations and deletions of genes, encoding NAC subunits are lethal in early development of multicellular eukaryotes. NAC is involved in the ribosome biogenesis. The beta-subunit interacts with caspase-3 and may be involved in the regulation of the apoptotic pathway. The variants of NAC proteins can be considered as chaperone complexes, involved in the response of the cell and the organism to stress factors, as well as regulators of apoptosis. The genes encoding beta-subunits are rapidly evolved, their duplications cause the formation of tissue specific beta-subunit variants with a different number of putative caspase cleavage sites. The homodimer of alpha-subunits is shown to be the RNA/DNA binding protein and acts as a transcriptional cofactor. The diversity in the functioning of NAC is a prime example of a protein that performs a variety of biological functions (moonlighting protein).


Electromotive force for an anisotropic turbulence: intermediate nonlinearity
A nonlinear electromotive force for an anisotropic turbulence in the case of intermediate nonlinearity is derived. The intermediate nonlinearity implies that the mean magnetic field is not strong enough to affect the correlation time of a turbulent velocity field. The nonlinear mean-field dependencies of the hydrodynamic and magnetic parts of the alpha effect, turbulent diffusion, and turbulent diamagnetic and paramagnetic velocities for an anisotropic turbulence are found. It is shown that the nonlinear turbulent diamagnetic and paramagnetic velocities are determined by both an inhomogeneity of the turbulence and an inhomogeneity of the mean magnetic field B. The latter implies that there are additional terms in the turbulent diamagnetic and paramagnetic velocities variation of [symbol: see text]B2 and variation of (B.[symbol: see text])B. These effects are caused by a tangling of a nonuniform mean magnetic field by hydrodynamic fluctuations. This increases the inhomogeneity of the mean magnetic field. It is also shown that in an isotropic turbulence the mean magnetic field causes an anisotropy of the nonlinear turbulent diffusion. Two types of nonlinearities in magnetic dynamo determined by algebraic and differential equations are discussed. Nonlinear systems of equations for axisymmetric alpha omega dynamos in both spherical and cylindrical coordinates are derived.


Comparative species divergence across eight triplets of spiny lizards (Sceloporus) using genomic sequence data.
Species divergence is typically thought to occur in the absence of gene flow, but many empirical studies are discovering that gene flow may be more pervasive during species formation. Although many examples of divergence with gene flow have been identified, few clades have been investigated in a comparative manner, and fewer have been studied using genome-wide sequence data. We contrast species divergence genetic histories across eight triplets of North American Sceloporus lizards using a maximum likelihood implementation of the isolation-migration (IM) model. Gene flow at the time of species divergence is modeled indirectly as variation in species divergence time across the genome or explicitly using a migration rate parameter. Likelihood ratio tests (LRTs) are used to test the null model of no gene flow at speciation against these two alternative gene flow models. We also use the Akaike information criterion to rank the models. Hundreds of loci are needed for the LRTs to have statistical power, and we use genome sequencing of reduced representation libraries to obtain DNA sequence alignments at many loci (between 340 and 3,478; mean = 1,678) for each triplet. We find that current species distributions are a poor predictor of whether a species pair diverged with gene flow. Interrogating the genome using the triplet method expedites the comparative study of species divergence history and the estimation of genetic parameters associated with speciation.


[Ectomesenchymal chondromyxoid tumor of the tongue, a rare and benign lesion].
Ectomesenchymal chondromyxoid tumor is a rare benign intraoral soft tissue neoplasm. Till date, 93 cases have been reported in literature. Clinically, it presents as a slowly growing, painless, firm, submucosal swelling mainly occurring on the anterior two thirds of the dorsum of the tongue. Histopathologically, the tumor is characterized by a well circumscribed, lobular proliferation of round, polygonal, or fusiform cells in a net-like pattern in a myxoid to chondromyxoid background. Although it shows a morphological resemblance to myoepitheliomas of soft tissue and skin, the exact histogenesis remains unclear; a recent publication of a large series has demonstrated recurrent RREB1-MKL2 gene fusions in 90% of the cases, suggesting the possibility of a new entity. The diagnosis is largely supported by immunhistochemical investigations. Here, we present a new case of ECT occurring in a 62-year-old male who presented with a leading complaint of slowly growing painless mass arising from the anterior part of the tongue measuring about 3 cm. This lesion was diagnosed 4 years before recent admittance, but the patient did not undergo the scheduled surgical intervention and was lost to follow-up. As the tumor was still persisting and moderately enlarging, he came back to our clinic. Finally, the mass was completely resected; after 24 month of follow-up, he is doing well, with no signs of recurrence. Orv Hetil. 2019; 160(33): 1319-1323.


Tea flavonoids may protect against atherosclerosis: the Rotterdam Study.
Epidemiological studies have indicated a protective role of dietary flavonoids in cardiovascular disease, but evidence is still conflicting. Tea is the major dietary source for flavonoids in Western populations. We studied the association of tea intake with aortic atherosclerosis in a general population. The present analysis formed part of the Rotterdam Study, a prospective study of men and women 55 years and older. Dietary intakes were assessed at baseline by a trained dietician who used a semiquantitative food frequency questionnaire. Calcified plaques in the abdominal aorta were radiographically detected after 2 to 3 years of follow-up. Aortic atherosclerosis was classified as "mild," "moderate," or "severe," according to the length of the calcified area (<1 cm, 1-5 cm, and >5 cm, respectively). The association of tea intake with severity of aortic atherosclerosis was studied in 3454 subjects who were free of cardiovascular disease at baseline. Data were analyzed by logistic regression, adjusting for age, sex, body mass index (calculated as weight in kilograms divided by the square of height in meters), smoking, education, and intake of alcohol, coffee, vitamin antioxidants, total fat, and total energy. Multivariable analyses showed a significant, inverse association of tea intake with severe aortic atherosclerosis. Odds ratios decreased from 0.54 (95% confidence interval [CI], 0.32-0.92) for drinking 125 to 250 mL (1-2 cups) of tea to 0.31 (CI, 0.16-0.59) for drinking more than 500 mL/d (4 cups per day). The associations were stronger in women than in men. The association of tea intake with mild and moderate atherosclerosis was not statistically significant. This study indicates a protective effect of tea drinking against ischemic heart disease.


Upstream regulatory sequences from two beta-conglycinin genes.
Genes encoding the beta-conglycinin seed storage proteins of soybean are expressed only in seeds during specific stages of development. The different subunits of beta-conglycinin, alpha', alpha and beta, are encoded by distinct members of a gene family. Yet there are marked differences in the regulation of the genes encoding the alpha'/alpha and beta subunits. Previous work (Chen et al., EMBO J 7: 297-302, 1988) identified a seed specific transcriptional enhancer upstream of a gene encoding the alpha' subunit. Mutations were made within this region to discern its functional components. Among those identified is a 62 bp region (between -77 and -140) that contains a vicilin box consensus sequence as well as a sequence that binds the soybean nuclear factor SEF4 in vitro. A second region, which contains a sequence homologous to the core of the legumin box consensus (i.e., CATGCAT-like or RY repeat element) at -246, was also shown to affect the activity of this enhancer in transgenic plants. A series of 5' terminal deletions were used to identify regulatory elements upstream of the beta subunit gene. Two regions were identified (from -553 to -442 and from -308 to -72) that, when deleted, led to a marked reduction in gene expression. Both of these elements contain sequences that bind SEF4 in vitro. The distal element also contains an AT-rich segment that recognizes a second nuclear factor, SEF1, in vitro. Neither of these elements contains any homology to the vicilin box consensus.


Control of voice fundamental frequency in speaking versus singing.
In order to investigate control of voice fundamental frequency (F0) in speaking and singing, 24 adults had to utter the nonsense word ['ta:tatas] repeatedly, while in selected trials their auditory feedback was frequency-shifted by 100 cents downwards. In the speaking condition the target speech rate and prosodic pattern were indicated by a rhythmic sequence made of white noise. In the singing condition the sequence consisted of piano notes, and subjects were instructed to match the pitch of the notes. In both conditions a response in voice F0 begins with a latency of about 150 ms. As predicted, response magnitude is greater in the singing condition (66 cents) than in the speaking condition (47 cents). Furthermore the singing condition seems to prolong the after-effect which is a continuation of the response in trials after the frequency shift. In the singing condition, response magnitude and the ability to match the target F0 correlate significantly. Results support the view that in speaking voice F0 is monitored mainly supra-segmentally and controlled less tightly than in singing.


Fabrication of a novel biomaterial with enhanced mechanical and conducting properties.
Conducting polymers have the combined advantages of metal conductivity with ease in processing and biocompatibility; making them extremely versatile for biosensor and tissue engineering applications. However, the inherent brittle property of conducting polymers limits their direct use in such applications which generally warrant soft and flexible material responses. Addition of fillers increases the material compliance, but is achieved at the cost of reduced electrical conductivity. To retain suitable conductivity without compromising the mechanical properties, we fabricate an electroactive blend (dPEDOT) using low grade PEDOT:PSS as the base conducting polymer with polyvinyl alcohol as filler and glycerol as a dopant. Bulk dPEDOT films show a thermally stable response till 110 °C with over seven fold increase in room temperature conductivity as compared to 0.002 S cm-1 for pristine PEDOT:PSS. We characterize the nonlinear stress-strain response of dPEDOT, well described using a Mooney-Rivlin hyperelastic model, and report elastomer-like moduli with ductility ∼ fives times its original length. Dynamic mechanical analysis shows constant storage moduli over a large range of frequencies with corresponding linear increase in tan(δ). We relate the enhanced performance of dPEDOT with the underlying structural constituents using FTIR and AFM microscopy. These data demonstrate specific interactions between individual components of dPEDOT, and their effect on surface topography and material properties. Finally, we show biocompatibility of dPEDOT using fibroblasts that have comparable cell morphologies and viability as the control, which make dPEDOT attractive as a biomaterial.


Cerebrospinal fluid is drained primarily via the spinal canal and olfactory route in young and aged spontaneously hypertensive rats.
Many aspects of CSF dynamics are poorly understood due to the difficulties involved in quantification and visualization. In particular, there is debate surrounding the route of CSF drainage. Our aim was to quantify CSF flow, volume, and drainage route dynamics in vivo in young and aged spontaneously hypertensive rats (SHR) using a novel contrast-enhanced computed tomography (CT) method. ICP was recorded in young (2-5 months) and aged (16 months) SHR. Contrast was administered into the lateral ventricles bilaterally and sequential CT imaging was used to visualize the entire intracranial CSF system and CSF drainage routes. A customized contrast decay software module was used to quantify CSF flow at multiple locations. ICP was significantly higher in aged rats than in young rats (11.52 ± 2.36 mmHg, versus 7.04 ± 2.89 mmHg, p = 0.03). Contrast was observed throughout the entire intracranial CSF system and was seen to enter the spinal canal and cross the cribriform plate into the olfactory mucosa within 9.1 ± 6.1 and 22.2 ± 7.1 minutes, respectively. No contrast was observed adjacent to the sagittal sinus. There were no significant differences between young and aged rats in either contrast distribution times or CSF flow rates. Mean flow rates (combined young and aged) were 3.0 ± 1.5 μL/min at the cerebral aqueduct; 3.5 ± 1.4 μL/min at the 3rd ventricle; and 2.8 ± 0.9 μL/min at the 4th ventricle. Intracranial CSF volumes (and as percentage total brain volume) were 204 ± 97 μL (8.8 ± 4.3%) in the young and 275 ± 35 μL (10.8 ± 1.9%) in the aged animals (NS). We have demonstrated a contrast-enhanced CT technique for measuring and visualising CSF dynamics in vivo. These results indicate substantial drainage of CSF via spinal and olfactory routes, but there was little evidence of drainage via sagittal sinus arachnoid granulations in either young or aged animals. The data suggests that spinal and olfactory routes are the primary routes of CSF drainage and that sagittal sinus arachnoid granulations play a minor role, even in aged rats with higher ICP.


A telehealth behavioral coaching intervention for neurocognitive disorder family carers.
This study examined the differential impact of two telehealth programs for women caring for an older adult with a neurocognitive disorder. Outcomes examined were depressive symptoms, upset following disruptive behaviors, anxious and angry mood states, and caregiving self-efficacy. Women cohabitating with a family member diagnosed with a neurocognitive disorder were assigned via random allocation to either of the following: (1) a 14-week behavioral intervention using video instructional materials, workbook and telephone coaching in behavioral management, pleasant events scheduling, and relaxation or (2) a basic education guide and telephone support comparison condition. Telephone assessments were conducted by interviewers blind to treatment condition at pre-intervention, post-intervention, and 6 months following intervention. For those providing in-home care at post-treatment, depressive symptoms, upset following disruptive behaviors, and negative mood states were statistically lower in the behavioral coaching condition than in the basic education and support condition. Reliable change index analyses for Beck Depression Inventory II scores favored the behavioral coaching condition. Caregiving self-efficacy scores for obtaining respite and for managing patient behavioral disturbances were significantly higher in the coaching condition. Effect sizes were moderate but not maintained at the 6-month follow-up. This study provides some initial evidence for the efficacy of a telehealth behavioral coaching intervention compared with basic education and telephone support. Carers' abilities to maintain strategy use during progressive disorders such as Alzheimer's disease likely require longer intervention contact than provided in the current study. Dementia carers, including those living in rural areas, can benefit from accessible and empirically supported interventions that can be easily disseminated across distances at modest cost.